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1
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Ye S, Shi D, Li X, Yang Y, Pan X, Wang L, Wu H. Development and bioevaluation of 18F-labeled bivalent cyclic peptides for PET imaging of αvβ6 integrin overexpression. Bioorg Chem 2025; 159:108362. [PMID: 40096805 DOI: 10.1016/j.bioorg.2025.108362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 03/01/2025] [Accepted: 03/07/2025] [Indexed: 03/19/2025]
Abstract
Integrin αvβ6 has emerged as a critical target in cancer diagnostics and therapeutics. In this study, we developed two bivalent ligands, NOTA-(SDM17)2 and NOTA-(AvB6)2, for positron emission tomography (PET) imaging of αvβ6 integrins. Surface plasmon resonance (SPR) revealed affinities for NOTA-(SDM17)2 and NOTA-(AvB6)2 with KD values of 2.15 μM and 5.21 μM, respectively. Micro-PET imaging demonstrated significantly higher uptake of [18F]AlF-NOTA-(SDM17)2 and [18F]AlF-NOTA-(AvB6)2 in H2009 tumors (αvβ6-positive) compared to MDA-MB-231 tumors (αvβ6-negative) ([18F]AlF-NOTA-(SDM17)2: 3.2 ± 0.3 vs. 0.3 ± 0.07 %ID/g; [18F]AlF-NOTA-(AvB6)2: 6.4 ± 0.5 vs. 1.0 ± 0.2 %ID/g at 60 min p.i., P < 0.05). Both bivalent tracers exhibited enhanced tumor uptake and retention relative to their monovalent counterparts ([18F]AlF-NOTA-SDM17 and [18F]AlF-NOTA-AvB6) at 60 min p.i., (P < 0.05). Notably, [18F]AlF-NOTA-(SDM17)2 demonstrated a superior tumor-to-liver ratio (13.24 vs. 5.93, P = 0.029) and longer retention, as confirmed by in vivo biodistribution studies. These findings highlight the potential of [18F]AlF-NOTA-(SDM17)2 and [18F]AlF-NOTA-(AvB6)2 as bivalent PET tracers to enhance tumor uptake and prolong retention. Among them, [18F]AlF-NOTA-(SDM17)2 shows particular promise for clinical translation due to its higher tumor-to-non-tumor ratio and prolonged retention.
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Affiliation(s)
- Shimin Ye
- GDMPA Key Laboratory for Quality Control and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, Guangdong Province 510515, China
| | - Dazhi Shi
- GDMPA Key Laboratory for Quality Control and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, Guangdong Province 510515, China
| | - Xuefei Li
- Central Research Institute, United Imaging Healthcare, 2258 Chengbei Road, Shanghai 201807, China
| | - Yali Yang
- GDMPA Key Laboratory for Quality Control and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, Guangdong Province 510515, China
| | - Xingzhu Pan
- GDMPA Key Laboratory for Quality Control and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, Guangdong Province 510515, China
| | - Lijuan Wang
- GDMPA Key Laboratory for Quality Control and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, Guangdong Province 510515, China.
| | - Hubing Wu
- GDMPA Key Laboratory for Quality Control and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, Guangdong Province 510515, China.
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Zhao Z, Li Q, Qu C, Jiang Z, Jia G, Lan G, Luan Y. A collagenase nanogel backpack improves CAR-T cell therapy outcomes in pancreatic cancer. NATURE NANOTECHNOLOGY 2025:10.1038/s41565-025-01924-1. [PMID: 40389641 DOI: 10.1038/s41565-025-01924-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 03/31/2025] [Indexed: 05/21/2025]
Abstract
Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of haematological malignancies. Challenges in overcoming physical barriers however greatly limit CAR-T cell efficacy in solid tumours. Here we show that an approach based on collagenase nanogel generally improves the outcome of T cell-based therapies, and specifically of CAR-T cell therapy. The nanogels are created by cross-linking collagenase and subsequently modifying them with a CXCR4 antagonist peptide. These nanogels can bind CAR-T cells via receptor-ligand interaction, resulting in cellular backpack delivery systems. The nanogel backpacks modulate tumoural infiltration and localization of CAR-T cells by surmounting physical barriers and disrupting chemokine-mediated CAR-T cell imprisonment, thereby addressing their navigation deficiency within solid tumours. Our approach offers a promising strategy for pancreatic cancer therapy and holds potential for advancing CAR-T cell therapy towards clinical applications.
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Affiliation(s)
- Zhipeng Zhao
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qian Li
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chenghao Qu
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Thoracic Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Zeyu Jiang
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Guoqing Jia
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Gongde Lan
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yuxia Luan
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
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3
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Liu H, Chen M, Hong B, Xiao Y, Chen Q, Qian Y. Single-nucleus RNA sequencing and spatial transcriptomics reveal an immunosuppressive tumor microenvironment related to metastatic dissemination during pancreatic cancer liver metastasis. Theranostics 2025; 15:5337-5357. [PMID: 40303346 PMCID: PMC12036881 DOI: 10.7150/thno.108925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 04/02/2025] [Indexed: 05/02/2025] Open
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by early liver metastasis and high mortality. The tumor microenvironment plays a pivotal role in tumor progression; however, the immune microenvironment's involvement in PDAC liver metastasis remains poorly understood. Methods: This study investigates cellular heterogeneity in primary tumor (PT) and liver metastasis (LM) tissues of PDAC using single-nucleus RNA sequencing and spatial transcriptomics. Intra-tumor heterogeneity and cell interactions were elucidated through deconvolution, intercellular signalling, pseudotime analysis, and immune infiltration profiling. The spatial distribution of immune cells was assessed by multiplexed immunofluorescence staining, and prognostic models were developed and validated through immunohistochemistry (IHC). Analyzing the regulatory role of CITED4 in the invasion and metastasis of pancreatic cancer cells through transwell assay and scratch wound healing assay. Results: A total of 62,326 cells were sequenced, with metastatic dissemination cells showing significant upregulation of epithelial-mesenchymal transition (EMT)-related genes during liver metastasis. Spatial transcriptomics revealed the enrichment of metastatic dissemination cells and FOXP3-related Treg cells at the tumor front in PT tissues. In comparison to LM tissues, the tumor front in PT tissues fosters an immunosuppressive microenvironment through the accumulation of Treg cells. Interaction analysis identified the SPP1 pathway as a key promoter of this immunosuppressive environment. Furthermore, prognostic models highlighted CITED4 as critical biomarkers in PDAC. Elevated CITED4 expression is correlated with liver metastasis and poor prognosis in patients with PDAC. siRNA-mediated knockdown of CITED4 suppresses the invasion and metastasis of pancreatic cancer cells. Conclusions: In summary, this study revealed that Treg cell alterations, mediated by metastatic dissemination cells within the immune microenvironment, significantly contribute to PDAC liver metastasis, and that CITED4 enhances the metastatic potential of metastatic dissemination cells.
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Affiliation(s)
- Hongsen Liu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, China
| | - Mengting Chen
- Department of Clinical Laboratory, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Bo Hong
- Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Yufei Xiao
- Department of Clinical Laboratory, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Qianming Chen
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, China
| | - Yun Qian
- Department of Clinical Laboratory, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
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Sun M, Angelillo J, Hugues S. Lymphatic transport in anti-tumor immunity and metastasis. J Exp Med 2025; 222:e20231954. [PMID: 39969537 PMCID: PMC11837853 DOI: 10.1084/jem.20231954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 10/18/2024] [Accepted: 02/06/2025] [Indexed: 02/20/2025] Open
Abstract
Although lymphatic vessels (LVs) are present in many tumors, their importance in cancer has long been underestimated. In contrast to the well-studied tumor-associated blood vessels, LVs were previously considered to function as passive conduits for tumor metastasis. However, emerging evidence over the last two decades has shed light on their critical role in locally shaping the tumor microenvironment (TME). Here we review the involvement of LVs in tumor progression, metastasis, and modulation of anti-tumor immune response.
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Affiliation(s)
- Mengzhu Sun
- Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland
| | - Julien Angelillo
- Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland
| | - Stéphanie Hugues
- Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland
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Gu Y, Mi Y, Cao Y, Yu K, Zhang Z, Lian P, Li D, Qin J, Zhao S. The lncRNA MIR181A1HG in extracellular vesicles derived from highly metastatic colorectal cancer cells promotes liver metastasis by remodeling the extracellular matrix and recruiting myeloid-derived suppressor cells. Cell Biosci 2025; 15:23. [PMID: 39972363 PMCID: PMC11841002 DOI: 10.1186/s13578-025-01365-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 02/10/2025] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND Colorectal liver metastasis (CRLM) is the main cause of death in colorectal cancer (CRC) patients worldwide. In the initial stage of metastasis, primary tumors provide the necessary conditions for metastasis by shaping the local microenvironment of the target organ, forming "premetastatic niches" (PMNs), and extracellular vesicles (EVs) play important roles in shaping PMNs. Therefore, investigating the EVs involved in the regulation of PMNs and their mechanism is highly valuable for the further understanding of CRLM. METHODS Transmission electron microscopy and differential ultracentrifugation were used to verify the existence of exosomes. In vivo and in vitro assays were used to identify the roles of MIR181A1HG in EVs in CRLM. RNA pull-down and dual-luciferase reporter assays were used to clarify the mechanism by which MIR181A1HG in EVs regulated the crosstalk between CRC cells and hepatic stellate cells (HSCs). RESULTS We demonstrated that the lncRNA MIR181A1HG was progressively upregulated in tissues, serum EVs from healthy normal controls to CRC and paired liver metastatic groups. Additionally, we verified that HNRNPA2B1 mediated the packaging of MIR181A1HG into CRC cell-derived EVs, which in turn functioned as a ceRNA by sponging miR373-3p to activate HSCs via the TGFβRII/Smad2/3 signaling pathway. Furthermore, activated HSCs could secrete the chemokine CXCL12 to promote CRLM by remodeling the extracellular matrix and recruiting myeloid-derived suppressor cells in the liver, which resulted in liver metastasis. CONCLUSIONS MIR181A1HG in EVs from highly metastatic CRC cells promoted CRLM by activating HSCs to form PMNs in the liver, which contributes to the further understanding of the mechanism of CRLM and provides potential predictive markers for CRLM.
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Affiliation(s)
- Yichao Gu
- Department of General Surgery, Zhongshan Hospital, 180 Fenglin Road, Shanghai, 200032, China
| | - Yushuai Mi
- Department of Gastrointestinal Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, No. 247 Beiyuan Street, Jinan, Shandong, 250033, China
| | - Yifan Cao
- Department of General Surgery, Zhongshan Hospital, 180 Fenglin Road, Shanghai, 200032, China
| | - Kuan Yu
- Department of General Surgery, Zhongshan Hospital, 180 Fenglin Road, Shanghai, 200032, China
| | - Zihao Zhang
- Department of General Surgery, Zhongshan Hospital, 180 Fenglin Road, Shanghai, 200032, China
| | - Peng Lian
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032, China
| | - Dawei Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032, China.
| | - Jing Qin
- Department of General Surgery, Zhongshan Hospital, 180 Fenglin Road, Shanghai, 200032, China.
| | - Senlin Zhao
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032, China.
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6
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Aksoy SA, Earl J, Grahovac J, Karakas D, Lencioni G, Sığırlı S, Bijlsma MF. Organoids, tissue slices and organotypic cultures: Advancing our understanding of pancreatic ductal adenocarcinoma through in vitro and ex vivo models. Semin Cancer Biol 2025; 109:10-24. [PMID: 39730107 DOI: 10.1016/j.semcancer.2024.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 12/14/2024] [Accepted: 12/19/2024] [Indexed: 12/29/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses of all common solid cancers. For the large majority of PDAC patients, only systemic therapies with very limited efficacy are indicated. In addition, immunotherapies have not brought the advances seen in other cancer types. Several key characteristics of PDAC contribute to poor treatment outcomes, and in this review, we will discuss how these characteristics are best captured in currently available ex vivo or in vitro model systems. For instance, PDAC is hallmarked by a highly desmoplastic and immune-suppressed tumor microenvironment that impacts disease progression and therapy resistance. Also, large differences in tumor biology exist between and within tumors, complicating treatment decisions. Furthermore, PDAC has a very high propensity for locally invasive and metastatic growth. The use of animal models is often not desirable or feasible and several in vitro and ex vivo model systems have been developed, such as organotypic cocultures and tissue slices, among others. However, the absence of a full host organism impacts the ability of these models to accurately capture the characteristics that contribute to poor outcomes in PDAC. We will discuss the caveats and advantages of these model systems in the context of PDAC's key characteristics and provide recommendations on model choice and the possibilities for optimization. These considerations should be of use to researchers aiming to study PDAC in the in vitro setting.
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Affiliation(s)
- Secil Ak Aksoy
- Bursa Uludag University, Faculty of Medicine, Department of Medical Microbiology, Bursa, Turkey
| | - Julie Earl
- Ramón y Cajal Health Research Institute (IRYCIS), Biomodels and Biomodels Platform Hospital Ramón y Cajal-IRYCIS, Carretera Colmenar Km 9,100, Madrid 28034, Spain; The Biomedical Research Network in Cancer (CIBERONC), Av. Monforte de Lemos, 3-5. Pabellón 11. Planta 0, Madrid 28029, Spain
| | - Jelena Grahovac
- Experimental Oncology Department, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia
| | - Didem Karakas
- Acibadem Mehmet Ali Aydinlar University, Department of Medical Biotechnology, Graduate School of Health Sciences, Istanbul, Turkey
| | - Giulia Lencioni
- Department of Biology, University of Pisa, Pisa, Italy; Fondazione Pisana per la Scienza, San Giuliano Terme, Pisa, Italy
| | - Sıla Sığırlı
- Acibadem Mehmet Ali Aydinlar University, Department of Medical Biotechnology, Graduate School of Health Sciences, Istanbul, Turkey
| | - Maarten F Bijlsma
- Amsterdam UMC Location University of Amsterdam, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands.
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7
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Link JM, Eng JR, Pelz C, MacPherson-Hawthorne K, Worth PJ, Sivagnanam S, Keith DJ, Owen S, Langer EM, Grossblatt-Wait A, Salgado-Garza G, Creason AL, Protzek S, Egger J, Holly H, Heskett MB, Chin K, Kirchberger N, Betre K, Bucher E, Kilburn D, Hu Z, Munks MW, English IA, Tsuda M, Goecks J, Demir E, Adey AC, Kardosh A, Lopez CD, Sheppard BC, Guimaraes A, Brinkerhoff B, Morgan TK, Mills GB, Coussens LM, Brody JR, Sears RC. Ongoing replication stress tolerance and clonal T cell responses distinguish liver and lung recurrence and outcomes in pancreatic cancer. NATURE CANCER 2025; 6:123-144. [PMID: 39789181 PMCID: PMC11779630 DOI: 10.1038/s43018-024-00881-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 11/15/2024] [Indexed: 01/12/2025]
Abstract
Patients with metastatic pancreatic ductal adenocarcinoma survive longer if disease spreads to the lung but not the liver. Here we generated overlapping, multi-omic datasets to identify molecular and cellular features that distinguish patients whose disease develops liver metastasis (liver cohort) from those whose disease develops lung metastasis without liver metastases (lung cohort). Lung cohort patients survived longer than liver cohort patients, despite sharing the same tumor subtype. We developed a primary organotropism (pORG) gene set enriched in liver cohort versus lung cohort primary tumors. We identified ongoing replication stress response pathways in high pORG/liver cohort tumors, whereas low pORG/lung cohort tumors had greater densities of lymphocytes and shared T cell clonal responses. Our study demonstrates that liver-avid pancreatic ductal adenocarcinoma is associated with tolerance to ongoing replication stress, limited tumor immunity and less-favorable outcomes, whereas low replication stress, lung-avid/liver-averse tumors are associated with active tumor immunity that may account for favorable outcomes.
