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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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Xiao G, Wang X, Xu Z, Liu Y, Jing J. Lung-specific metastasis: the coevolution of tumor cells and lung microenvironment. Mol Cancer 2025; 24:118. [PMID: 40241074 PMCID: PMC12001740 DOI: 10.1186/s12943-025-02318-6] [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: 02/12/2025] [Accepted: 03/31/2025] [Indexed: 04/18/2025] Open
Abstract
The vast majority of cancer-related deaths are attributed to metastasis. The lung, being a common site for cancer metastasis, is highly prone to being a target for multiple cancer types and causes a heavy disease burden. Accumulating evidence has demonstrated that tumor metastasis necessitates continuous interactions between tumor cells and distant metastatic niches. Nevertheless, a comprehensive elucidation of the underlying mechanisms governing lung-specific metastasis still poses a formidable challenge. In this review, we depict the lung susceptibility and the molecular profiles of tumors with the potential for lung metastasis. Under the conceptual framework of "Reciprocal Tumor-Lung Metastatic Symbiosis" (RTLMS), we mechanistically delineate the bidirectional regulatory dynamics and coevolutionary adaptation between tumor cells and distal pulmonary niches during lung-specific metastasis, including the induction of pre-metastatic-niches, positive responses of the lung, tumor colonization, dormancy, and reawakening. An enhanced understanding of the latest mechanisms is essential for developing targeted strategies to counteract lung-specific metastasis.
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Affiliation(s)
- Guixiu Xiao
- Breast Disease Center and Institute for Breast Health Medicine, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Xinmin Wang
- Institute of Breast Health Medicine, West China Hospital, Sichuan University Chengdu, Sichuan, 610041, China
| | - Zihan Xu
- Institute of Breast Health Medicine, West China Hospital, Sichuan University Chengdu, Sichuan, 610041, China
- Department of Medical Oncology, West China Hospital, Sichuan University, Cancer Center, Chengdu, Sichuan, 610041, China
| | - Yanyang Liu
- Department of Medical Oncology, West China Hospital, Sichuan University, Cancer Center, Chengdu, Sichuan, 610041, China.
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
| | - Jing Jing
- Breast Disease Center and Institute for Breast Health Medicine, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
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Zhu Z, Nie G, Peng X, Zhan X, Ding D. KAT8 catalyzes the acetylation of SEPP1 at lysine 247/249 and modulates the activity of CD8 + T cells via LRP8 to promote anti-tumor immunity in pancreatic cancer. Cell Biosci 2025; 15:24. [PMID: 39972392 PMCID: PMC11841300 DOI: 10.1186/s13578-025-01356-3] [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: 07/03/2024] [Accepted: 01/21/2025] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND Pancreatic cancer (PC) remains one of the most lethal malignancies with unfavorable prognosis globally. Bioinformatics analysis predicted that SEPP1 was low expressed in PC and related to tumor immune microenvironment, but its biological function was still unclear. METHODS PC xenograft and liver metastasis mouse models, as well as PC cell-MDSCs co-culture system, were established for in vivo and in vitro studies, respectively. The expression and localization of key molecules were detected by qRT-PCR, western blot, immunohistochemistry and immunofluorescence. Flow cytometry was employed to assess the abundance of immune cells and cell apoptosis. The interactions among KAT8, SEPP1 and LRP8 were detected by co-IP. Cell viability, migration and invasion were monitored by CCK-8 and transwell assays. RESULTS SEPP1 was downregulated in pancreatic tumors, and it was positively correlated with the abundance of CD8+ T cells. In vivo overexpression of SEPP1 impaired PC tumor growth and liver metastasis via modulating the abundance of CD8+ T cell and MDSCs. KAT8 upregulated SEPP1 transcription and protein level via catalyzing the acetylation at K247/249 on SEPP1, and SEPP1 impaired MDSCs survival via its receptor LRP8, thus regulating CD8+ T cell-mediated immune responses in PC. In vivo studies further revealed that SEPP1 recombinant protein enhanced the efficacy of anti-PD-1 therapy in PC xenograft mouse model. CONCLUSION KAT8 catalyzed the acetylation of SEPP1 at K247/249 and modulated the activity of CD8+ T cells via LRP8 to promote anti-tumor immunity in PC.
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Affiliation(s)
- Zhongfei Zhu
- Department of Hepatobiliary, Pancreatic and Spleen Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China
| | - Gang Nie
- Department of Hepatobiliary, Pancreatic and Spleen Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China
| | - Xiaobo Peng
- Department of Oncology, The First Affiliated Hospital of Naval Medical University, No. 168, Changhai Road, Yangpu District, Shanghai, 200433, China.
| | - Xianbao Zhan
- Department of Oncology, The First Affiliated Hospital of Naval Medical University, No. 168, Changhai Road, Yangpu District, Shanghai, 200433, China.
| | - Dan Ding
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Naval Medical University, No. 168, Changhai Road, Yangpu District, Shanghai, 200433, China.
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Zhang F, Xia Y, Su J, Quan F, Zhou H, Li Q, Feng Q, Lin C, Wang D, Jiang Z. Neutrophil diversity and function in health and disease. Signal Transduct Target Ther 2024; 9:343. [PMID: 39638788 PMCID: PMC11627463 DOI: 10.1038/s41392-024-02049-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 09/21/2024] [Accepted: 10/31/2024] [Indexed: 12/07/2024] Open
Abstract
Neutrophils, the most abundant type of granulocyte, are widely recognized as one of the pivotal contributors to the acute inflammatory response. Initially, neutrophils were considered the mobile infantry of the innate immune system, tasked with the immediate response to invading pathogens. However, recent studies have demonstrated that neutrophils are versatile cells, capable of regulating various biological processes and impacting both human health and disease. Cytokines and other active mediators regulate the functional activity of neutrophils by activating multiple receptors on these cells, thereby initiating downstream signal transduction pathways. Dysfunctions in neutrophils and disruptions in neutrophil homeostasis have been implicated in the pathogenesis of numerous diseases, including cancer and inflammatory disorders, often due to aberrant intracellular signaling. This review provides a comprehensive synthesis of neutrophil biological functions, integrating recent advancements in this field. Moreover, it examines the biological roles of receptors on neutrophils and downstream signaling pathways involved in the regulation of neutrophil activity. The pathophysiology of neutrophils in numerous human diseases and emerging therapeutic approaches targeting them are also elaborated. This review also addresses the current limitations within the field of neutrophil research, highlighting critical gaps in knowledge that warrant further investigation. In summary, this review seeks to establish a comprehensive and multidimensional model of neutrophil regulation, providing new perspectives for potential clinical applications and further research.
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Affiliation(s)
- Fengyuan Zhang
- Department of Hand and Foot Surgery, Orthopedics Center, The First Hospital of Jilin University, Changchun, People's Republic of China
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China
| | - Yidan Xia
- Department of Hand and Foot Surgery, Orthopedics Center, The First Hospital of Jilin University, Changchun, People's Republic of China
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China
| | - Jiayang Su
- Department of Hand and Foot Surgery, Orthopedics Center, The First Hospital of Jilin University, Changchun, People's Republic of China
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China
| | - Fushi Quan
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Hengzong Zhou
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Qirong Li
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Qiang Feng
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Chao Lin
- School of Grain Science and Technology, Jilin Business and Technology College, Changchun, China
| | - Dongxu Wang
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China.
| | - Ziping Jiang
- Department of Hand and Foot Surgery, Orthopedics Center, The First Hospital of Jilin University, Changchun, People's Republic of China.
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China.
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Valdivia-Silva J, Chinney-Herrera A. Chemokine receptors and their ligands in breast cancer: The key roles in progression and metastasis. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 388:124-161. [PMID: 39260935 DOI: 10.1016/bs.ircmb.2024.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/13/2024]
Abstract
Chemokines and their receptors are a family of chemotactic cytokines with important functions in the immune response in both health and disease. Their known physiological roles such as the regulation of leukocyte trafficking and the development of immune organs generated great interest when it was found that they were also related to the control of early and late inflammatory stages in the tumor microenvironment. In fact, in breast cancer, an imbalance in the synthesis of chemokines and/or in the expression of their receptors was attributed to be involved in the regulation of disease progression, including invasion and metastasis. Research in this area is progressing rapidly and the development of new agents based on chemokine and chemokine receptor antagonists are emerging as attractive alternative strategies. This chapter provides a snapshot of the different functions reported for chemokines and their receptors with respect to the potential to regulate breast cancer progression.
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Affiliation(s)
- Julio Valdivia-Silva
- Centro de Investigación en Bioingenieria (BIO), Universidad de Ingenieria y Tecnologia-UTEC, Barranco, Lima, Peru.