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Affiliation(s)
- Jason M Link
- Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA.
| | - Jennifer R Eng
- Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
| | - Carl Pelz
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA
| | | | - Patrick J Worth
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA
- Knight Cancer Institute, Portland, OR, USA
- Department of Surgery, Oregon Health and Science University, Portland, OR, USA
| | - Shamaline Sivagnanam
- Department of Cell, Development and Cancer Biology, Oregon Health and Science University, Portland, OR, USA
| | - Dove J Keith
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA
| | - Sydney Owen
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA
| | - Ellen M Langer
- Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA
- Knight Cancer Institute, Portland, OR, USA
- Center for Early Detection Advanced Research, Oregon Health and Science University, Portland, OR, USA
| | - Alison Grossblatt-Wait
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA
- Center for Early Detection Advanced Research, Oregon Health and Science University, Portland, OR, USA
| | | | - Allison L Creason
- Knight Cancer Institute, Portland, OR, USA
- Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA
| | - Sara Protzek
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA
| | - Julian Egger
- Knight Cancer Institute, Portland, OR, USA
- Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA
| | - Hannah Holly
- Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
| | | | - Koei Chin
- Knight Cancer Institute, Portland, OR, USA
- Center for Early Detection Advanced Research, Oregon Health and Science University, Portland, OR, USA
- Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA
| | - Nell Kirchberger
- Department of Cell, Development and Cancer Biology, Oregon Health and Science University, Portland, OR, USA
| | - Konjit Betre
- Department of Cell, Development and Cancer Biology, Oregon Health and Science University, Portland, OR, USA
| | - Elmar Bucher
- Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA
| | - David Kilburn
- Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA
| | - Zhi Hu
- Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA
| | - Michael W Munks
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA
| | - Isabel A English
- Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
| | - Motoyuki Tsuda
- Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
| | - Jeremy Goecks
- Knight Cancer Institute, Portland, OR, USA
- Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA
| | - Emek Demir
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA
- Knight Cancer Institute, Portland, OR, USA
- Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA
| | - Andrew C Adey
- Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
- Knight Cancer Institute, Portland, OR, USA
| | - Adel Kardosh
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA
- Knight Cancer Institute, Portland, OR, USA
- Department of Hematology and Oncology, Oregon Health and Science University, Portland, OR, USA
| | - Charles D Lopez
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA
- Knight Cancer Institute, Portland, OR, USA
- Department of Hematology and Oncology, Oregon Health and Science University, Portland, OR, USA
| | - Brett C Sheppard
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA
- Knight Cancer Institute, Portland, OR, USA
- Department of Surgery, Oregon Health and Science University, Portland, OR, USA
| | - Alex Guimaraes
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA
- Knight Cancer Institute, Portland, OR, USA
- Department of Radiology, Oregon Health and Science University, Portland, OR, USA
| | - Brian Brinkerhoff
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA
- Department of Pathology and Laboratory Medicine, Oregon Health and Science University, Portland, OR, USA
| | - Terry K Morgan
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA
- Knight Cancer Institute, Portland, OR, USA
- Center for Early Detection Advanced Research, Oregon Health and Science University, Portland, OR, USA
- Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA
- Department of Pathology and Laboratory Medicine, Oregon Health and Science University, Portland, OR, USA
| | - Gordon B Mills
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA
- Knight Cancer Institute, Portland, OR, USA
- Department of Oncological Sciences, Oregon Health and Science University, Portland, OR, USA
| | - Lisa M Coussens
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA
- Knight Cancer Institute, Portland, OR, USA
- Department of Cell, Development and Cancer Biology, Oregon Health and Science University, Portland, OR, USA
| | - Jonathan R Brody
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA
- Knight Cancer Institute, Portland, OR, USA
- Department of Surgery, Oregon Health and Science University, Portland, OR, USA
- Department of Cell, Development and Cancer Biology, Oregon Health and Science University, Portland, OR, USA
| | - Rosalie C Sears
- Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA.
- Knight Cancer Institute, Portland, OR, USA.
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8
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Li D, Chu X, Ma Y, Zhang F, Tian X, Yang Y, Yang Y. Tumor-derived exosomes: Unravelling the pathogenesis of pancreatic cancer with liver metastases and exploring the potential for clinical translation. Cancer Lett 2024; 611:217403. [PMID: 39709178 DOI: 10.1016/j.canlet.2024.217403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 12/23/2024]
Abstract
Pancreatic cancer (PC) is one of the most malignant solid cancers, and PC metastasis, particularly liver metastasis, is a major cause of cancer mortality. A key event in tumor metastasis is the formation of pre-metastatic niche (PMN), which provides a microenvironment conducive to tumor cells colonization and progression. Various molecules loaded in tumor-derived exosomes (TDEs) contribute to PMN formation and distant tumor metastasis, by regulating immune and stromal cell function, inducing angiogenesis, and promoting metabolic reprogramming. Therefore, therapies targeting PMN may offer novel advantages to prevent tumor metastasis at an earlier stage. In this review, we summarize multifaceted mechanisms underlying hepatic PMN formation, with a focus on how PC TDEs participate in angiogenesis and vascular permeability, create immune suppressive microenvironment, remodel the extracellular matrix, and regulate metabolic reprogramming. In addition, we highlight the promise of TDEs for early diagnosis and effective therapy of PC liver metastases.
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Affiliation(s)
- Dongqi Li
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, 100034, China
| | - Xiangyu Chu
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, State Key Lab of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Yongsu Ma
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, 100034, China
| | - Fusheng Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, 100034, China
| | - Xiaodong Tian
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, 100034, China.
| | - Yanlian Yang
- CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China.
| | - Yinmo Yang
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, 100034, China.
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9
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Nair ST, Abhi C, Kamalasanan K, Pavithran K, Unni AR, Sithara MS, Sarma M, Mangalanandan TS. Pathophysiology-Driven Approaches for Overcoming Nanomedicine Resistance in Pancreatic Cancer. Mol Pharm 2024; 21:5960-5988. [PMID: 39561094 DOI: 10.1021/acs.molpharmaceut.4c00801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2024]
Abstract
Tumor heterogeneity poses a significant challenge in cancer therapy. To address this, we analyze pharmacotherapeutic challenges by categorizing them into static and dynamic barriers, reframing these challenges to improve drug delivery, efficacy, and the development of controlled-release nanomedicines (CRNMs). This pathophysiology-driven approach facilitates the design of novel therapeutics tailored to overcome obstacles in pancreatic ductal adenocarcinoma (PDAC) using nanotechnology. Advanced biomaterials in nanodrug delivery systems offer innovative solutions by combining controlled release, stimuli sensitivity, and smart design strategies. CRNMs are engineered to modulate spatiotemporal signaling and control drug release in PDAC, where resistance to conventional therapies is particularly high. This review explores pharmacokinetic considerations for nanomedicine design, RNA interference (RNAi) for stromal modulation, and the development of targeted nanomedicine strategies. Additionally, we highlight the limitations of current animal models in capturing the complexities of PDAC and discuss notable clinical failures, such as PEGylated hyaluronidase (Phase III HALO 109-301 trial) and evofosfamide (TH-302) with gemcitabine (MAESTRO trial), underscoring the need for improved models and treatment strategies. By targeting pathways like Notch and Hedgehog and incorporating stimuli-sensitive and pathway-modulating agents, CRNMs offer a promising avenue to enhance drug penetration and efficacy, reshaping the paradigm of pancreatic cancer treatment.
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Affiliation(s)
- Sreejith Thrivikraman Nair
- Department of Pharmaceutics, Amrita School of Pharmacy, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - C Abhi
- Department of Pharmaceutics, Amrita School of Pharmacy, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - Kaladhar Kamalasanan
- Department of Pharmaceutics, Amrita School of Pharmacy, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - K Pavithran
- Department of Medical Oncology and Hematology, School of Medicine, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - Ashok R Unni
- Department of Veterinary Medicine, Central Animal Facility, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - M S Sithara
- Department of Veterinary Medicine, Central Animal Facility, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - Manjit Sarma
- Department of Nuclear Medicine, Amrita School of Medicine, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - T S Mangalanandan
- Department of Endocrinology, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
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10
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Hirway SU, Nairon KG, Skardal A, Weinberg SH. A Multicellular Mechanochemical Model to Investigate Tumor Microenvironment Remodeling and Pre-Metastatic Niche Formation. Cell Mol Bioeng 2024; 17:573-596. [PMID: 39926379 PMCID: PMC11799507 DOI: 10.1007/s12195-024-00831-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 10/27/2024] [Indexed: 02/11/2025] Open
Abstract
Introduction Colorectal cancer (CRC) is a major cause of cancer related deaths in the United States, with CRC metastasis to the liver being a common occurrence. The development of an optimal metastatic environment is essential process prior to tumor metastasis. This process, called pre-metastatic niche (PMN) formation, involves activation of key resident liver cells, including fibroblast-like stellate cells and macrophages such as Kupffer cells. Tumor-mediated factors introduced to this environment transform resident cells that secrete additional growth factors and remodel the extracellular matrix (ECM), which is thought to promote tumor colonization and metastasis in the secondary environment. Methods To investigate the underlying mechanisms of these dynamics, we developed a multicellular computational model to characterize the spatiotemporal dynamics of the PMN formation in tissue. This modeling framework integrates intracellular and extracellular signaling, and traction and junctional forces into a Cellular Potts model, and represents multiple cell types with varying levels of cellular activation. We perform numerical experiments to investigate the role of key factors in PMN formation and tumor invasiveness, including growth factor concentration, timing of tumor arrival, relative composition of resident cells, and the size of invading tumor cluster. Results These parameter studies identified growth factor availability and ECM concentration in the environment as two of the key determinants of tumor invasiveness. We further predict that both the ECM concentration potential and growth factor sensitivity of the stellate cells are key drivers of the PMN formation and associated ECM concentration. Conclusions Overall, this modeling framework represents a significant step towards simulating cancer metastasis and investigating the role of key factors on PMN formation. Supplementary Information The online version contains supplementary material available at 10.1007/s12195-024-00831-0.
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Affiliation(s)
- Shreyas U. Hirway
- Department of Biomedical Engineering, The Ohio State University, Columbus, OH USA
| | - Kylie G. Nairon
- Department of Biomedical Engineering, The Ohio State University, Columbus, OH USA
| | - Aleksander Skardal
- Department of Biomedical Engineering, The Ohio State University, Columbus, OH USA
| | - Seth H. Weinberg
- Department of Biomedical Engineering, The Ohio State University, Columbus, OH USA
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11
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Khaliq AM, Rajamohan M, Saeed O, Mansouri K, Adil A, Zhang C, Turk A, Carstens JL, House M, Hayat S, Nagaraju GP, Pappas SG, Wang YA, Zyromski NJ, Opyrchal M, Lee KP, O'Hagan H, El Rayes B, Masood A. Spatial transcriptomic analysis of primary and metastatic pancreatic cancers highlights tumor microenvironmental heterogeneity. Nat Genet 2024; 56:2455-2465. [PMID: 39294496 DOI: 10.1038/s41588-024-01914-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 08/19/2024] [Indexed: 09/20/2024]
Abstract
Although the spatial, cellular and molecular landscapes of resected pancreatic ductal adenocarcinoma (PDAC) are well documented, the characteristics of its metastatic ecology remain elusive. By applying spatially resolved transcriptomics to matched primary and metastatic PDAC samples, we discovered a conserved continuum of fibrotic, metabolic and immunosuppressive spatial ecotypes across anatomical regions. We observed spatial tumor microenvironment heterogeneity spanning beyond that previously appreciated in PDAC. Through comparative analysis, we show that the spatial ecotypes exhibit distinct enrichment between primary and metastatic sites, implying adaptability to the local environment for survival and progression. The invasive border ecotype exhibits both pro-tumorigenic and anti-tumorigenic cell-type enrichment, suggesting a potential immunotherapy target. The ecotype heterogeneity across patients emphasizes the need to map individual patient landscapes to develop personalized treatment strategies. Collectively, our findings provide critical insights into metastatic PDAC biology and serve as a valuable resource for future therapeutic exploration and molecular investigations.
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Affiliation(s)
- Ateeq M Khaliq
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Meenakshi Rajamohan
- Luddy School of Informatics, Computing, and Engineering, Indiana University, Indianapolis, IN, USA
| | - Omer Saeed
- Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kimia Mansouri
- Luddy School of Informatics, Computing, and Engineering, Indiana University, Indianapolis, IN, USA
| | - Asif Adil
- Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Chi Zhang
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Anita Turk
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Julienne L Carstens
- Division of Hematology and Oncology, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Michael House
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
| | | | - Ganji P Nagaraju
- Division of Hematology and Oncology, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Sam G Pappas
- Division of Surgical Oncology, Rush University Medical Center, Chicago, IL, USA
| | - Y Alan Wang
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Nicholas J Zyromski
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Mateusz Opyrchal
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kelvin P Lee
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Heather O'Hagan
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Bassel El Rayes
- Division of Hematology and Oncology, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Ashiq Masood
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
- Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, USA.
- Luddy School of Informatics, Computing, and Engineering, Indiana University, Indianapolis, IN, USA.
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12
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Wang Y, Jia J, Wang F, Fang Y, Yang Y, Zhou Q, Yuan W, Gu X, Hu J, Yang S. Pre-metastatic niche: formation, characteristics and therapeutic implication. Signal Transduct Target Ther 2024; 9:236. [PMID: 39317708 PMCID: PMC11422510 DOI: 10.1038/s41392-024-01937-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 06/29/2024] [Accepted: 07/23/2024] [Indexed: 09/26/2024] Open
Abstract
Distant metastasis is a primary cause of mortality and contributes to poor surgical outcomes in cancer patients. Before the development of organ-specific metastasis, the formation of a pre-metastatic niche is pivotal in promoting the spread of cancer cells. This review delves into the intricate landscape of the pre-metastatic niche, focusing on the roles of tumor-derived secreted factors, extracellular vesicles, and circulating tumor cells in shaping the metastatic niche. The discussion encompasses cellular elements such as macrophages, neutrophils, bone marrow-derived suppressive cells, and T/B cells, in addition to molecular factors like secreted substances from tumors and extracellular vesicles, within the framework of pre-metastatic niche formation. Insights into the temporal mechanisms of pre-metastatic niche formation such as epithelial-mesenchymal transition, immunosuppression, extracellular matrix remodeling, metabolic reprogramming, vascular permeability and angiogenesis are provided. Furthermore, the landscape of pre-metastatic niche in different metastatic organs like lymph nodes, lungs, liver, brain, and bones is elucidated. Therapeutic approaches targeting the cellular and molecular components of pre-metastatic niche, as well as interventions targeting signaling pathways such as the TGF-β, VEGF, and MET pathways, are highlighted. This review aims to enhance our understanding of pre-metastatic niche dynamics and provide insights for developing effective therapeutic strategies to combat tumor metastasis.
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Affiliation(s)
- Yuhang Wang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China
| | - Jiachi Jia
- College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Fuqi Wang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China
| | - Yingshuai Fang
- College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Yabing Yang
- College of Medicine, Zhengzhou University, Zhengzhou, 450001, China
| | - Quanbo Zhou
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China
| | - Weitang Yuan
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China
| | - Xiaoming Gu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China.
| | - Junhong Hu
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China.
| | - Shuaixi Yang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou, 450000, China.
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13
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Andryszkiewicz W, Misiąg P, Karwowska A, Resler Z, Wojno A, Kulbacka J, Szewczyk A, Rembiałkowska N. Cancer Metastases to the Liver: Mechanisms of Tumor Cell Colonization. Pharmaceuticals (Basel) 2024; 17:1251. [PMID: 39338413 PMCID: PMC11434846 DOI: 10.3390/ph17091251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 09/18/2024] [Accepted: 09/19/2024] [Indexed: 09/30/2024] Open
Abstract
The liver is one of the most common sites for metastasis, which involves the spread from primary tumors to surrounding organs and tissues in the human body. There are a few steps in cancer expansion: invasion, inflammatory processes allowing the hepatic niche to be created, adhesions to ECM, neovascularization, and secretion of enzymes. The spread of tumor cells depends on the microenvironment created by the contribution of many biomolecules, including proteolytic enzymes, cytokines, growth factors, and cell adhesion molecules that enable tumor cells to interact with the microenvironment. Moreover, the microenvironment plays a significant role in tumor growth and expansion. The secreted enzymes help cancer cells facilitate newly formed hepatic niches and promote migration and invasion. Our study discusses pharmacological methods used to prevent liver metastasis by targeting the tumor microenvironment and cancer cell colonization in the liver. We examine randomized studies focusing on median survival duration and median overall survival in patients administered placebo compared with those treated with bevacizumab, ramucirumab, regorafenib, and ziv-aflibercept in addition to current chemotherapy. We also include research on mice and their responses to these medications, which may suppress metastasis progression. Finally, we discuss the significance of non-pharmacological methods, including surgical procedures, radiotherapy, cryotherapy, radiofrequency ablation (RFA), and transarterial embolization (TAE). In conclusion, the given methods can successfully prevent metastases to the liver and prolong the median survival duration and median overall survival in patients suffering from cancer.
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Affiliation(s)
- Wiktoria Andryszkiewicz
- The Students' Research Group, No. 148., Faculty of Medicine, Wroclaw Medical University, Pasteura 1, 50-367 Wroclaw, Poland
| | - Piotr Misiąg
- The Students' Research Group, No. 148., Faculty of Medicine, Wroclaw Medical University, Pasteura 1, 50-367 Wroclaw, Poland
| | - Anna Karwowska
- The Students' Research Group, No. 148., Faculty of Medicine, Wroclaw Medical University, Pasteura 1, 50-367 Wroclaw, Poland
| | - Zofia Resler
- The Students' Research Group, No. 148., Faculty of Medicine, Wroclaw Medical University, Pasteura 1, 50-367 Wroclaw, Poland
| | - Aleksandra Wojno
- The Students' Research Group, No. 148., Faculty of Medicine, Wroclaw Medical University, Pasteura 1, 50-367 Wroclaw, Poland
| | - Julita Kulbacka
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Anna Szewczyk
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Nina Rembiałkowska
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
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14
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Habib JR, Javed AA, Wolfgang CL. The Significance of Circulating Tumor Cells in Pancreatic Cancer. Adv Surg 2024; 58:135-142. [PMID: 39089773 DOI: 10.1016/j.yasu.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/04/2024]
Abstract
The notion that technically resectable pancreatic ductal adenocarcinoma presents as localized disease is now known to be inaccurate. Evidence supports that most patients have subclinical systemic dissemination at the time of diagnosis. It is now widely accepted that both a local and systemic component of disease coexist, each requiring treatment of improved survival and potential cure. The advent of multiagent chemotherapy regimens has resulted in a modest improvement in survival. Consequently, this article will emphasize the expanding potential and significance of circulating tumor cells in the prognostication and management of patients with pancreatic cancer.
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Affiliation(s)
- Joseph R Habib
- Department of Surgery, New York University Langone Health, 550 First Avenue, New York, NY 10016, USA
| | - Ammar A Javed
- Department of Surgery, New York University Langone Health, 550 First Avenue, New York, NY 10016, USA
| | - Christopher L Wolfgang
- Department of Surgery, New York University Langone Health, 550 First Avenue, New York, NY 10016, USA.
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15
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Qin C, Li T, Lin C, Zhao B, Li Z, Zhao Y, Wang W. The systematic role of pancreatic cancer exosomes: distant communication, liquid biopsy and future therapy. Cancer Cell Int 2024; 24:264. [PMID: 39054529 PMCID: PMC11271018 DOI: 10.1186/s12935-024-03456-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 07/18/2024] [Indexed: 07/27/2024] Open
Abstract
Pancreatic cancer remains one of the most lethal diseases worldwide. Cancer-derived exosomes, benefiting from the protective role of the lipid membrane, exhibit remarkable stability in the circulatory system. These exosomes, released by tumor microenvironment, contain various biomolecules such as proteins, RNAs, and lipids that plays a pivotal role in mediating distant communication between the local pancreatic tumor and other organs or tissues. They facilitate the transfer of oncogenic factors to distant sites, contributing to the compromised body immune system, distant metastasis, diabetes, cachexia, and promoting a microenvironment conducive to tumor growth and metastasis in pancreatic cancer patients. Beyond their intrinsic roles, circulating exosomes in peripheral blood can be detected to facilitate accurate liquid biopsy. This approach offers a novel and promising method for the diagnosis and management of pancreatic cancer. Consequently, circulating exosomes are not only crucial mediators of systemic cell-cell communication during pancreatic cancer progression but also hold great potential as precise tools for pancreatic cancer management and treatment. Exosome-based liquid biopsy and therapy represent promising advancements in the diagnosis and treatment of pancreatic cancer. Exosomes can serve as drug delivery vehicles, enhancing the targeting and efficacy of anticancer treatments, modulating the immune system, and facilitating gene editing to suppress tumor growth. Ongoing research focuses on biomarker identification, drug delivery systems, and clinical trials to validate the safety and efficacy of exosome-based therapies, offering new possibilities for early diagnosis and precision treatment in pancreatic cancer. Leveraging the therapeutic potential of exosomes, including their ability to deliver targeted drugs and modulate immune responses, opens new avenues for innovative treatment strategies.
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Affiliation(s)
- Cheng Qin
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tianyu Li
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chen Lin
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bangbo Zhao
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zeru Li
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yutong Zhao
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Weibin Wang
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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16
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Zhu YH, Jia QY, Yao HF, Duan ZH, Ma XSY, Zheng JH, Yin YF, Liu W, Zhang JF, Hua R, Ma D, Sun YW, Yang JY, Liu DJ, Huo YM. The lncRNA LINC01605 promotes the progression of pancreatic ductal adenocarcinoma by activating the mTOR signaling pathway. Cancer Cell Int 2024; 24:262. [PMID: 39048994 PMCID: PMC11271012 DOI: 10.1186/s12935-024-03440-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 07/08/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND This study investigated the molecular mechanism of long intergenic non-protein coding RNA 1605 (LINC01605) in the process of tumor growth and liver metastasis of pancreatic ductal adenocarcinoma (PDAC). METHODS LINC01605 was filtered out with specificity through TCGA datasets (related to DFS) and our RNA-sequencing data of PDAC tissue samples from Renji Hospital. The expression level and clinical relevance of LINC01605 were then verified in clinical cohorts and samples by immunohistochemical staining assay and survival analysis. Loss- and gain-of-function experiments were performed to estimate the regulatory effects of LINC01605 in vitro. RNA-seq of LINC01605-knockdown PDAC cells and subsequent inhibitor-based cellular function, western blotting, immunofluorescence and rescue experiments were conducted to explore the mechanisms by which LINC01605 regulates the behaviors of PDAC tumor cells. Subcutaneous xenograft models and intrasplenic liver metastasis models were employed to study its role in PDAC tumor growth and liver metastasis in vivo. RESULTS LINC01605 expression is upregulated in both PDAC primary tumor and liver metastasis tissues and correlates with poor clinical prognosis. Loss and gain of function experiments in cells demonstrated that LINC01605 promotes the proliferation and migration of PDAC cells in vitro. In subsequent verification experiments, we found that LINC01605 contributes to PDAC progression through cholesterol metabolism regulation in a LIN28B-interacting manner by activating the mTOR signaling pathway. Furthermore, the animal models showed that LINC01605 facilitates the proliferation and metastatic invasion of PDAC cells in vivo. CONCLUSIONS Our results indicate that the upregulated lncRNA LINC01605 promotes PDAC tumor cell proliferation and migration by regulating cholesterol metabolism via activation of the mTOR signaling pathway in a LIN28B-interacting manner. These findings provide new insight into the role of LINC01605 in PDAC tumor growth and liver metastasis as well as its value for clinical approaches as a metabolic therapeutic target in PDAC.
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Affiliation(s)
- Yu-Heng Zhu
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Qin-Yuan Jia
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Hong-Fei Yao
- Department of Hepato-Biliary-Pancreatic Surgery, General Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, China
| | - Zong-Hao Duan
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Xue-Shi-Yu Ma
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Jia-Hao Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yi-Fan Yin
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Wei Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Jun-Feng Zhang
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Rong Hua
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Ding Ma
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Yong-Wei Sun
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
| | - Jian-Yu Yang
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
| | - De-Jun Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
| | - Yan-Miao Huo
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
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17
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Zheng B, Ding G, Lu G, Li L. Development and external validation of a prognostic nomogram to predict survival in patients aged ≥60 years with pancreatic ductal adenocarcinoma. Transl Cancer Res 2024; 13:2751-2766. [PMID: 38988930 PMCID: PMC11231776 DOI: 10.21037/tcr-24-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 05/07/2024] [Indexed: 07/12/2024]
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC), which accounts for the vast majority of pancreatic cancer (PC), is a highly aggressive malignancy with a dismal prognosis. Age is shown to be an independent factor affecting survival outcomes in patients with PDAC. Our study aimed to identify prognostic factors and construct a nomogram to predict survival in PDAC patients aged ≥60 years. Methods Data of PDAC patients aged ≥60 years were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Multivariate Cox regression analysis was used to determined prognostic factors of overall survival (OS) and cancer-specific survival (CSS), and two nomograms were constructed and validated by calibration plots, concordance index (C-index) and decision curve analysis (DCA). Additionally, 432 patients from the First Affiliated Hospital of Wenzhou Medical University were included as an external cohort. Kaplan-Meier curves were applied to further verify the clinical validity of the nomograms. Results Ten independent prognostic factors were identified to establish the nomograms. The C-indexes of the training and validation groups based on the OS nomogram were 0.759 and 0.760, higher than those of the tumor-node-metastasis (TNM) staging system (0.638 and 0.636, respectively). Calibration curves showed high consistency between predictions and observations. Better area under the receiver operator characteristic (ROC) curve (AUC) values and DCA were also obtained compared to the TNM system. The risk stratification based on the nomogram could distinguish patients with different survival risks. Conclusions We constructed and externally validated a population-based survival-predicting nomogram for PDAC patients aged ≥60 years. The new model could help clinicians personalize survival prediction and risk assessment.
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Affiliation(s)
- Binjiao Zheng
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China
| | - Gangfeng Ding
- The First Clinical Medical College of Wenzhou Medical University, Wenzhou, China
| | - Guangrong Lu
- Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lili Li
- Department of Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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18
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Kou Z, Liu C, Zhang W, Sun C, Liu L, Zhang Q. Heterogeneity of primary and metastatic CAFs: From differential treatment outcomes to treatment opportunities (Review). Int J Oncol 2024; 64:54. [PMID: 38577950 PMCID: PMC11015919 DOI: 10.3892/ijo.2024.5642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 03/13/2024] [Indexed: 04/06/2024] Open
Abstract
Compared with primary tumor sites, metastatic sites appear more resistant to treatments and respond differently to the treatment regimen. It may be due to the heterogeneity in the microenvironment between metastatic sites and primary tumors. Cancer‑associated fibroblasts (CAFs) are widely present in the tumor stroma as key components of the tumor microenvironment. Primary tumor CAFs (pCAFs) and metastatic CAFs (mCAFs) are heterogeneous in terms of source, activation mode, markers and functional phenotypes. They can shape the tumor microenvironment according to organ, showing heterogeneity between primary tumors and metastases, which may affect the sensitivity of these sites to treatment. It was hypothesized that understanding the heterogeneity between pCAFs and mCAFs can provide a glimpse into the difference in treatment outcomes, providing new ideas for improving the rate of metastasis control in various cancers.
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Affiliation(s)
- Zixing Kou
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China
| | - Cun Liu
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Wenfeng Zhang
- State Key Laboratory of Quality Research in Chinese Medicine and Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa Island 999078, Macau SAR, P.R. China
| | - Changgang Sun
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, Shandong 621000, P.R. China
| | - Lijuan Liu
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, Shandong 621000, P.R. China
| | - Qiming Zhang
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China
- Department of Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100007, P.R. China
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19
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Wang P, Jie Y, Yao L, Sun YM, Jiang DP, Zhang SQ, Wang XY, Fan Y. Cells in the liver microenvironment regulate the process of liver metastasis. Cell Biochem Funct 2024; 42:e3969. [PMID: 38459746 DOI: 10.1002/cbf.3969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 01/31/2024] [Accepted: 02/26/2024] [Indexed: 03/10/2024]
Abstract
The research of liver metastasis is a developing field. The ability of tumor cells to invade the liver depends on the complicated interactions between metastatic cells and local subpopulations in the liver (including Kupffer cells, hepatic stellate cells, liver sinusoidal endothelial cells, and immune-related cells). These interactions are mainly mediated by intercellular adhesion and the release of cytokines. Cell populations in the liver microenvironment can play a dual role in the progression of liver metastasis through different mechanisms. At the same time, we can see the participation of liver parenchymal cells and nonparenchymal cells in the process of liver metastasis of different tumors. Therefore, the purpose of this article is to summarize the relationship between cellular components of liver microenvironment and metastasis and emphasize the importance of different cells in the occurrence or potential regression of liver metastasis.