| | - Alberto Chinney-Herrera
- Facultad de Medicina, Universidad Nacional Autonoma de Mexico-UNAM, Ciudad Universitaria, Coyoacan, Ciudad de Mexico, Mexico
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Chu X, Zhong X, Zang S, Wang M, Li P, Ma Y, Tian X, Yang Y, Wang C, Yang Y. Stem cell-like circulating tumor cells identified by Pep@MNP and their clinical significance in pancreatic cancer metastasis. Front Oncol 2024; 14:1327280. [PMID: 38983932 PMCID: PMC11231205 DOI: 10.3389/fonc.2024.1327280] [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: 10/26/2023] [Accepted: 06/10/2024] [Indexed: 07/11/2024] Open
Abstract
Objective The circulating tumor cells (CTCs) could be captured by the peptide functionalized magnetic nanoparticles (Pep@MNP) detection system in pancreatic ductal adenocarcinoma (PDAC). CTCs and the CXCR4 expression were detected to explore their clinical significance. The CXCR4+ CTCs, this is highly metastatic-prone stem cell-like subsets of CTCs (HM-CTCs), were found to be associated with the early recurrence and metastasis of PDAC. Methods CTCs were captured by Pep@MNP. CTCs were identified via immunofluorescence with CD45, cytokeratin antibodies, and the CXCR4 positive CTCs were assigned to be HM-CTCs. Results The over-expression of CXCR4 could promote the migration of pancreatic cancer cell in vitro and in vivo. In peripheral blood (PB), CTCs were detected positive in 79.0% of all patients (49/62, 9 (0-71)/2mL), among which 63.3% patients (31/49, 3 (0-23)/2mL) were HM-CTCs positive. In portal vein blood (PVB), CTCs were positive in 77.5% of patients (31/40, 10 (0-40)/2mL), and 67.7% of which (21/31, 4 (0-15)/2mL) were HM-CTCs positive CTCs enumeration could be used as diagnostic biomarker of pancreatic cancer (AUC = 0.862), and the combination of CTCs positive and CA19-9 increase shows improved diagnostic accuracy (AUC = 0.963). in addition, PVB HM-CTCs were more accurate to predict the early recurrence and liver metastasis than PB HM-CTCs (AUC 0.825 vs. 0.787 and 0.827 vs. 0.809, respectively). Conclusions The CTCs identified by Pep@MNP detection system could be used as diagnostic and prognostic biomarkers of PDAC patients. We identified and defined the CXCR4 over-expressed CTC subpopulation as highly metastatic-prone CTCs, which was proved to identify patients who were prone to suffering from early recurrence and metastasis.
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Affiliation(s)
- Xiangyu Chu
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, China
- Chinese Academy of Sciences Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences Key Laboratory of Standardization and Measurement for Nanotechnology, Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
| | - Xiejian Zhong
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, China
| | - Shouge Zang
- Department of General Surgery, Fuyang People's Hospital of Anhui Medical University, Fuyang, China
| | - Mengting Wang
- Chinese Academy of Sciences Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences Key Laboratory of Standardization and Measurement for Nanotechnology, Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
| | - Ping Li
- Chinese Academy of Sciences Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences Key Laboratory of Standardization and Measurement for Nanotechnology, Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
| | - Yongsu Ma
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, China
| | - Xiaodong Tian
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, China
| | - Yanlian Yang
- Chinese Academy of Sciences Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences Key Laboratory of Standardization and Measurement for Nanotechnology, Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
- School of Nanoscience and Engineering, University of Chinese Academy of Sciences, Beijing, China
| | - Chen Wang
- Chinese Academy of Sciences Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences Key Laboratory of Standardization and Measurement for Nanotechnology, Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
- School of Nanoscience and Engineering, University of Chinese Academy of Sciences, Beijing, China
| | - Yinmo Yang
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, China
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El-Mouty Raslan MA, Kassem IAA, Ghaly NS, El-Manawaty MA, Melek FR, Nabil M. Aloe juvenna Brandham & S.Carter as α-Amylase Inhibitor and Hypoglycaemic Agent with Anti-inflammatory Properties for Diabetes Management. Chem Biodivers 2024; 21:e202400245. [PMID: 38436134 DOI: 10.1002/cbdv.202400245] [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: 01/30/2024] [Revised: 03/01/2024] [Accepted: 03/04/2024] [Indexed: 03/05/2024]
Abstract
Despite Aloe's traditional use, Aloe juvenna Brandham & S.Carter is poorly characterized. Other Aloes are known for their antidiabetic activity. This study describes the antidiabetic potentials and phytoconstituents of the A. juvenna leaves methanolic extract (AJME). Twenty-six phytoconstituents of AJME were described using HPLC/MS-MS. Lupeol and vitexin were isolated using column chromatography. The antidiabetic activity of AJME was investigated using an in vivo high-fat diet/streptozotocin-induced diabetic rat model and in vitro α-glucosidase and α-amylase inhibitory activity assays. AJME demonstrated its α-amylase inhibitory activity (IC50=313±39.9 ppm) with no effect on α-glucosidase. In vivo, AJME dose-dependently improved hyperglycaemia in a high-fat diet/streptozotocin-induced diabetic rat model. Notably, the higher dose (1600 mg/kg) of AJME significantly downregulated serum interleukin-6, tumor necrosis factor-α, and matrix metalloproteinase-1 genes, suggesting its anti-inflammatory effect. These findings indicate AJME's potential as a significant antidiabetic agent through its α-amylase inhibition, hypoglycaemic, and anti-inflammatory properties.