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Affiliation(s)
- Pei Wang
- Cancer Institute, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yu Jie
- Cancer Institute, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Lin Yao
- Cancer Institute, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yi-Meng Sun
- Cancer Institute, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Da-Peng Jiang
- Cancer Institute, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Shi-Qi Zhang
- Department of Gastroenterology, The Affiliated Suqian First People's Hospital of Xuzhou Medical University, Suqian, Jiangsu, China
| | - Xiao-Yan Wang
- Department of Gastroenterology, The Affiliated Suqian First People's Hospital of Xuzhou Medical University, Suqian, Jiangsu, China
| | - Yu Fan
- Cancer Institute, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
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20
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Zhang X, Detering L, Heo GS, Sultan D, Luehmann H, Li L, Somani V, Lesser J, Tao J, Kang LI, Li A, Lahad D, Rho S, Ruzinova MB, DeNardo DG, Dehdashti F, Lim KH, Liu Y. Chemokine Receptor 2 Targeted PET/CT Imaging Distant Metastases in Pancreatic Ductal Adenocarcinoma. ACS Pharmacol Transl Sci 2024; 7:285-293. [PMID: 38230294 PMCID: PMC10789124 DOI: 10.1021/acsptsci.3c00303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/15/2023] [Accepted: 11/16/2023] [Indexed: 01/18/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and treatment-refractory malignancies. The lack of an effective screening tool results in the majority of patients being diagnosed at late stages, which underscores the urgent need to develop more sensitive and specific imaging modalities, particularly in detecting occult metastases, to aid clinical decision-making. The tumor microenvironment of PDAC is heavily infiltrated with myeloid-derived suppressor cells (MDSCs) that express C-C chemokine receptor type 2 (CCR2). These CCR2-expressing MDSCs accumulate at a very early stage of metastasis and greatly outnumber PDAC cells, making CCR2 a promising target for detecting early, small metastatic lesions that have scant PDAC cells. Herein, we evaluated a CCR2 targeting PET tracer (68Ga-DOTA-ECL1i) for PET imaging on PDAC metastasis in two mouse models. Positron emission tomography/computed tomography (PET/CT) imaging of 68Ga-DOTA-ECL1i was performed in a hemisplenic injection metastasis model (KI) and a genetically engineered orthotopic PDAC model (KPC), which were compared with 18F-FDG PET concurrently. Autoradiography, hematoxylin and eosin (H&E), and CCR2 immunohistochemical staining were performed to characterize the metastatic lesions. PET/CT images visualized the PDAC metastases in the liver/lung of KI mice and in the liver of KPC mice. Quantitative uptake analysis revealed increased metastasis uptake during disease progression in both models. In comparison, 18F-FDG PET failed to detect any metastases during the time course studies. H&E staining showed metastases in the liver and lung of KI mice, within which immunostaining clearly demonstrated the overexpression of CCR2 as well as CCR2+ cell infiltration into the normal liver. H&E staining, CCR2 staining, and autoradiography also confirmed the expression of CCR2 and the uptake of 68Ga-DOTA-ECL1i in the metastatic foci in KPC mice. Using our novel CCR2 targeted radiotracer 68Ga-DOTA-ECL1i and PET/CT, we demonstrated the sensitive and specific detection of CCR2 in the early PDAC metastases in two mouse models, indicating its potential in future clinical translation.
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Affiliation(s)
- Xiaohui Zhang
- Department
of Radiology, Washington University in St.
Louis, St. Louis, Missouri 63110, United States
| | - Lisa Detering
- Department
of Radiology, Washington University in St.
Louis, St. Louis, Missouri 63110, United States
| | - Gyu Seong Heo
- Department
of Radiology, Washington University in St.
Louis, St. Louis, Missouri 63110, United States
| | - Deborah Sultan
- Department
of Radiology, Washington University in St.
Louis, St. Louis, Missouri 63110, United States
| | - Hannah Luehmann
- Department
of Radiology, Washington University in St.
Louis, St. Louis, Missouri 63110, United States
| | - Lin Li
- Division
of Oncology, Department of Medicine, Washington
University in St. Louis, St. Louis, Missouri 63110, United States
| | - Vikas Somani
- Division
of Oncology, Department of Medicine, Washington
University in St. Louis, St. Louis, Missouri 63110, United States
| | - Josie Lesser
- Department
of Anthropology, Washington University in
St. Louis, St. Louis, Missouri 63110, United States
| | - Joan Tao
- Department
of Medicine, University of Missouri, Columbia, Missouri 65211, United States
| | - Liang-I. Kang
- Department
of Pathology and Immunology, Washington
University in St. Louis, St. Louis, Missouri 63110, United States
| | - Alexandria Li
- Department
of Radiology, Washington University in St.
Louis, St. Louis, Missouri 63110, United States
| | - Divangana Lahad
- Department
of Radiology, Washington University in St.
Louis, St. Louis, Missouri 63110, United States
| | - Shinji Rho
- Department
of Medicine, Washington University in St.
Louis, St. Louis, Missouri 63110, United States
| | - Marianna B. Ruzinova
- Department
of Pathology and Immunology, Washington
University in St. Louis, St. Louis, Missouri 63110, United States
| | - David G. DeNardo
- Division
of Oncology, Department of Medicine, Washington
University in St. Louis, St. Louis, Missouri 63110, United States
- Department
of Pathology and Immunology, Washington
University in St. Louis, St. Louis, Missouri 63110, United States
| | - Farrokh Dehdashti
- Department
of Radiology, Washington University in St.
Louis, St. Louis, Missouri 63110, United States
| | - Kian-Huat Lim
- Division
of Oncology, Department of Medicine, Washington
University in St. Louis, St. Louis, Missouri 63110, United States
| | - Yongjian Liu
- Department
of Radiology, Washington University in St.
Louis, St. Louis, Missouri 63110, United States
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21
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Wang LT, Yang J, Wu J, Lu WJ. Combined Therapy of Chemotherapy and Radiofrequency Ablation for Pancreatic Cancer Patients With Metachronous Hepatic Metastatic Lesions After Radical Pancreatic Resection. Cancer Control 2024; 31:10732748241274559. [PMID: 39150275 PMCID: PMC11329956 DOI: 10.1177/10732748241274559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 07/09/2024] [Accepted: 07/22/2024] [Indexed: 08/17/2024] Open
Abstract
PURPOSE Hepatic metastasis frequently occurs in patients who have undergone radical pancreatic resection for pancreatic cancer. Besides chemotherapy, various local treatment approaches targeting hepatic lesions have been explored. However, research on radiofrequency ablation (RFA) as a localized therapy for hepatic metastasis is limited. Therefore, we conducted this retrospective study to provide clinical evidence. METHODS This is a single-center, retrospective, cohort study. After radical pancreaticoduodenectomy, 32 patients developed metachronous hepatic metastasis with fewer than 3 lesions, the largest of which was less than 3 cm in diameter. These patients underwent combined treatment with chemotherapy and RFA. After 8 weeks of chemotherapy, patients received RFA for hepatic lesions. Additional chemotherapy was administered, and the patients' tumor status and survival were monitored. The primary endpoint of this study was overall survival (OS). Factors affecting OS were analyzed using the Cox risk model. RESULTS Among the 32 patients, the mean OS was 28.4 months. Univariate and multivariate Cox regression analysis revealed that the time (in months) of liver metastasis (HR = 0.04, 95% CI: 0.01 to 0.19; P < 0.001), the number of liver metastases (HR = 7.08, 95% CI: 1.85 to 27.08, P = 0.004), and PD (progressive disease) response to the second round of chemotherapy (HR = 29.50, 95% CI: 1.46 to 597.27; P = 0.027) were independent predictors of poorer survival. CONCLUSION Combined therapy with RFA and chemotherapy is safe in patients with hepatic metastasis after radical pancreaticoduodenectomy. Early recurrence (≤12 months), three liver metastatic lesions, and a poor response to the second round of chemotherapy were associated with poor survival.
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Affiliation(s)
- L. T. Wang
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - J. Yang
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - J. Wu
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - W. J. Lu
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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22
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Zuo H, Yang M, Ji Q, Fu S, Pu X, Zhang X, Wang X. Targeting Neutrophil Extracellular Traps: A Novel Antitumor Strategy. J Immunol Res 2023; 2023:5599660. [PMID: 38023616 PMCID: PMC10653965 DOI: 10.1155/2023/5599660] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 10/09/2023] [Accepted: 10/20/2023] [Indexed: 12/01/2023] Open
Abstract
The clinical efficacy of surgery, radiotherapy, and chemotherapy for cancer is usually limited by the deterioration of tumor microenvironment (TME). Neutrophil extracellular traps (NETs) are decondensed chromatin extruded by neutrophils and are widely distributed among various cancers, such as pancreatic cancer, breast cancer, and hepatocellular carcinoma. In the TME, NETs interact with stromal components, immune cells and cancer cells, which allows for the reshaping of the matrix and the extracellular environment that favors the initiation, progression, and metastasis of cancer. In addition, NETs impair the proliferation and activation of T cells and NK cells, thus producing a suppressive TME that restricts the effect of immunotherapy. A better understanding of the function of NETs in the TME will provide new opportunities for the prevention of cancer metastasis and the discovery of novel therapy strategies.
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Affiliation(s)
- Hao Zuo
- Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Mengjie Yang
- Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
- Department of Nursing, Nanjing University, Nanjing, Jiangsu, China
| | - Qian Ji
- Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Shengqiao Fu
- Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Xi Pu
- Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
- Department of Gastroenterology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Xu Zhang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Xu Wang
- Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
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23
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Vidal L, Pando E, Blanco L, Fabregat-Franco C, Castet F, Sierra A, Macarulla T, Balsells J, Charco R, Vivancos A. Liquid biopsy after resection of pancreatic adenocarcinoma and its relation to oncological outcomes. Systematic review and meta-analysis. Cancer Treat Rev 2023; 120:102604. [PMID: 37572593 DOI: 10.1016/j.ctrv.2023.102604] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/02/2023] [Accepted: 08/04/2023] [Indexed: 08/14/2023]
Abstract
BACKGROUND It has been hypothesised that manipulation during surgery releases tumoral components into circulation. We investigate the effect of surgery on plasma-borne DNA biomarkers and the oncological outcomes in resectable pancreatic ductal adenocarcinoma (PDAC). We also compare non-touch isolation techniques (NTIT) with standard techniques. MATERIALS AND METHODS We performed a systematic review and a meta-analysis of studies analysing liquid biopsy as circulating tumour DNA (ctDNA), circulating tumour cells (CTCs), and messenger RNA (mRNA) in resectable PDAC patients who underwent surgery and its association with overall survival (OS) and disease-free survival (DFS). Research in EMBASE, Web of Science and PubMed was performed. The ctDNA shift negative-to-positive (ctDNA -/+) or ctDNA shift positive-to-negative (ctDNA +/-) before and after surgery was evaluated. RESULTS Twelve studies comprising 413 patients were included. Shorter OS and DFS were identified in patients with positive ctDNA status before (HR = 2.28, p = 0.005 and HR = 2.16, p = 0.006) or after surgery (HR = 3.88, p < 0.0001 and HR = 3.81, p = 0.03), respectively. Surgical resection increased the rate of ctDNA +/-. There were no differences in OS or DFS in the ctDNA +/- group compared with ctDNA +/+ or ctDNA -/+. However, there was a trend to shorter OS in the ctDNA -/+ group (HR = 5.00, p = 0.09). No differences between NTIT and standard techniques on liquid biopsy status were found. CONCLUSION Positive ctDNA in the perioperative period is associated with a worse prognosis. Surgical resection has a role in the negativisation of liquid biopsy status. More studies are needed to assess the potential of minimally invasive techniques on ctDNA dynamics.
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Affiliation(s)
- Laura Vidal
- Department of HPB and Transplant Surgery, Vall d'Hebron University Hospital, Barcelona, Spain; Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Elizabeth Pando
- Department of HPB and Transplant Surgery, Vall d'Hebron University Hospital, Barcelona, Spain; Universitat Autònoma de Barcelona, Barcelona, Spain.
| | - Laia Blanco
- Department of HPB and Transplant Surgery, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Carles Fabregat-Franco
- Gastrointestinal and Endocrine Tumour Unit, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Florian Castet
- Gastrointestinal and Endocrine Tumour Unit, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Alexandre Sierra
- Gastrointestinal and Endocrine Tumour Unit, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Teresa Macarulla
- Gastrointestinal and Endocrine Tumour Unit, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Joaquim Balsells
- Department of HPB and Transplant Surgery, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Ramón Charco
- Department of HPB and Transplant Surgery, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Ana Vivancos
- Cancer Genomics Lab, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
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24
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Li S, Qu Y, Liu L, Wang C, Yuan L, Bai H, Wang J. Tumour-derived exosomes in liver metastasis: A Pandora's box. Cell Prolif 2023; 56:e13452. [PMID: 36941028 PMCID: PMC10542622 DOI: 10.1111/cpr.13452] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 02/24/2023] [Accepted: 03/07/2023] [Indexed: 03/23/2023] Open
Abstract
The liver is a common secondary metastasis site of many malignant tumours, such as the colorectum, pancreas, stomach, breast, prostate, and lung cancer. The clinical management of liver metastases is challenging because of their strong heterogeneity, rapid progression, and poor prognosis. Now, exosomes, small membrane vesicles that are 40-160 nm in size, are released by tumour cells, namely, tumour-derived exosomes (TDEs), and are being increasingly studied because they can retain the original characteristics of tumour cells. Cell-cell communication via TDEs is pivotal for liver pre-metastatic niche (PMN) formation and liver metastasis; thus, TDEs can provide a theoretical basis to intensively study the potential mechanisms of liver metastasis and new insights into the diagnosis and treatment of liver metastasis. Here, we systematically review current research progress about the roles and possible regulatory mechanisms of TDE cargos in liver metastasis, focusing on the functions of TDEs in liver PMN formation. In addition, we discuss the clinical utility of TDEs in liver metastasis, including TDEs as potential biomarkers, and therapeutic approaches for future research reference in this field.
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Affiliation(s)
- Sini Li
- National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Yan Qu
- National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Lihui Liu
- National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- CAMS Key Laboratory of Translational Research on Lung Cancer, State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Chao Wang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Li Yuan
- National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Hua Bai
- National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- CAMS Key Laboratory of Translational Research on Lung Cancer, State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Jie Wang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- CAMS Key Laboratory of Translational Research on Lung Cancer, State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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25
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McDonald B, Barth K, Schmidt MHH. The origin of brain malignancies at the blood-brain barrier. Cell Mol Life Sci 2023; 80:282. [PMID: 37688612 PMCID: PMC10492883 DOI: 10.1007/s00018-023-04934-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 08/21/2023] [Accepted: 08/22/2023] [Indexed: 09/11/2023]
Abstract
Despite improvements in extracranial therapy, survival rate for patients suffering from brain metastases remains very poor. This is coupled with the incidence of brain metastases continuing to rise. In this review, we focus on core contributions of the blood-brain barrier to the origin of brain metastases. We first provide an overview of the structure and function of the blood-brain barrier under physiological conditions. Next, we discuss the emerging idea of a pre-metastatic niche, namely that secreted factors and extracellular vesicles from a primary tumor site are able to travel through the circulation and prime the neurovasculature for metastatic invasion. We then consider the neurotropic mechanisms that circulating tumor cells possess or develop that facilitate disruption of the blood-brain barrier and survival in the brain's parenchyma. Finally, we compare and contrast brain metastases at the blood-brain barrier to the primary brain tumor, glioma, examining the process of vessel co-option that favors the survival and outgrowth of brain malignancies.
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Affiliation(s)
- Brennan McDonald
- Institute of Anatomy, Medical Faculty Carl Gustav Carus, Technische Universität Dresden School of Medicine, Dresden, Germany.
| | - Kathrin Barth
- Institute of Anatomy, Medical Faculty Carl Gustav Carus, Technische Universität Dresden School of Medicine, Dresden, Germany
| | - Mirko H H Schmidt
- Institute of Anatomy, Medical Faculty Carl Gustav Carus, Technische Universität Dresden School of Medicine, Dresden, Germany
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26
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Gautam SK, Batra SK, Jain M. Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma. Mol Cancer 2023; 22:118. [PMID: 37488598 PMCID: PMC10367391 DOI: 10.1186/s12943-023-01813-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 06/23/2023] [Indexed: 07/26/2023] Open
Abstract
Immunosuppression is a hallmark of pancreatic ductal adenocarcinoma (PDAC), contributing to early metastasis and poor patient survival. Compared to the localized tumors, current standard-of-care therapies have failed to improve the survival of patients with metastatic PDAC, that necessecitates exploration of novel therapeutic approaches. While immunotherapies such as immune checkpoint blockade (ICB) and therapeutic vaccines have emerged as promising treatment modalities in certain cancers, limited responses have been achieved in PDAC. Therefore, specific mechanisms regulating the poor response to immunotherapy must be explored. The immunosuppressive microenvironment driven by oncogenic mutations, tumor secretome, non-coding RNAs, and tumor microbiome persists throughout PDAC progression, allowing neoplastic cells to grow locally and metastasize distantly. The metastatic cells escaping the host immune surveillance are unique in molecular, immunological, and metabolic characteristics. Following chemokine and exosomal guidance, these cells metastasize to the organ-specific pre-metastatic niches (PMNs) constituted by local resident cells, stromal fibroblasts, and suppressive immune cells, such as the metastasis-associated macrophages, neutrophils, and myeloid-derived suppressor cells. The metastatic immune microenvironment differs from primary tumors in stromal and immune cell composition, functionality, and metabolism. Thus far, multiple molecular and metabolic pathways, distinct from primary tumors, have been identified that dampen immune effector functions, confounding the immunotherapy response in metastatic PDAC. This review describes major immunoregulatory pathways that contribute to the metastatic progression and limit immunotherapy outcomes in PDAC. Overall, we highlight the therapeutic vulnerabilities attributable to immunosuppressive factors and discuss whether targeting these molecular and immunological "hot spots" could improve the outcomes of PDAC immunotherapies.
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Affiliation(s)
- Shailendra K Gautam
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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Chen D, Cao Y, Tang H, Zang L, Yao N, Zhu Y, Jiang Y, Zhai S, Liu Y, Shi M, Zhao S, Wang W, Wen C, Peng C, Chen H, Deng X, Jiang L, Shen B. Comprehensive machine learning-generated classifier identifies pro-metastatic characteristics and predicts individual treatment in pancreatic cancer: A multicenter cohort study based on super-enhancer profiling. Theranostics 2023; 13:3290-3309. [PMID: 37351165 PMCID: PMC10283048 DOI: 10.7150/thno.84978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 05/13/2023] [Indexed: 06/24/2023] Open
Abstract
Rationale: Accumulating evidence illustrated that the reprogramming of the super-enhancers (SEs) landscape could promote the acquisition of metastatic features in pancreatic cancer (PC). Given the anatomy-based TNM staging is limited by the heterogeneous clinical outcomes in treatment, it is of great clinical significance to tailor individual stratification and to develop alternative therapeutic strategies for metastatic PC patients based on SEs. Methods: In our study, ChIP-Seq analysis for H3K27ac was performed in primary pancreatic tumors (PTs) and hepatic metastases (HMs). Bootstrapping and univariate Cox analysis were implemented to screen prognostic HM-acquired, SE-associated genes (HM-SE genes). Then, based on 1705 PC patients from 14 multicenter cohorts, 188 machine-learning (ML) algorithm integrations were utilized to develop a comprehensive super-enhancer-related metastatic (SEMet) classifier. Results: We established a novel SEMet classifier based on 38 prognostic HM-SE genes. Compared to other clinical traits and 33 published signatures, the SEMet classifier possessed robust and powerful performance in predicting prognosis. In addition, patients in the SEMetlow subgroup owned dismal survival rates, more frequent genomic alterations, and more activated cancer immunity cycle as well as better benefits in immunotherapy. Remarkably, there existed a tight correlation between the SEMetlow subgroup and metastatic phenotypes of PC. Among 18 SEMet genes, we demonstrated that E2F7 may promote PC metastasis through the upregulation of TGM2 and DKK1. Finally, after in silico screening of potential compounds targeted SEMet classifier, results revealed that flumethasone could enhance the sensitivity of metastatic PC to routine gemcitabine chemotherapy. Conclusion: Overall, our study provided new insights into personalized treatment approaches in the clinical management of metastatic PC patients.
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Affiliation(s)
- Dongjie Chen
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Yizhi Cao
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Haoyu Tang
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Longjun Zang
- Department of General Surgery, Taiyuan Central Hospital, Shanxi, P.R. China
| | - Na Yao
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Youwei Zhu
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Yongsheng Jiang
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Shuyu Zhai
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Yihao Liu
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Minmin Shi
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Shulin Zhao
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Weishen Wang
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Chenlei Wen
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Chenghong Peng
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Hao Chen
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Xiaxing Deng
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Lingxi Jiang
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Baiyong Shen
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China
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Matellan C, Lachowski D, Cortes E, Chiam KN, Krstic A, Thorpe SD, Del Río Hernández AE. Retinoic acid receptor β modulates mechanosensing and invasion in pancreatic cancer cells via myosin light chain 2. Oncogenesis 2023; 12:23. [PMID: 37130839 PMCID: PMC10154384 DOI: 10.1038/s41389-023-00467-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 04/10/2023] [Accepted: 04/13/2023] [Indexed: 05/04/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal form of pancreatic cancer, characterised by stromal remodelling, elevated matrix stiffness and high metastatic rate. Retinoids, compounds derived from vitamin A, have a history of clinical use in cancer for their anti-proliferative and differentiation effects, and more recently have been explored as anti-stromal therapies in PDAC for their ability to induce mechanical quiescence in cancer associated fibroblasts. Here, we demonstrate that retinoic acid receptor β (RAR-β) transcriptionally represses myosin light chain 2 (MLC-2) expression in pancreatic cancer cells. As a key regulatory component of the contractile actomyosin machinery, MLC-2 downregulation results in decreased cytoskeletal stiffness and traction force generation, impaired response to mechanical stimuli via mechanosensing and reduced ability to invade through the basement membrane. This work highlights the potential of retinoids to target the mechanical drivers of pancreatic cancer.
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Affiliation(s)
- Carlos Matellan
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London, SW7 2AZ, UK
| | - Dariusz Lachowski
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London, SW7 2AZ, UK
| | - Ernesto Cortes
- Department of Physiology, School of Medicine, Autonomous University of Madrid, 28029, Madrid, Spain
| | - Kai Ning Chiam
- UCD School of Medicine, University College Dublin, Dublin, Ireland
| | - Aleksandar Krstic
- UCD School of Medicine, University College Dublin, Dublin, Ireland
- Systems Biology Ireland, University College Dublin, Dublin, Ireland
| | - Stephen D Thorpe
- UCD School of Medicine, University College Dublin, Dublin, Ireland.
- UCD Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin, Ireland.
- Trinity Centre for Biomedical Engineering, Trinity College Dublin, Dublin, Ireland.
| | - Armando E Del Río Hernández
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London, SW7 2AZ, UK.
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Palma AM, Bushnell GG, Wicha MS, Gogna R. Tumor microenvironment interactions with cancer stem cells in pancreatic ductal adenocarcinoma. Adv Cancer Res 2023; 159:343-372. [PMID: 37268400 PMCID: PMC11218813 DOI: 10.1016/bs.acr.2023.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer in the United States. Additionally, the low survival rate makes PDAC the third-leading cause of cancer-related mortality in the United States, and it is projected that by 2030, it will become the second-leading cause of cancer mortality. Several biological factors contribute to PDAC aggressiveness, and their understanding will narrow the gap from biology to clinical care of PDAC, leading to earlier diagnoses and the development of better treatment options. In this review, we describe the origins of PDAC highlighting the role of cancer stem cells (CSC). CSC, also known as tumor initiating cells, which exhibit a unique metabolism that allows them to maintain a highly plastic, quiescent, immune- and therapy-evasive state. However, CSCs can exit quiescence during proliferation and differentiation, with the capacity to form tumors while constituting a small population in tumor tissues. Tumorigenesis depends on the interactions between CSCs and other cellular and non-cellular components in the microenvironment. These interactions are fundamental to support CSC stemness and are maintained throughout tumor development and metastasis. PDAC is characterized by a massive desmoplastic reaction, which result from the deposition of high amounts of extracellular matrix components by stromal cells. Here we review how this generates a favorable environment for tumor growth by protecting tumor cells from immune responses and chemotherapy and inducing tumor cell proliferation and migration, leading to metastasis formation ultimately leading to death. We emphasize the interactions between CSCs and the tumor microenvironment leading to metastasis formation and posit that better understanding and targeting of these interactions will improve patient outcomes.
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Affiliation(s)
| | - Grace G Bushnell
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
| | - Max S Wicha
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States.
| | - Rajan Gogna
- VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States.
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30
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The Role of Exosomes in Pancreatic Ductal Adenocarcinoma Progression and Their Potential as Biomarkers. Cancers (Basel) 2023; 15:cancers15061776. [PMID: 36980662 PMCID: PMC10046651 DOI: 10.3390/cancers15061776] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 03/05/2023] [Accepted: 03/08/2023] [Indexed: 03/17/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic malignancy, is an aggressive and lethal cancer with a dismal five-year survival rate. Despite remarkable improvements in cancer therapeutics, the clinical outcome of PDAC patients remains poor due to late diagnosis of the disease. This highlights the importance of early detection, wherein biomarker evaluation including exosomes would be helpful. Exosomes, small extracellular vesicles (sEVs), are cell-secreted entities with diameters ranging from 50 to 150 nm that deliver cellular contents (e.g., proteins, lipids, and nucleic acids) from parent cells to regulate the cellular processes of targeted cells. Recently, an increasing number of studies have reported that exosomes serve as messengers to facilitate stromal-immune crosstalk within the PDAC tumor microenvironment (TME), and their contents are indicative of disease progression. Moreover, evidence suggests that exosomes with specific surface markers are capable of distinguishing patients with PDAC from healthy individuals. Detectable exosomes in bodily fluids (e.g., blood, urine, saliva, and pancreatic juice) are omnipresent and may serve as promising biomarkers for improving early detection and evaluating patient prognosis. In this review, we shed light on the involvement of exosomes and their cargos in processes related to disease progression, including chemoresistance, angiogenesis, invasion, metastasis, and immunomodulation, and their potential as prognostic markers. Furthermore, we highlight feasible clinical applications and the limitations of exosomes in liquid biopsies as tools for early diagnosis as well as disease monitoring. Taking advantage of exosomes to improve diagnostic capacity may provide hope for PDAC patients, although further investigation is urgently needed.
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Liu X, Song J, Zhang H, Liu X, Zuo F, Zhao Y, Zhao Y, Yin X, Guo X, Wu X, Zhang H, Xu J, Hu J, Jing J, Ma X, Shi H. Immune checkpoint HLA-E:CD94-NKG2A mediates evasion of circulating tumor cells from NK cell surveillance. Cancer Cell 2023; 41:272-287.e9. [PMID: 36706761 DOI: 10.1016/j.ccell.2023.01.001] [Citation(s) in RCA: 160] [Impact Index Per Article: 80.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 08/22/2022] [Accepted: 01/04/2023] [Indexed: 01/27/2023]
Abstract
Circulating tumor cells (CTCs), shed by primary malignancies, function as "seeds" for distant metastasis. However, it is still largely unknown how CTCs escape immune surveillance. Here, we characterize the transcriptomes of human pancreatic ductal adenocarcinoma CTCs, primary, and metastatic lesions at single-cell scale. Cell-interaction analysis and functional studies in vitro and in vivo reveal that CTCs and natural killer (NK) cells interact via the immune checkpoint molecule pair HLA-E:CD94-NKG2A. Disruption of this interaction by blockade of NKG2A or knockdown of HLA-E expression enhances NK-mediated tumor cell killing in vitro and prevents tumor metastasis in vivo. Mechanistic studies indicate that platelet-derived RGS18 promotes the expression of HLA-E through AKT-GSK3β-CREB signaling, and overexpression of RGS18 facilitates pancreatic tumor hepatic metastasis. In conclusion, platelet-derived RGS18 protects CTCs from NK-mediated immune surveillance by engaging the immune checkpoint HLA-E:CD94-NKG2A. Interruption of the suppressive signaling prevents tumor metastasis in vivo by immune elimination of CTCs.
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Affiliation(s)
- Xiaowei Liu
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China
| | - Jinen Song
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China
| | - Hao Zhang
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xinyu Liu
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China
| | - Fengli Zuo
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China
| | - Yunuo Zhao
- Department of Biotherapy, West China Hospital and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yujie Zhao
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China
| | - Xiaomeng Yin
- Department of Biotherapy, West China Hospital and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xinyu Guo
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China
| | - Xi Wu
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China
| | - Hu Zhang
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China
| | - Jie Xu
- Institutes of Biological Sciences, Zhongshan-Xuhui Hospital, Fudan University, Shanghai 200032, China
| | - Jianping Hu
- College of Pharmacy and Biological Engineering, Chengdu University, Chengdu, Sichuan 610106, China
| | - Jing Jing
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China
| | - Xuelei Ma
- Department of Biotherapy, West China Hospital and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, China.
| | - Hubing Shi
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China.
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Barrera LN, Ridley PM, Bermejo-Rodriguez C, Costello E, Perez-Mancera PA. The role of microRNAs in the modulation of cancer-associated fibroblasts activity during pancreatic cancer pathogenesis. J Physiol Biochem 2023; 79:193-204. [PMID: 35767180 PMCID: PMC9905185 DOI: 10.1007/s13105-022-00899-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 05/17/2022] [Indexed: 02/08/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the deadliest of the common cancers. A major hallmark of PDAC is an abundant and dense fibrotic stroma, the result of a disproportionate deposition of extracellular matrix (ECM) proteins. Cancer-associated fibroblasts (CAFs) are the main mediators of PDAC desmoplasia. CAFs represent a heterogenous group of activated fibroblasts with different origins and activation mechanisms. microRNAs (miRNAs) are small non-coding RNAs with critical activity during tumour development and resistance to chemotherapy. Increasing evidence has revealed that miRNAs play a relevant role in the differentiation of normal fibroblasts into CAFs in PDAC. In this review, we discuss recent findings on the role of miRNAs in the activation of CAFs during the progression of PDAC and its response to therapy, as well as the potential role that PDAC-derived exosomal miRNAs may play in the activation of hepatic stellate cells (HSCs) and formation of liver metastasis. Since targeting of CAF activation may be a viable strategy for PDAC therapy, and miRNAs have emerged as potential therapeutic targets, understanding the biology underpinning miRNA-mediated tumour cell-CAF interactions is an important component in guiding rational approaches to treating this deadly disease.