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Affiliation(s)
- Mona Abd El-Mouty Raslan
- Pharmacognosy Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, 12622, Giza, Egypt
| | - Iman AbdelKhalek AbdelKhalek Kassem
- Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, 12622, Giza, Egypt
| | - Neveen Sabry Ghaly
- Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, 12622, Giza, Egypt
| | - May Aly El-Manawaty
- Drug Bioassay-Cell Culture Laboratory, Pharmacognosy Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, Giza, 12622, Egypt
| | - Farouk Rasmy Melek
- Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, 12622, Giza, Egypt
| | - Marian Nabil
- Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, 12622, Giza, Egypt
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MacLean MR, Walker OL, Arun RP, Fernando W, Marcato P. Informed by Cancer Stem Cells of Solid Tumors: Advances in Treatments Targeting Tumor-Promoting Factors and Pathways. Int J Mol Sci 2024; 25:4102. [PMID: 38612911 PMCID: PMC11012648 DOI: 10.3390/ijms25074102] [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: 02/28/2024] [Revised: 03/30/2024] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Cancer stem cells (CSCs) represent a subpopulation within tumors that promote cancer progression, metastasis, and recurrence due to their self-renewal capacity and resistance to conventional therapies. CSC-specific markers and signaling pathways highly active in CSCs have emerged as a promising strategy for improving patient outcomes. This review provides a comprehensive overview of the therapeutic targets associated with CSCs of solid tumors across various cancer types, including key molecular markers aldehyde dehydrogenases, CD44, epithelial cellular adhesion molecule, and CD133 and signaling pathways such as Wnt/β-catenin, Notch, and Sonic Hedgehog. We discuss a wide array of therapeutic modalities ranging from targeted antibodies, small molecule inhibitors, and near-infrared photoimmunotherapy to advanced genetic approaches like RNA interference, CRISPR/Cas9 technology, aptamers, antisense oligonucleotides, chimeric antigen receptor (CAR) T cells, CAR natural killer cells, bispecific T cell engagers, immunotoxins, drug-antibody conjugates, therapeutic peptides, and dendritic cell vaccines. This review spans developments from preclinical investigations to ongoing clinical trials, highlighting the innovative targeting strategies that have been informed by CSC-associated pathways and molecules to overcome therapeutic resistance. We aim to provide insights into the potential of these therapies to revolutionize cancer treatment, underscoring the critical need for a multi-faceted approach in the battle against cancer. This comprehensive analysis demonstrates how advances made in the CSC field have informed significant developments in novel targeted therapeutic approaches, with the ultimate goal of achieving more effective and durable responses in cancer patients.
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Affiliation(s)
- Maya R. MacLean
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Olivia L. Walker
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Raj Pranap Arun
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Wasundara Fernando
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
- Department of Biology, Acadia University, Wolfville, NS B4P 2R6, Canada
| | - Paola Marcato
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Nova Scotia Health Authority, Halifax, NS B3H 4R2, Canada
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Zahra M, Abrahamse H, George BP. Green nanotech paradigm for enhancing sesquiterpene lactone therapeutics in cancer. Biomed Pharmacother 2024; 173:116426. [PMID: 38471274 DOI: 10.1016/j.biopha.2024.116426] [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: 01/23/2024] [Revised: 03/06/2024] [Accepted: 03/08/2024] [Indexed: 03/14/2024] Open
Abstract
In the field of cancer therapy, sesquiterpene lactones (SLs) derived from diverse Dicoma species demonstrate noteworthy bioactivity. However, the translation of their full therapeutic potential into clinical applications encounters significant challenges, primarily related to solubility, bioavailability, and precise drug targeting. Despite these obstacles, our comprehensive review introduces an innovative paradigm shift that integrates the inherent therapeutic properties of SLs with the principles of green nanotechnology. To overcome issues of solubility, bioavailability, and targeted drug delivery, eco-friendly strategies are proposed for synthesizing nanocarriers. Green nanotechnology has emerged as a focal point in addressing environmental and health concerns linked to conventional treatments. This progressive approach of green nanotechnology holds promise for the development of safe and sustainable nanomaterials, particularly in the field of drug delivery. This groundbreaking methodology signifies a pioneering advancement in the creation of novel and effective anticancer therapeutics. It holds substantial potential for transforming cancer treatment and advancing the landscape of natural product research.
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Affiliation(s)
- Mehak Zahra
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 1711, Doornfontein 2028, South Africa
| | - Heidi Abrahamse
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 1711, Doornfontein 2028, South Africa
| | - Blassan P George
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 1711, Doornfontein 2028, South Africa.
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Wahab WAA, Shafey HI, Mahrous KF, Esawy MA, Saleh SAA. Coculture of bacterial levans and evaluation of its anti-cancer activity against hepatocellular carcinoma cell lines. Sci Rep 2024; 14:3173. [PMID: 38326332 PMCID: PMC10850072 DOI: 10.1038/s41598-024-52699-9] [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: 08/02/2023] [Accepted: 01/22/2024] [Indexed: 02/09/2024] Open
Abstract
This research represents a novel study to assess how coculture affects levan yield, structure, bioactivities, and molecular weight. Among the 16 honey isolates, four bacterial strains recorded the highest levan yield. The Plackett-Burman design showed that the coculture (M) of isolates G2 and K2 had the maximum levan yield (52 g/L) and the effective factors were sucrose, incubation time, and sugarcane bagasse. The CCD showed that the most proper concentrations for maximum levan yield (81 g/L): were 130 g/L of sucrose and 6 g/f of sugarcane bagasse. Levan's backbone was characterized, and the molecular weight was determined. G2 and K2 isolates were identified based on 16 sRNA as Bacillus megaterium strain YM1C10 and Rhizobium sp. G6-1. M levan had promising antioxidant activity (99.66%), slowed the migration activity to a great extent, and recorded 70.70% inhibition against the hepatoblastoma cell line (HepG2) at 1000 µg/mL. Gene expression analysis in liver cancer cell lines (HePG2) revealed that M levan decreased the expression of CCL20), 2GRB2, and CCR6) genes and was superior to Doxo. While increasing the expression of the IL4R and IL-10 genes. The DNA damage values were significantly increased (P < 0.01) in treated liver cancer cell lines with levan M and Doxo. The results referred to the importance of each of the hydroxyl and carboxyl groups and the molecular weight in levans bioactivities.
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Affiliation(s)
- Walaa A Abdel Wahab
- Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, Cairo, Egypt
| | - Heba I Shafey
- Cell Biology Department, Biotechnology Research Institute, National Research Centre, Dokki, Cairo, Egypt
| | - Karima F Mahrous
- Cell Biology Department, Biotechnology Research Institute, National Research Centre, Dokki, Cairo, Egypt
| | - Mona A Esawy
- Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, Cairo, Egypt.
| | - Shireen A A Saleh
- Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, Cairo, Egypt
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Sroor FM, Mahrous KF, El-Kader HAMA, Othman AM, Ibrahim NS. Impact of trifluoromethyl and sulfonyl groups on the biological activity of novel aryl-urea derivatives: synthesis, in-vitro, in-silico and SAR studies. Sci Rep 2023; 13:17560. [PMID: 37845243 PMCID: PMC10579241 DOI: 10.1038/s41598-023-44753-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 10/11/2023] [Indexed: 10/18/2023] Open
Abstract
We designed and prepared a novel series of urea derivatives with/without sulfonyl group in their structures to investigate the impact of the sulfonyl group on the biological activity of the evaluated compounds. Antibacterial investigations indicated that derivatives 7, 8, 9, and 11 had the most antibacterial property of all the compounds examined, their minimum inhibitory concentrations (MICs) determined against B. mycoides, E. coli, and C. albicans, with compound 8 being the most active at a MIC value of 4.88 µg/mL. Anti-cancer activity has been tested against eight human cancer cell lines; A549, HCT116, PC3, A431, HePG2, HOS, PACA2 and BJ1. Compounds 7, 8 and 9 emerged IC50 values better than Doxorubicin as a reference drug. Compounds 7 and 8 showed IC50 = 44.4 and 22.4 μM respectively against PACA2 compared to Doxorubicin (IC50 = 52.1 μM). Compound 9 showed IC50 = 17.8, 12.4, and 17.6 μM against HCT116, HePG2, and HOS, respectively. qRT-PCR revealed the down-regulation of PALB2 in compounds 7 and 15 treated PACA2 cells. Also, the down-regulation of BRCA1 and BRCA2 was shown in compound 7 treated PC3 cells. As regard A549 cells, compound 8 decreased the expression level of EGFR and KRAS genes. While compounds 7 and 9 down-regulated TP53 and FASN in HCT116 cells. Molecular docking was done against Escherichia coli enoyl reductase and human Son of sevenless homolog 1 (SOS1) and the results showed the promising inhibition of the studied proteins.
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Affiliation(s)
- Farid M Sroor
- Organometallic and Organometalloid Chemistry Department, National Research Centre, Cairo, 12622, Egypt.
| | - Karima F Mahrous
- Cell Biology Department, National Research Centre, Dokki, 12622, Egypt
| | | | - Abdelmageed M Othman
- Microbial Chemistry Department, Biotechnology Research Institute, National Research Centre, Dokki, 12622, Egypt
| | - Nada S Ibrahim
- Department of Chemistry (Biochemistry Branch), Faculty of Science, Cairo University, Giza, Egypt
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12
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Bordeaux ZA, Reddy SV, Lee K, Lu W, Choi J, Miller M, Roberts C, Pollizzi A, Kwatra SG, Kwatra MM. Differential Response of Mycosis Fungoides Cells to Vorinostat. Int J Mol Sci 2023; 24:ijms24098075. [PMID: 37175780 PMCID: PMC10179468 DOI: 10.3390/ijms24098075] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 04/23/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023] Open
Abstract
Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL) and is characterized by epidermotrophism of malignant CD4+ T-lymphocytes. When MF advances to a recurrent stage, patients require treatment with systemic therapies such as vorinostat, a histone deacetylase inhibitor. While vorinostat has been shown to exhibit anti-tumor activity in MF, its exact molecular mechanism has yet to be fully discerned. In the present study, we examined the transcriptomic and proteomic profiles of vorinostat treatment in two MF cell lines, Myla 2059 and HH. We find that vorinostat downregulates CTLA-4, CXCR4, and CCR7 in both cell lines, but its effect on several key pathways differs between the two MF cell lines. For example, vorinostat upregulates CCL5, CCR5, and CXCL10 expression in Myla cells but downregulates CCL5 and CXCL10 expression in HH cells. Furthermore, vorinostat upregulates IFN-γ and IL-23 signaling and downregulates IL-6, IL-7, and IL-15 signaling in Myla cells but does not affect these pathways in HH cells. Although Myla and HH represent established MF cell lines, their distinct tumor origin from separate patients demonstrates that inherent phenotypic variations within the disease persist, underscoring the importance of using a variety of MF cells in the preclinical development of MF therapeutics.