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Affiliation(s)
- Lawrence N Barrera
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
- Department of Molecular Cell Biology, School of Medicine, Faculty of Clinical and Biomedical Sciences, University of Central Lancashire, Preston, PR1 1JQ, UK
| | - P Matthew Ridley
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
| | | | - Eithne Costello
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
| | - Pedro A Perez-Mancera
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
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Gheorghe G, Ionescu VA, Moldovan H, Diaconu CC. Clinical and Biological Data in Patients with Pancreatic Cancer vs. Chronic Pancreatitis-A Single Center Comparative Analysis. Diagnostics (Basel) 2023; 13:369. [PMID: 36766475 PMCID: PMC9914010 DOI: 10.3390/diagnostics13030369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/15/2023] [Accepted: 01/17/2023] [Indexed: 01/21/2023] Open
Abstract
INTRODUCTION In some patients with chronic pancreatitis, the diagnosis of pancreatic cancer can be missed. The objective of the study was to identify clinical and paraclinical data with statistical significance in the differential diagnosis between chronic pancreatitis and pancreatic cancer. MATERIALS AND METHODS We conducted a retrospective, observational study on a cohort of 120 patients hospitalized over 3 years. The patients were equally distributed in two groups: group A, with 60 patients with pancreatic cancer, and group B, with 60 patients with chronic pancreatitis. The statistical analysis was carried out by using the R program. RESULTS The comparative analysis of pancreatic cancer vs. chronic pancreatitis revealed a stronger link between pancreatic cancer, female gender (p = 0.001) and age over 60 years (p < 0.001). Patients with pancreatic cancer had higher serum values of aspartate aminotransferase (p 0.005), alanine aminotransferase (p 0.006), total bilirubin (p < 0.001), direct bilirubin (p < 0.001), alkaline phosphatase (p 0.030), C-reactive protein (p = 0.049) and uric acid (p 0.001), while patients with chronic pancreatitis presented slightly higher values of amylase (p 0.020) and lipase (p 0.029). CONCLUSIONS Female gender, advanced age, elevated aminotransferases, cholestasis markers and uric acid were associated with a higher probability of pancreatic cancer.
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Affiliation(s)
- Gina Gheorghe
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania
- Gastroenterology Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Vlad Alexandru Ionescu
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania
- Gastroenterology Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Horatiu Moldovan
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania
- Department of Cardiovascular Surgery, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
- Medical Sciences Section, Academy of Romanian Scientists, 050085 Bucharest, Romania
| | - Camelia Cristina Diaconu
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania
- Medical Sciences Section, Academy of Romanian Scientists, 050085 Bucharest, Romania
- Internal Medicine Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
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Cao BY, Tong F, Zhang LT, Kang YX, Wu CC, Wang QQ, Yang W, Wang J. Risk factors, prognostic predictors, and nomograms for pancreatic cancer patients with initially diagnosed synchronous liver metastasis. World J Gastrointest Oncol 2023; 15:128-142. [PMID: 36684042 PMCID: PMC9850760 DOI: 10.4251/wjgo.v15.i1.128] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/17/2022] [Accepted: 12/08/2022] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Liver metastasis (LM) remains a major cause of cancer-related death in patients with pancreatic cancer (PC) and is associated with a poor prognosis. Therefore, identifying the risk and prognostic factors in PC patients with LM (PCLM) is essential as it may aid in providing timely medical interventions to improve the prognosis of these patients. However, there are limited data on risk and prognostic factors in PCLM patients.
AIM To investigate the risk and prognostic factors of PCLM and develop corresponding diagnostic and prognostic nomograms.
METHODS Patients with primary PC diagnosed between 2010 and 2015 were reviewed from the Surveillance, Epidemiology, and Results Database. Risk factors were identified using multivariate logistic regression analysis to develop the diagnostic mode. The least absolute shrinkage and selection operator Cox regression model was used to determine the prognostic factors needed to develop the prognostic model. The performance of the two nomogram models was evaluated using receiver operating characteristic (ROC) curves, calibration plots, decision curve analysis (DCA), and risk subgroup classification. The Kaplan-Meier method with a log-rank test was used for survival analysis.
RESULTS We enrolled 33459 patients with PC in this study. Of them, 11458 (34.2%) patients had LM at initial diagnosis. Age at diagnosis, primary site, lymph node metastasis, pathological type, tumor size, and pathological grade were identified as independent risk factors for LM in patients with PC. Age > 70 years, adenocarcinoma, poor or anaplastic differentiation, lung metastases, no surgery, and no chemotherapy were the independently associated risk factors for poor prognosis in patients with PCLM. The C- index of diagnostic and prognostic nomograms were 0.731 and 0.753, respectively. The two nomograms could accurately predict the occurrence and prognosis of patients with PCLM based on the observed analysis results of ROC curves, calibration plots, and DCA curves. The prognostic nomogram could stratify patients into prognostic groups and perform well in internal validation.
CONCLUSION Our study identified the risk and prognostic factors in patients with PCLM and developed corresponding diagnostic and prognostic nomograms to help clinicians in subsequent clinical evaluation and intervention. External validation is required to confirm these results.
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Affiliation(s)
- Bi-Yang Cao
- Department of Radiation Oncology, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
- Medical School of Chinese PLA, Beijing 100853, China
| | - Fang Tong
- Department of Radiation Oncology, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Le-Tian Zhang
- Department of Radiation Oncology, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
- Medical School of Chinese PLA, Beijing 100853, China
| | - Yi-Xin Kang
- Department of Radiation Oncology, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
- Medical School of Chinese PLA, Beijing 100853, China
| | - Chen-Chen Wu
- Department of Radiation Oncology, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
- Medical School of Chinese PLA, Beijing 100853, China
| | - Qian-Qian Wang
- Department of Radiation Oncology, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Wei Yang
- Department of Radiation Oncology, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Jing Wang
- Department of Radiation Oncology, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
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Beckinger S, Daunke T, Aldag L, Krüger S, Heckl S, Wesch D, Schäfer H, Röcken C, Rahn S, Sebens S. Hepatic myofibroblasts exert immunosuppressive effects independent of the immune checkpoint regulator PD-L1 in liver metastasis of pancreatic ductal adenocarcinoma. Front Oncol 2023; 13:1160824. [PMID: 37207152 PMCID: PMC10189124 DOI: 10.3389/fonc.2023.1160824] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 04/17/2023] [Indexed: 05/21/2023] Open
Abstract
Introduction Pancreatic ductal adenocarcinoma (PDAC) represents the 4th most common cause of cancer-related deaths in Western countries. Most patients are diagnosed at advanced stages, often already with metastases. The main site of metastasis is the liver and hepatic myofibroblasts (HMF) play a pivotal role in metastatic outgrowth. Immune checkpoint inhibitors (ICI) targeting programmed death ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1) improved treatment of several cancers but not of PDAC. Therefore, this study aimed to better understand the impact of HMF on PD-L1 expression and immune evasion of PDAC cells during liver metastasis. Methods Formalin-fixed and paraffin embedded biopsy samples or diagnostic resection specimens from liver metastases of 15 PDAC patients were used for immunohistochemical analyses. Serial sections were stained with antibodies directed against Pan-Cytokeratin, αSMA, CD8, and PD-L1. To investigate whether the PD-1/PD-L1 axis and HMF contribute to immune escape of PDAC liver metastases, a stroma enriched 3D spheroid coculture model was established in vitro, using two different PDAC cell lines, HMF, and CD8+ T cells. Here, functional and flow cytometry analyses were conducted. Results Immunohistochemical analysis of liver tissue sections of PDAC patients revealed that HMF represent an abundant stroma population in liver metastases, with clear differences in the spatial distribution in small (1500 µm) and large (> 1500 μm) metastases. In the latter, PD-L1 expression was mainly located at the invasion front or evenly distributed, while small metastases either lacked PD-L1 expression or showed mostly weak expression in the center. Double stainings revealed that PD-L1 is predominantly expressed by stromal cells, especially HMF. Small liver metastases with no or low PD-L1 expression comprised more CD8+ T cells in the tumor center, while large metastases exhibiting stronger PD-L1 expression comprised less CD8+ T cells being mostly located at the invasion front. HMF-enriched spheroid cocultures with different ratios of PDAC cells and HMF well mimicking conditions of hepatic metastases in situ. Here, HMF impaired the release of effector molecules by CD8+ T cells and the induction of PDAC cell death, an effect that was dependent on the amount of HMF but also of PDAC cells. ICI treatment led to elevated secretion of distinct CD8+ T cell effector molecules but did not increase PDAC cell death under either spheroid condition. Conclusion Our findings indicate a spatial reorganization of HMF, CD8+ T cells, and PD-L1 expression during progression of PDAC liver metastases. Furthermore, HMF potently impair the effector phenotype of CD8+ T cells but the PD-L1/PD-1 axis apparently plays a minor role in this scenario suggesting that immune evasion of PDAC liver metastases relies on other immunosuppressive mechanisms.
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Affiliation(s)
- Silje Beckinger
- Institute for Experimental Cancer Research, Kiel University and University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
| | - Tina Daunke
- Institute for Experimental Cancer Research, Kiel University and University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
| | - Leon Aldag
- Institute for Experimental Cancer Research, Kiel University and University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
| | - Sandra Krüger
- Department of Pathology, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
| | - Steffen Heckl
- Department of Pathology, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
- Department of Internal Medicine II, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
| | - Daniela Wesch
- Institute of Immunology, Kiel University and University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
| | - Heiner Schäfer
- Institute for Experimental Cancer Research, Kiel University and University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
| | - Christoph Röcken
- Department of Internal Medicine II, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
| | - Sascha Rahn
- Institute of Biochemistry, Kiel University, Kiel, Germany
| | - Susanne Sebens
- Institute for Experimental Cancer Research, Kiel University and University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
- *Correspondence: Susanne Sebens,
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Buxton AK, Abbasova S, Bevan CL, Leach DA. Liver Microenvironment Response to Prostate Cancer Metastasis and Hormonal Therapy. Cancers (Basel) 2022; 14:6189. [PMID: 36551674 PMCID: PMC9777323 DOI: 10.3390/cancers14246189] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 12/12/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Prostate cancer-associated deaths arise from disease progression and metastasis. Metastasis to the liver is associated with the worst clinical outcomes for prostate cancer patients, and these metastatic tumors can be particularly resistant to the currently widely used chemotherapy and hormonal therapies, such as anti-androgens which block androgen synthesis or directly target the androgen receptor. The incidence of liver metastases is reportedly increasing, with a potential correlation with use of anti-androgen therapies. A key player in prostate cancer progression and therapeutic response is the microenvironment of the tumor(s). This is a dynamic and adaptive collection of cells and proteins, which impart signals and stimuli that can alter biological processes within prostate cancer cells. Investigation in the prostate primary site has demonstrated that cells of the microenvironment are also responsive to hormones and hormonal therapies. In this review, we collate information about what happens when cancer moves to the liver: the types of prostate cancer cells that metastasize there, the response of resident mesenchymal cells of the liver, and how the interactions between the cancer cells and the microenvironment may be altered by hormonal therapy.
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Affiliation(s)
| | | | - Charlotte L. Bevan
- Division of Cancer, Imperial Centre for Translational & Experimental Medicine, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
| | - Damien A. Leach
- Division of Cancer, Imperial Centre for Translational & Experimental Medicine, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
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Zheng JH, Yao HF, Duan ZH, Ji PX, Yang J, Zhu YH, Jia QY, Yang JY, Liu DJ, Sun YW, Chen PC, Shi PD, Chen L. Exploitation and Verification of a Stroma- and Metastasis-Associated Risk Prognostic Signature in Pancreatic Adenocarcinoma. Pharmaceuticals (Basel) 2022; 15:1336. [PMID: 36355508 PMCID: PMC9696859 DOI: 10.3390/ph15111336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 10/25/2022] [Accepted: 10/26/2022] [Indexed: 09/10/2024] Open
Abstract
Pancreatic adenocarcinoma (PAAD), one of the most malignant tumors, not only has abundant mesenchymal components, but is also characterized by an extremely high metastatic risk. The purpose of this study was to construct a model of stroma- and metastasis-associated prognostic signature, aiming to benefit the existing clinical staging system and predict the prognosis of patients. First, stroma-associated genes were screened from the TCGA database with the ESTIMATE algorithm. Subsequently, transcriptomic data from clinical tissues in the RenJi cohort were screened for metastasis-associated genes. Integrating the two sets of genes, we constructed a risk prognostic signature by Cox and LASSO regression analysis. We then obtained a risk score by a quantitative formula and divided all samples into high- and low-risk groups based on the scores. The results demonstrated that patients with high-risk scores have a worse prognosis than those with low-risk scores, both in the TCGA database and in the RenJi cohort. In addition, tumor mutation burden, chemotherapeutic drug sensitivity and immune infiltration analysis also exhibited significant differences between the two groups. In exploring the potential mechanisms of how stromal components affect tumor metastasis, we simulated different matrix stiffness in vitro to explore its effect on EMT key genes in PAAD cells. We found that cancer cells stimulated by high matrix stiffness may trigger EMT and promote PAAD metastasis.
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Affiliation(s)
- Jia-Hao Zheng
- State Key Laboratory of Oncogenes and Related Genes, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Hong-Fei Yao
- State Key Laboratory of Oncogenes and Related Genes, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Zong-Hao Duan
- State Key Laboratory of Oncogenes and Related Genes, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Pei-Xuan Ji
- Shanghai Institute of Digestive Disease, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
| | - Jian Yang
- State Key Laboratory of Oncogenes and Related Genes, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yu-Heng Zhu
- State Key Laboratory of Oncogenes and Related Genes, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Qin-Yuan Jia
- State Key Laboratory of Oncogenes and Related Genes, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Jian-Yu Yang
- State Key Laboratory of Oncogenes and Related Genes, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - De-Jun Liu
- State Key Laboratory of Oncogenes and Related Genes, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yong-Wei Sun
- State Key Laboratory of Oncogenes and Related Genes, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Peng-Cheng Chen
- Department of General Surgery, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai 201800, China
| | - Pei-Dong Shi
- Department of General Surgery, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai 201800, China
| | - Li Chen
- State Key Laboratory of Oncogenes and Related Genes, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
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Yao ZX, Tu JH, Zhou B, Huang Y, Liu YL, Xue XF. Risk factors and survival prediction of pancreatic cancer with lung metastases: A population-based study. Front Oncol 2022; 12:952531. [PMID: 36212473 PMCID: PMC9533144 DOI: 10.3389/fonc.2022.952531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 09/02/2022] [Indexed: 11/30/2022] Open
Abstract
Background The risk and prognosis of pancreatic cancer with lung metastasis (PCLM) are not well-defined. Thus, this study aimed to identify the risk and prognostic factors for these patients, and establish predictive nomogram models. Methods Patients diagnosed with PCLM between 2010 and 2016 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Independent risk factors and prognostic factors were identified using logistic regression and Cox regression analyses. Nomograms were constructed to predict the risk and survival of PCLM, and the area under the curve (AUC), C-index, and calibration curve were used to determine the predictive accuracy and discriminability of the established nomogram, while the decision curve analysis was used to confirm the clinical effectiveness. Results A total of 11287 cases with complete information were included; 601 (5.3%) patients with PC had lung metastases. Multivariable logistic analysis demonstrated that primary site, histological subtype, and brain, bone, and liver metastases were independent risk factors for lung metastases. We constructed a risk prediction nomogram model for the development of lung metastases among PC patients. The c-index of the established diagnostic nomogram was 0.786 (95%CI 0.726-0.846). Multivariable Cox regression analysis demonstrated that primary site, liver metastases, surgery, and chemotherapy were independent prognostic factors for both overall survival (OS) and cancer-specific survival (CSS), while bone metastases were independent prognostic factors for CSS. The C-indices for the OS and CSS prediction nomograms were 0.76 (95% CI 0.74-0.78) and 0.76 (95% CI 0.74-0.78), respectively. Based on the AUC of the receiver operating characteristic (ROC) analysis, calibration plots, and decision curve analysis (DCA), we concluded that the risk and prognosis model of PCBM exhibits excellent performance. Conclusions The present study identified the risk and prognostic factors of PCLM and further established nomograms, which can help clinicians effectively identify high-risk patients and predict their clinical outcomes.