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Affiliation(s)
- Zachary A Bordeaux
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Anesthesiology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Sriya V Reddy
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Anesthesiology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Kevin Lee
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Weiying Lu
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Justin Choi
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Anesthesiology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Meghan Miller
- Department of Anesthesiology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Callie Roberts
- Department of Anesthesiology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Anthony Pollizzi
- Department of Anesthesiology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Shawn G Kwatra
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Madan M Kwatra
- Department of Anesthesiology, Duke University School of Medicine, Durham, NC 27710, USA
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA
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13
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Nengroo MA, Khan MA, Verma A, Datta D. Demystifying the CXCR4 conundrum in cancer biology: Beyond the surface signaling paradigm. Biochim Biophys Acta Rev Cancer 2022; 1877:188790. [PMID: 36058380 DOI: 10.1016/j.bbcan.2022.188790] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 08/25/2022] [Accepted: 08/26/2022] [Indexed: 10/14/2022]
Abstract
The oncogenic chemokine duo CXCR4-CXCL12/SDF-1 (C-X-C Receptor 4-C-X-C Ligand 12/ Stromal-derived factor 1) has been the topic of intense scientific disquisitions since Muller et al., in her ground-breaking research, described this axis as a critical determinant of organ-specific metastasis in breast cancer. Elevated CXCR4 levels correlate with distant metastases, poor prognosis, and unfavourable outcomes in most solid tumors. Therapeutic impediment of the axis in clinics with Food and Drug Administration (FDA) approved inhibitors like AMD3100 or Plerixafor yield dubious results, contrary to pre-clinical developments. Clinical trials entailing inhibition of CXCR7 (C-X-C Receptor 7), another convicted chemokine receptor that exhibits affinity for CXCL12, reveal outcomes analogous to that of CXCR4-CXCL12 axis blockade. Of note, the cellular CXCR4 knockout phenotype varies largely from that of inhibitor treatments. These shaky findings pique great curiosity to delve further into the realm of this infamous chemokine receptor to provide a probable explanation. A multitude of recent reports suggests the presence of an increased intracellular CXCR4 pool in various cancers, both cytoplasmic and nuclear. This intracellular CXCR4 protein reserve seems active as it correlates with vital tumor attributes, viz. prognosis, aggressiveness, metastasis, and disease-free survival. Diminishing this entire intracellular CXCR4 load apart from the surface signals looks encouraging from a therapeutic point of view. Transcending beyond the classically accepted concept of ligand-mediated surface signaling, this review sheds new light on plausible associations of intracellularly compartmentalised CXCR4 with various aspects of tumorigenesis. Besides, this review also puts forward a comprehensive account of CXCR4 regulation in different cancers.
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Affiliation(s)
- Mushtaq Ahmad Nengroo
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow-226031, India
| | - Muqtada Ali Khan
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow-226031, India
| | - Ayushi Verma
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow-226031, India
| | - Dipak Datta
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow-226031, India; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh 201002, India.
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Oncogenic Kras-Mediated Cytokine CCL15 Regulates Pancreatic Cancer Cell Migration and Invasion through ROS. Cancers (Basel) 2022; 14:cancers14092153. [PMID: 35565279 PMCID: PMC9104113 DOI: 10.3390/cancers14092153] [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: 03/25/2022] [Revised: 04/19/2022] [Accepted: 04/21/2022] [Indexed: 11/30/2022] Open
Abstract
Simple Summary Oncogenic KrasG12D and tumor inflammation are critical components of the development and dissemination of pancreatic ductal adenocarcinoma (PDAC). The aim of this study is to investigate a lesser-known cytokine, CCL15, that functions as a new downstream target of KrasG12D with the purpose of regulating PDAC cell migration and invasion. We showed increased levels of CCL15 as well as the presence of its receptors, including CCR1 and CCR3, in PDAC tissues and cell lines. The knockdown of CCL15 diminished metastatic Panc-1 cell migration, whereas the treatment of CCL15 in non-metastatic BxPC-3 cells promoted BxPC-3 cell motility. Similar results were verified using murine metastatic PDAC KP-2 cells. Furthermore, we demonstrated that CCL15-modulated PDAC cell migration through the upregulation of cellular reactive oxygen species (ROS) levels and the knockdown of KrasG12D resulted in a decrease in CCL15. Altogether, our data unveiled a new mechanism of oncogenic KrasG12D in modulating PDAC inflammation and spreading. Abstract Pancreatic ductal adenocarcinoma (PDAC) is well known for its high death rate due to prompt cancer metastasis caused by cancer cell migration and invasion within the early stages of its development. Here, we reveal a new function of cytokine CCL15, namely the upregulation of PDAC cell migration and invasion. We showed increased levels of CCL15 transcripts and protein expressions in human PDAC tissue samples, as well as in cultured cell lines. Furthermore, PDAC cells also expressed CCL15 receptors, including CCR1 and CCR3. Murine PDAC cell lines and tissues strengthened this finding. The manipulation of CCL15 in metastatic Panc-1 cells through CCL15 knockdown or CCL15 neutralization decreased Panc-1 cell motility and invasiveness. In addition, treating non-metastatic BxPC-3 cells with recombinant CCL15 accelerated the cell migration of BxPC-3. A reduction in the levels of reactive oxygen species (ROS) by either N-Acetyl-L-Cysteine treatment or p22phox knockdown led to a decrease in Panc-1 cell migration and a reversed effect on recombinant CCL15-promoted BxPC-3 cell movement. Importantly, the knockdown of oncogenic Kras in Panc-1 cells abolished CCL15 protein expression and impeded cell migration without affecting PDAC cell growth. Altogether, our work elucidates an additional molecular pathway of oncogenic Kras to promote PDAC metastasis through the upregulation of cell migration and invasion by the Kras downstream CCL15, a lesser-known cytokine within the cancer research field.
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15
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Kato T, Matsuo Y, Ueda G, Murase H, Aoyama Y, Omi K, Hayashi Y, Imafuji H, Saito K, Morimoto M, Ogawa R, Takahashi H, Takiguchi S. Enhanced CXCL12/CXCR4 signaling increases tumor progression in radiation‑resistant pancreatic cancer. Oncol Rep 2022; 47:68. [PMID: 35119076 PMCID: PMC8848476 DOI: 10.3892/or.2022.8279] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 01/20/2022] [Indexed: 11/17/2022] Open
Abstract
Pancreatic cancer (PaCa) exhibits one of the poorest prognoses among all gastrointestinal cancers due to the rapid development of treatment resistance, which renders chemotherapy and radiotherapy no longer effective. However, the mechanisms through which PaCa becomes resistant to radiotherapy are unknown. Here, we established radiation‑resistant PaCa cell lines to investigate the factors involved in radiation resistance. The role of the C‑X‑C motif chemokine ligand 12 (CXCL12)/C‑X‑C chemokine receptor type 4 (CXCR4) axis in radiation resistance in PaCa and the effects of a CXCR4 antagonist on radiation‑resistant PaCa cell lines were investigated. As confirmed by immunofluorescence staining, reverse transcription quantitative polymerase chain reaction, and western blotting, the expression of CXCR4 was higher in radiation‑resistant PaCa cell lines than that noted in normal PaCa cell lines. The invasion ability of radiation‑resistant PaCa cell lines was greater than that of normal cell lines and was enhanced by CXCL12 treatment and coculture with fibroblasts; this enhanced invasion ability was suppressed by the CXCR4 antagonist AMD070. Irradiation after treatment with the CXCR4 antagonist suppressed the colonization of radiation‑resistant PaCa cell lines. In conclusion, the CXCL12/CXCR4 axis may be involved in the radiation resistance of PaCa. These findings may facilitate the development of novel treatments for PaCa.
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Affiliation(s)
- Tomokatsu Kato
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Yoichi Matsuo
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Goro Ueda
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Hiromichi Murase
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Yoshinaga Aoyama
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Kan Omi
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Yuichi Hayashi
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Hiroyuki Imafuji
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Kenta Saito
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Mamoru Morimoto
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Ryo Ogawa
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Hiroki Takahashi
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Shuji Takiguchi
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
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16
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Falasca V, Falasca M. Targeting the Endocannabinoidome in Pancreatic Cancer. Biomolecules 2022; 12:320. [PMID: 35204820 PMCID: PMC8869154 DOI: 10.3390/biom12020320] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/08/2022] [Accepted: 02/08/2022] [Indexed: 02/07/2023] Open
Abstract
Pancreatic Ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is an aggressive and lethal form of cancer with a very high mortality rate. High heterogeneity, asymptomatic initial stages and a lack of specific diagnostic markers result in an end-stage diagnosis when the tumour has locally advanced or metastasised. PDAC is resistant to most of the available chemotherapy and radiation therapy treatments, making surgery the most potent curative treatment. The desmoplastic tumour microenvironment contributes to determining PDAC pathophysiology, immune response and therapeutic efficacy. The existing therapeutic approaches such as FDA-approved chemotherapeutics, gemcitabine, abraxane and folfirinox, prolong survival marginally and are accompanied by adverse effects. Several studies suggest the role of cannabinoids as anti-cancer agents. Cannabinoid receptors are known to be expressed in pancreatic cells, with a higher expression reported in pancreatic cancer patients. Therefore, pharmacological targeting of the endocannabinoid system might offer therapeutic benefits in pancreatic cancer. In addition, emerging data suggest that cannabinoids in combination with chemotherapy can increase survival in transgenic pancreatic cancer murine models. This review provides an overview of the regulation of the expanded endocannabinoid system, or endocannabinoidome, in PDAC and will explore the potential of targeting this system for novel anticancer approaches.