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Affiliation(s)
- Zong-Xi Yao
- Department of General Surgery, Suzhou Wuzhong People’s Hospital, Suzhou, China
| | - Jun-Hao Tu
- Department of General Surgery, Suzhou Wuzhong People’s Hospital, Suzhou, China
| | - Bin Zhou
- Department of General Surgery, Suzhou Wuzhong People’s Hospital, Suzhou, China
| | - Yang Huang
- Department of General Surgery, Suzhou Wuzhong People’s Hospital, Suzhou, China
| | - Yu-Lin Liu
- Department of General Surgery, Suzhou Wuzhong People’s Hospital, Suzhou, China
- *Correspondence: Xiao-Feng Xue, ; Yu-Lin Liu,
| | - Xiao-Feng Xue
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
- *Correspondence: Xiao-Feng Xue, ; Yu-Lin Liu,
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Kubo H, Ohgi K, Sugiura T, Ashida R, Yamada M, Otsuka S, Yamazaki K, Todaka A, Sasaki K, Uesaka K. The Association Between Neoadjuvant Therapy and Pathological Outcomes in Pancreatic Cancer Patients After Resection: Prognostic Significance of Microscopic Venous Invasion. Ann Surg Oncol 2022; 29:4992-5002. [PMID: 35368218 DOI: 10.1245/s10434-022-11628-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 03/04/2022] [Indexed: 12/17/2023]
Abstract
BACKGROUND The impact of neoadjuvant therapy (NAT) on pathological outcomes, including microscopic venous invasion (MVI), remains unclear in pancreatic cancer. METHODS A total of 456 patients who underwent pancreatectomy for resectable and borderline resectable pancreatic cancer between July 2012 and February 2020 were retrospectively reviewed. Patients were divided into two groups: patients with NAT (n = 120, 26%) and those without NAT (n = 336, 74%). Clinicopathological factors, survival outcomes and recurrence patterns were analyzed. RESULTS Regarding pathological findings, the proportion of MVI was significantly lower in patients with NAT than in those without NAT (43% vs 62%, P = 0.001). The 5-year survival rate in patients with NAT was significantly better than that in those without NAT (54% vs 45%, P = 0.030). A multivariate analysis showed that MVI was an independent prognostic factor for the overall survival (OS) (hazard ratio 2.86, P = 0.003) in patients who underwent NAT. MVI was an independent risk factor for liver recurrence (odds ratio [OR] 2.38, P = 0.016) and multiple-site recurrence (OR 1.92, P = 0.027) according to a multivariate analysis. The OS in patients with liver recurrence was significantly worse than that in patients with other recurrence patterns (vs lymph node, P = 0.047; vs local, P < 0.001; vs lung, P < 0.001). The absence of NAT was a significant risk factor for MVI (OR 1.93, P = 0.007). CONCLUSION MVI was a crucial prognostic factor associated with liver and multiple-site recurrence in pancreatic cancer patients with NAT. MVI may be reduced by NAT, which may contribute to the improvement of survival in pancreatic cancer patients.
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Affiliation(s)
- Hidemasa Kubo
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Katsuhisa Ohgi
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan.
| | - Teiichi Sugiura
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Ryo Ashida
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Mihoko Yamada
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Shimpei Otsuka
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Kentaro Yamazaki
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Akiko Todaka
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Keiko Sasaki
- Division of Diagnostic Pathology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Katsuhiko Uesaka
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
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Zambirinis CP, Midya A, Chakraborty J, Chou JF, Zheng J, McIntyre CA, Koszalka MA, Wang T, Do RK, Balachandran VP, Drebin JA, Kingham TP, D'Angelica MI, Allen PJ, Gönen M, Simpson AL, Jarnagin WR. Recurrence After Resection of Pancreatic Cancer: Can Radiomics Predict Patients at Greatest Risk of Liver Metastasis? Ann Surg Oncol 2022; 29:4962-4974. [PMID: 35366706 PMCID: PMC9253095 DOI: 10.1245/s10434-022-11579-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 02/21/2022] [Indexed: 07/20/2023]
Abstract
BACKGROUND Liver metastasis (LM) after pancreatic ductal adenocarcinoma (PDAC) resection is common but difficult to predict and has grave prognosis. We combined preoperative clinicopathological variables and quantitative analysis of computed tomography (CT) imaging to predict early LM. METHODS We retrospectively evaluated patients with PDAC submitted to resection between 2005 and 2014 and identified clinicopathological variables associated with early LM. We performed liver radiomic analysis on preoperative contrast-enhanced CT scans and developed a logistic regression classifier to predict early LM (< 6 months). RESULTS In 688 resected PDAC patients, there were 516 recurrences (75%). The cumulative incidence of LM at 5 years was 41%, and patients who developed LM first (n = 194) had the lowest 1-year overall survival (OS) (34%), compared with 322 patients who developed extrahepatic recurrence first (61%). Independent predictors of time to LM included poor tumor differentiation (hazard ratio (HR) = 2.30; P < 0.001), large tumor size (HR = 1.17 per 2-cm increase; P = 0.048), lymphovascular invasion (HR = 1.50; P = 0.015), and liver Fibrosis-4 score (HR = 0.89 per 1-unit increase; P = 0.029) on multivariate analysis. A model using radiomic variables that reflect hepatic parenchymal heterogeneity identified patients at risk for early LM with an area under the receiver operating characteristic curve (AUC) of 0.71; the performance of the model was improved by incorporating preoperative clinicopathological variables (tumor size and differentiation status; AUC = 0.74, negative predictive value (NPV) = 0.86). CONCLUSIONS We confirm the adverse survival impact of early LM after resection of PDAC. We further show that a model using radiomic data from preoperative imaging combined with tumor-related variables has great potential for identifying patients at high risk for LM and may help guide treatment selection.
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Affiliation(s)
- Constantinos P Zambirinis
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Abhishek Midya
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jayasree Chakraborty
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Joanne F Chou
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jian Zheng
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Caitlin A McIntyre
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maura A Koszalka
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Tiegong Wang
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Cangzhou Central Hospital, Cangzhou City, Hebei Province, China
| | - Richard K Do
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Vinod P Balachandran
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jeffrey A Drebin
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - T Peter Kingham
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael I D'Angelica
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Peter J Allen
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mithat Gönen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Amber L Simpson
- Department of Biomedical and Molecular Sciences and School of Computing, Queen's University, Kingston, ON, Canada
| | - William R Jarnagin
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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Rojas A, Schneider I, Lindner C, Gonzalez I, Morales M. The RAGE/multiligand axis: a new actor in tumor biology. Biosci Rep 2022; 42:BSR20220395. [PMID: 35727208 PMCID: PMC9251583 DOI: 10.1042/bsr20220395] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 06/02/2022] [Accepted: 06/21/2022] [Indexed: 01/06/2023] Open
Abstract
The receptor for advanced glycation end-products (RAGE) is a multiligand binding and single-pass transmembrane protein which actively participates in several chronic inflammation-related diseases. RAGE, in addition to AGEs, has a wide repertoire of ligands, including several damage-associated molecular pattern molecules or alarmins such as HMGB1 and members of the S100 family proteins. Over the last years, a large and compelling body of evidence has revealed the active participation of the RAGE axis in tumor biology based on its active involvement in several crucial mechanisms involved in tumor growth, immune evasion, dissemination, as well as by sculpturing of the tumor microenvironment as a tumor-supportive niche. In the present review, we will detail the consequences of the RAGE axis activation to fuel essential mechanisms to guarantee tumor growth and spreading.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Labs., Universidad Catolica del Maule, Facultad de Medicina, 3605 San Miguel Ave., Talca, Chile
| | - Ivan Schneider
- Biomedical Research Labs., Universidad Catolica del Maule, Facultad de Medicina, 3605 San Miguel Ave., Talca, Chile
| | - Cristian Lindner
- Biomedical Research Labs., Universidad Catolica del Maule, Facultad de Medicina, 3605 San Miguel Ave., Talca, Chile
| | - Ileana Gonzalez
- Biomedical Research Labs., Universidad Catolica del Maule, Facultad de Medicina, 3605 San Miguel Ave., Talca, Chile
| | - Miguel A. Morales
- Department of Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Universidad de Chile, Santiago 8320000, Chile, Santiago, Chile
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MALDI-MSI: A Powerful Approach to Understand Primary Pancreatic Ductal Adenocarcinoma and Metastases. Molecules 2022; 27:molecules27154811. [PMID: 35956764 PMCID: PMC9369872 DOI: 10.3390/molecules27154811] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 07/25/2022] [Accepted: 07/25/2022] [Indexed: 11/17/2022] Open
Abstract
Cancer-related deaths are very commonly attributed to complications from metastases to neighboring as well as distant organs. Dissociate response in the treatment of pancreatic adenocarcinoma is one of the main causes of low treatment success and low survival rates. This behavior could not be explained by transcriptomics or genomics; however, differences in the composition at the protein level could be observed. We have characterized the proteomic composition of primary pancreatic adenocarcinoma and distant metastasis directly in human tissue samples, utilizing mass spectrometry imaging. The mass spectrometry data was used to train and validate machine learning models that could distinguish both tissue entities with an accuracy above 90%. Model validation on samples from another collection yielded a correct classification of both entities. Tentative identification of the discriminative molecular features showed that collagen fragments (COL1A1, COL1A2, and COL3A1) play a fundamental role in tumor development. From the analysis of the receiver operating characteristic, we could further advance some potential targets, such as histone and histone variations, that could provide a better understanding of tumor development, and consequently, more effective treatments.
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Periostin in lymph node pre-metastatic niches governs lymphatic endothelial cell functions and metastatic colonization. Cell Mol Life Sci 2022; 79:295. [PMID: 35567669 PMCID: PMC9107454 DOI: 10.1007/s00018-022-04262-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 03/03/2022] [Accepted: 03/18/2022] [Indexed: 12/25/2022]
Abstract
Although lymph node (LN) metastasis is an important prognostic parameter in cervical cancer, the tissue remodeling at a pre-metastatic state is poorly documented in LNs. We here identified periostin (POSTN) as a component of non-metastatic LNs by applying proteomic analyses and computerized image quantifications on LNs of patients with cervical cancer. We provide evidence for remarkable modifications of POSTN and lymphatic vessel distributions and densities in non-metastatic sentinel and metastatic human LNs, when compared to distant non-metastatic LNs. POSTN deposition at a pre-metastatic stage was demonstrated in a pre-clinical murine model (the ear sponge assay). Its expression by fibroblastic LN cells was assessed by in situ hybridization and in vitro cultures. In vitro, POSTN promoted lymphatic endothelial cell functions and tumor cell proliferation. Accordingly, the in vivo injection of recombinant POSTN together with VEGF-C boosted the lymphangiogenic response, while the metastatic potential of tumor cells was drastically reduced using a POSTN blocking antibody. This translational study also supports the existence of an unprecedented dialog “in cascade”, between the primary tumor and the first pelvic nodal relay in early cervical cancer, and subsequently from pelvic LN to para-aortic LNs in locally advanced cervical cancers. Collectively, this work highlights the association of POSTN deposition with lymphangiogenesis in LNs, and provides evidence for a key contribution of POSTN in promoting VEGF-C driven lymphangiogenesis and the seeding of metastatic cells.
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Karlsson S, Nyström H. The extracellular matrix in colorectal cancer and its metastatic settling – alterations and biological implications. Crit Rev Oncol Hematol 2022; 175:103712. [DOI: 10.1016/j.critrevonc.2022.103712] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 05/05/2022] [Accepted: 05/11/2022] [Indexed: 12/12/2022] Open
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Yanagihara K, Iino Y, Yokozaki H, Kubo T, Oda T, Kubo T, Komatsu M, Sasaki H, Ichikawa H, Kuwata T, Seyama T, Ochiai A. A Comparative Study of Patient-Derived Tumor Models of Pancreatic Ductal Adenocarcinoma Involving Orthotopic Implantation. Pathobiology 2022; 89:222-232. [PMID: 35272288 DOI: 10.1159/000521714] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 12/23/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDA) is associated with very poor prognoses. Therefore, new therapies and preclinical models are urgently needed. In the present study, we sought to develop more realistic experimental models for use in PDA research. METHODS We developed patient-derived xenografts (PDXs), established PDX-derived cell lines (PDCLs), and generated cell line-derived xenografts (CDXs), which we integrated to create 13 matched "trios" - i.e., patient-derived tumor models of PDA. We then compared and contrasted histological and molecular alterations between these three model systems. RESULTS Orthotopic implantation (OI) of the PDCLs resulted in tumorigenesis and metastases to the liver and peritoneum. Morphological comparisons of OI-CDXs and OI-PDXs with passaged tumors revealed that the histopathological features of the original tumor were maintained in both models. Molecular alterations in PDX tumors (including those to KRAS, TP53, SMAD4, and CDKN2A) were similar to those in the respective PDCLs and CDX tumors. When gene expression levels in the PDCLs, ectopic tumors, and OI tumors were compared, the distant metastasis-promoting gene CXCR4 was specifically upregulated in OI tumors, whose immunohistochemical profiles suggested epithelial-mesenchymal transition and adeno-squamous trans-differentiation. CONCLUSION These patient-derived tumor models provide useful tools for monitoring responses to antineoplastic agents and for studying PDA biology.
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Affiliation(s)
- Kazuyoshi Yanagihara
- Division of Biomarker Discovery, Exploratory Oncology and Clinical Trial Center, National Cancer Center, Chiba, Japan
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
- Department of Life Sciences, Yasuda Women's University Faculty of Pharmacy, Hiroshima, Japan
| | - Yuki Iino
- Division of Biomarker Discovery, Exploratory Oncology and Clinical Trial Center, National Cancer Center, Chiba, Japan
| | - Hiroshi Yokozaki
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takanori Kubo
- Department of Life Sciences, Yasuda Women's University Faculty of Pharmacy, Hiroshima, Japan
| | - Tatsuya Oda
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Takashi Kubo
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
- Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Masayuki Komatsu
- Department of Translational Oncology, Fundamental Innovative Oncology Core Center, National Cancer Center Research Institute, Tokyo, Japan
| | - Hiroki Sasaki
- Department of Translational Oncology, Fundamental Innovative Oncology Core Center, National Cancer Center Research Institute, Tokyo, Japan
| | - Hitoshi Ichikawa
- Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Takeshi Kuwata
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Chiba, Japan
| | - Toshio Seyama
- Department of Life Sciences, Yasuda Women's University Faculty of Pharmacy, Hiroshima, Japan
| | - Atsushi Ochiai
- Division of Biomarker Discovery, Exploratory Oncology and Clinical Trial Center, National Cancer Center, Chiba, Japan
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Xie Z, Gao Y, Ho C, Li L, Jin C, Wang X, Zou C, Mao Y, Wang X, Li Q, Fu D, Zhang YF. Exosome-delivered CD44v6/C1QBP complex drives pancreatic cancer liver metastasis by promoting fibrotic liver microenvironment. Gut 2022; 71:568-579. [PMID: 33827783 DOI: 10.1136/gutjnl-2020-323014] [Citation(s) in RCA: 116] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 03/23/2021] [Accepted: 03/24/2021] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Pancreatic ductal adenocarcinoma (PDAC) shows a remarkable predilection for liver metastasis. Pro-oncogenic secretome delivery and trafficking via exosomes are crucial for pre-metastatic microenvironment formation and metastasis. This study aimed to explore the underlying mechanisms of how PDAC-derived exosomes (Pex) modulate the liver microenvironment and promote metastasis. DESIGN C57BL/6 mice were 'educated' by tail vein Pex injection. The intrasplenic injection liver metastasis and PDAC orthotopic transplantation models were used to evaluate liver metastasis. Stable cell lines CD44v6 (CD44 variant isoform 6) or C1QBP (complement C1q binding protein) knockdown or overexpression was established using lentivirus transfection or gateway systems. A total of 142 patients with PDAC in Huashan Hospital were retrospectively enrolled. Prognosis and liver metastasis were predicted using Kaplan-Meier survival curves and logistic regression models. RESULTS Pex tail vein injection induced the deposition of liver fibrotic extracellular matrix, which promoted PDAC liver metastasis. Specifically, the exosomal CD44v6/C1QBP complex was delivered to the plasma membrane of hepatic satellite cells (HSCs), leading to phosphorylation of insulin-like growth factor 1 signalling molecules, which resulted in HSC activation and liver fibrosis. Expression of Pex CD44v6 and C1QBP in PDAC patients with liver metastasis was significantly higher than in PDAC patients without liver metastasis, and simultaneous high expression of exosomal CD44v6 and C1QBP correlated with a worse prognosis and a higher risk of postoperative PDAC liver metastasis. CONCLUSION The Pex-derived CD44v6/C1QBP complex is essential for the formation of a fibrotic liver microenvironment and PDAC liver metastasis. Highly expressed exosomal CD44v6 and C1QBP are promising biomarkers for predicting prognosis and liver metastasis in patients with PDAC.
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Affiliation(s)
- Zhibo Xie
- Department of Otorhinolaryngology Head and Neck Surgery, Shanghai Children's Hospital, Shanghai, China
- Department of Pancreatic Surgery, Huashan Hospital Fudan University, Shanghai, Shanghai, China
| | - Ya Gao
- Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, Shanghai, China
| | - Chiakang Ho
- Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, Shanghai, China
| | - Lequn Li
- Department of Hepatobiliary and Pancreas Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Guangxi, China
| | - Chen Jin
- Department of Pancreatic Surgery, Huashan Hospital Fudan University, Shanghai, Shanghai, China
| | - Xiaoyi Wang
- Department of Pancreatic Surgery, Huashan Hospital Fudan University, Shanghai, Shanghai, China
| | - Caifeng Zou
- Department of Pancreatic Surgery, Huashan Hospital Fudan University, Shanghai, Shanghai, China
| | - Yishen Mao
- Department of Pancreatic Surgery, Huashan Hospital Fudan University, Shanghai, Shanghai, China
| | - Xiaobo Wang
- Department of Hepatobiliary and Pancreas Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Guangxi, China
| | - Qingfeng Li
- Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, Shanghai, China
| | - Deliang Fu
- Department of Pancreatic Surgery, Huashan Hospital Fudan University, Shanghai, Shanghai, China
| | - Yi-Fan Zhang
- Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, Shanghai, China
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47
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Wang R, Nissen NN, Zhang Y, Shao C, Chu CY, Huynh C, Posadas EM, Tomlinson JS, Lewis MS, Pandol SJ. Circulating Fatty Objects and Their Preferential Presence in Pancreatic Cancer Patient Blood Samples. Front Physiol 2022; 13:827531. [PMID: 35237181 PMCID: PMC8883044 DOI: 10.3389/fphys.2022.827531] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 01/10/2022] [Indexed: 01/28/2023] Open
Abstract
Human cancers are often complicated with increased incidences of blood vessel occlusion, which are mostly insensitive to anticoagulation therapy. We searched for causal factors of cancer-associated embolism. A total of 2,017 blood samples was examined for visible abnormalities. Examined were peripheral blood samples from cancer patients who were about to undergo surgical treatment for genitourinary, breast, gastrointestinal or abdominal tumors. Samples from ambulatory patients being treated for recurrent or castration-resistant prostate cancers were included in the study. The lipid-rich nature was studied with lipophilic stains and lipid panel analysis, while surface membrane was assessed with specific staining and antibody detection. We identified a new entity, lipid droplet-like objects or circulating fatty objects (CFOs), visible in the blood samples of many cancer patients, with the potential of causing embolism. CFOs were defined as lipid-rich objects with a membrane, capable of gaining in volume through interaction with peripheral blood mononuclear cells in ex vivo culture. Blood samples from pancreatic cancer patients were found to have the highest CFO incidence and largest CFO numbers. Most noticeably, CFOs from many pancreatic cancer samples presented as large clusters entangled in insoluble fiber networks, suggestive of intravascular clotting. This study identifies CFO as an abnormal entity in cancer patient blood, and a contributory factor to intravascular embolism during cancer development and progression.
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Affiliation(s)
- Ruoxiang Wang
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Nicholas N. Nissen
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Yi Zhang
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Chen Shao
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Chia-Yi Chu
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Carissa Huynh
- Biobank and Translational Research Core, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Edwin M. Posadas
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - James S. Tomlinson
- Department of Surgery, VA Greater Los Angeles Healthcare System, Los Angeles, CA, United States
| | - Michael S. Lewis
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Department of Pathology, VA Greater Los Angeles Healthcare System, Los Angeles, CA, United States
| | - Stephen J. Pandol
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
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Rafaeva M, Horton ER, Jensen AR, Madsen CD, Reuten R, Willacy O, Brøchner CB, Jensen TH, Zornhagen KW, Crespo M, Grønseth DS, Nielsen SR, Idorn M, Straten PT, Rohrberg K, Spanggaard I, Højgaard M, Lassen U, Erler JT, Mayorca‐Guiliani AE. Modeling Metastatic Colonization in a Decellularized Organ Scaffold-Based Perfusion Bioreactor. Adv Healthc Mater 2022; 11:e2100684. [PMID: 34734500 PMCID: PMC11469127 DOI: 10.1002/adhm.202100684] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 10/25/2021] [Indexed: 12/26/2022]
Abstract
Metastatic cancer spread is responsible for most cancer-related deaths. To colonize a new organ, invading cells adapt to, and remodel, the local extracellular matrix (ECM), a network of proteins and proteoglycans underpinning all tissues, and a critical regulator of homeostasis and disease. However, there is a major lack in tools to study cancer cell behavior within native 3D ECM. Here, an in-house designed bioreactor, where mouse organ ECM scaffolds are perfused and populated with cells that are challenged to colonize it, is presented. Using a specialized bioreactor chamber, it is possible to monitor cell behavior microscopically (e.g., proliferation, migration) within the organ scaffold. Cancer cells in this system recapitulate cell signaling observed in vivo and remodel complex native ECM. Moreover, the bioreactors are compatible with co-culturing cell types of different genetic origin comprising the normal and tumor microenvironment. This degree of experimental flexibility in an organ-specific and 3D context, opens new possibilities to study cell-cell and cell-ECM interplay and to model diseases in a controllable organ-specific system ex vivo.
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Affiliation(s)
- Maria Rafaeva
- Biotech Research and Innovation Centre (BRIC)University of Copenhagen (UCPH)Ole Maaloes Vej 5Copenhagen2200Denmark
| | - Edward R. Horton
- Biotech Research and Innovation Centre (BRIC)University of Copenhagen (UCPH)Ole Maaloes Vej 5Copenhagen2200Denmark
| | - Adina R.D. Jensen
- Biotech Research and Innovation Centre (BRIC)University of Copenhagen (UCPH)Ole Maaloes Vej 5Copenhagen2200Denmark
| | - Chris D. Madsen
- Division of Translational Cancer ResearchDepartment of Laboratory MedicineLund UniversityLund22242Sweden
| | - Raphael Reuten
- Biotech Research and Innovation Centre (BRIC)University of Copenhagen (UCPH)Ole Maaloes Vej 5Copenhagen2200Denmark
- Present address:
Institute of Experimental and Clinical Pharmacology and ToxicologyMedical FacultyUniversity of Freiburg.FreiburgGermany
| | - Oliver Willacy
- Biotech Research and Innovation Centre (BRIC)University of Copenhagen (UCPH)Ole Maaloes Vej 5Copenhagen2200Denmark
| | - Christian B. Brøchner
- Department of Pathology, RigshospitaletCopenhagen University HospitalBlegdamsvej 9Copenhagen2100Denmark
| | - Thomas H. Jensen
- Department of Pathology, RigshospitaletCopenhagen University HospitalBlegdamsvej 9Copenhagen2100Denmark
| | - Kamilla Westarp Zornhagen
- Biotech Research and Innovation Centre (BRIC)University of Copenhagen (UCPH)Ole Maaloes Vej 5Copenhagen2200Denmark
| | - Marina Crespo
- Biotech Research and Innovation Centre (BRIC)University of Copenhagen (UCPH)Ole Maaloes Vej 5Copenhagen2200Denmark
| | - Dina S. Grønseth
- Biotech Research and Innovation Centre (BRIC)University of Copenhagen (UCPH)Ole Maaloes Vej 5Copenhagen2200Denmark
| | - Sebastian R. Nielsen
- Biotech Research and Innovation Centre (BRIC)University of Copenhagen (UCPH)Ole Maaloes Vej 5Copenhagen2200Denmark
| | - Manja Idorn
- National Center for Cancer Immune Therapy (CCIT)Department of OncologyUniversity Hospital Herlev and Department of Immunology and MicrobiologyUniversity of Copenhagen (UCPH)Herlev Ringvej 75Herlev2730Denmark
| | - Per thor Straten
- National Center for Cancer Immune Therapy (CCIT)Department of OncologyUniversity Hospital Herlev and Department of Immunology and MicrobiologyUniversity of Copenhagen (UCPH)Herlev Ringvej 75Herlev2730Denmark
| | - Kristoffer Rohrberg
- Department of OncologyCentre for Cancer and Organ Diseases, RigshospitaletCopenhagen University HospitalBlegdamsvej 9Copenhagen2100Denmark
| | - Iben Spanggaard
- Department of OncologyCentre for Cancer and Organ Diseases, RigshospitaletCopenhagen University HospitalBlegdamsvej 9Copenhagen2100Denmark
| | - Martin Højgaard
- Department of OncologyCentre for Cancer and Organ Diseases, RigshospitaletCopenhagen University HospitalBlegdamsvej 9Copenhagen2100Denmark
| | - Ulrik Lassen
- Department of OncologyCentre for Cancer and Organ Diseases, RigshospitaletCopenhagen University HospitalBlegdamsvej 9Copenhagen2100Denmark
| | - Janine T. Erler
- Biotech Research and Innovation Centre (BRIC)University of Copenhagen (UCPH)Ole Maaloes Vej 5Copenhagen2200Denmark
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Gonçalves JPL, Bollwein C, Schlitter AM, Martin B, Märkl B, Utpatel K, Weichert W, Schwamborn K. The Impact of Histological Annotations for Accurate Tissue Classification Using Mass Spectrometry Imaging. Metabolites 2021; 11:metabo11110752. [PMID: 34822410 PMCID: PMC8624953 DOI: 10.3390/metabo11110752] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 10/27/2021] [Accepted: 10/28/2021] [Indexed: 01/31/2023] Open
Abstract
Knowing the precise location of analytes in the tissue has the potential to provide information about the organs’ function and predict its behavior. It is especially powerful when used in diagnosis and prognosis prediction of pathologies, such as cancer. Spatial proteomics, in particular mass spectrometry imaging, together with machine learning approaches, has been proven to be a very helpful tool in answering some histopathology conundrums. To gain accurate information about the tissue, there is a need to build robust classification models. We have investigated the impact of histological annotation on the classification accuracy of different tumor tissues. Intrinsic tissue heterogeneity directly impacts the efficacy of the annotations, having a more pronounced effect on more heterogeneous tissues, as pancreatic ductal adenocarcinoma, where the impact is over 20% in accuracy. On the other hand, in more homogeneous samples, such as kidney tumors, histological annotations have a slenderer impact on the classification accuracy.
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Affiliation(s)
- Juliana Pereira Lopes Gonçalves
- Institute of Pathology, School of Medicine, Technical University of Munich, Trogerstraße 18, 81675 Munich, Germany; (J.P.L.G.); (C.B.); (A.M.S.); (W.W.)
| | - Christine Bollwein
- Institute of Pathology, School of Medicine, Technical University of Munich, Trogerstraße 18, 81675 Munich, Germany; (J.P.L.G.); (C.B.); (A.M.S.); (W.W.)
| | - Anna Melissa Schlitter
- Institute of Pathology, School of Medicine, Technical University of Munich, Trogerstraße 18, 81675 Munich, Germany; (J.P.L.G.); (C.B.); (A.M.S.); (W.W.)
- German Cancer Consortium (DKTK), Partner Site Munich, 80336 Munich, Germany
| | - Benedikt Martin
- General Pathology and Molecular Diagnostics, Medical Faculty, University Hospital of Augsburg, 86156 Augsburg, Germany; (B.M.); (B.M.)
| | - Bruno Märkl
- General Pathology and Molecular Diagnostics, Medical Faculty, University Hospital of Augsburg, 86156 Augsburg, Germany; (B.M.); (B.M.)
| | - Kirsten Utpatel
- Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany;
| | - Wilko Weichert
- Institute of Pathology, School of Medicine, Technical University of Munich, Trogerstraße 18, 81675 Munich, Germany; (J.P.L.G.); (C.B.); (A.M.S.); (W.W.)
- German Cancer Consortium (DKTK), Partner Site Munich, 80336 Munich, Germany
- Comprehensive Cancer Center Munich (CCCM), Marchioninistraße 15, 81377 Munich, Germany
| | - Kristina Schwamborn
- Institute of Pathology, School of Medicine, Technical University of Munich, Trogerstraße 18, 81675 Munich, Germany; (J.P.L.G.); (C.B.); (A.M.S.); (W.W.)
- Correspondence:
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50
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Miquel M, Zhang S, Pilarsky C. Pre-clinical Models of Metastasis in Pancreatic Cancer. Front Cell Dev Biol 2021; 9:748631. [PMID: 34778259 PMCID: PMC8578999 DOI: 10.3389/fcell.2021.748631] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 09/20/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a hostile solid malignancy coupled with an extremely high mortality rate. Metastatic disease is already found in most patients at the time of diagnosis, resulting in a 5-year survival rate below 5%. Improved comprehension of the mechanisms leading to metastasis is pivotal for the development of new targeted therapies. A key field to be improved are modeling strategies applied in assessing cancer progression, since traditional platforms fail in recapitulating the complexity of PDAC. Consequently, there is a compelling demand for new preclinical models that mirror tumor progression incorporating the pressure of the immune system, tumor microenvironment, as well as molecular aspects of PDAC. We suggest the incorporation of 3D organoids derived from genetically engineered mouse models or patients as promising new tools capable to transform PDAC pre-clinical modeling and access new frontiers in personalized medicine.
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Affiliation(s)
- Maria Miquel
- Department of Surgery, University Hospital, Erlangen, Germany
- Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Shuman Zhang
- Department of Surgery, University Hospital, Erlangen, Germany
- Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Christian Pilarsky
- Department of Surgery, University Hospital, Erlangen, Germany
- Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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