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Affiliation(s)
- Valerio Falasca
- School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia;
| | - Marco Falasca
- Metabolic Signalling Group, Curtin Health Innovation Research Institute, Curtin Medical School, Curtin University, Perth, WA 6102, Australia
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17
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Urbanova M, Buocikova V, Trnkova L, Strapcova S, Kajabova VH, Melian EB, Novisedlakova M, Tomas M, Dubovan P, Earl J, Bizik J, Svastova E, Ciernikova S, Smolkova B. DNA Methylation Mediates EMT Gene Expression in Human Pancreatic Ductal Adenocarcinoma Cell Lines. Int J Mol Sci 2022; 23:2117. [PMID: 35216235 PMCID: PMC8879087 DOI: 10.3390/ijms23042117] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 01/31/2022] [Accepted: 02/10/2022] [Indexed: 12/14/2022] Open
Abstract
Due to abundant stroma and extracellular matrix, accompanied by lack of vascularization, pancreatic ductal adenocarcinoma (PDAC) is characterized by severe hypoxia. Epigenetic regulation is likely one of the mechanisms driving hypoxia-induced epithelial-to-mesenchymal transition (EMT), responsible for PDAC aggressiveness and dismal prognosis. To verify the role of DNA methylation in this process, we assessed gene expression and DNA methylation changes in four PDAC cell lines. BxPC-3, MIA PaCa-2, PANC-1, and SU.86.86 cells were exposed to conditioned media containing cytokines and inflammatory molecules in normoxic and hypoxic (1% O2) conditions for 2 and 6 days. Cancer Inflammation and Immunity Crosstalk and Human Epithelial to Mesenchymal Transition RT² Profiler PCR Arrays were used to identify top deregulated inflammatory and EMT-related genes. Their mRNA expression and DNA methylation were quantified by qRT-PCR and pyrosequencing. BxPC-3 and SU.86.86 cell lines were the most sensitive to hypoxia and inflammation. Although the methylation of gene promoters correlated with gene expression negatively, it was not significantly influenced by experimental conditions. However, DNA methyltransferase inhibitor decitabine efficiently decreased DNA methylation up to 53% and reactivated all silenced genes. These results confirm the role of DNA methylation in EMT-related gene regulation and uncover possible new targets involved in PDAC progression.
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Affiliation(s)
- Maria Urbanova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (M.U.); (V.B.); (L.T.); (V.H.K.); (M.T.); (P.D.); (J.B.); (S.C.)
| | - Verona Buocikova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (M.U.); (V.B.); (L.T.); (V.H.K.); (M.T.); (P.D.); (J.B.); (S.C.)
| | - Lenka Trnkova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (M.U.); (V.B.); (L.T.); (V.H.K.); (M.T.); (P.D.); (J.B.); (S.C.)
| | - Sabina Strapcova
- Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (S.S.); (E.S.)
| | - Viera Horvathova Kajabova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (M.U.); (V.B.); (L.T.); (V.H.K.); (M.T.); (P.D.); (J.B.); (S.C.)
| | - Emma Barreto Melian
- Molecular Epidemiology and Predictive Tumor Markers Group, Ramón y Cajal Health Research Institute (IRYCIS), Biomedical Research Network in Cancer (CIBERONC), Carretera Colmenar Km 9,100, 28034 Madrid, Spain; (E.B.M.); (J.E.)
| | - Maria Novisedlakova
- Oncology Outpatient Clinic, Hospital of the Hospitaller Order of Saint John of God, 814 65 Bratislava, Slovakia;
| | - Miroslav Tomas
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (M.U.); (V.B.); (L.T.); (V.H.K.); (M.T.); (P.D.); (J.B.); (S.C.)
- Department of Surgical Oncology, National Cancer Institute, Slovak Medical University, Klenova 1, 833 10 Bratislava, Slovakia
| | - Peter Dubovan
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (M.U.); (V.B.); (L.T.); (V.H.K.); (M.T.); (P.D.); (J.B.); (S.C.)
- Department of Surgical Oncology, National Cancer Institute, Slovak Medical University, Klenova 1, 833 10 Bratislava, Slovakia
| | - Julie Earl
- Molecular Epidemiology and Predictive Tumor Markers Group, Ramón y Cajal Health Research Institute (IRYCIS), Biomedical Research Network in Cancer (CIBERONC), Carretera Colmenar Km 9,100, 28034 Madrid, Spain; (E.B.M.); (J.E.)
| | - Jozef Bizik
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (M.U.); (V.B.); (L.T.); (V.H.K.); (M.T.); (P.D.); (J.B.); (S.C.)
| | - Eliska Svastova
- Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (S.S.); (E.S.)
| | - Sona Ciernikova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (M.U.); (V.B.); (L.T.); (V.H.K.); (M.T.); (P.D.); (J.B.); (S.C.)
| | - Bozena Smolkova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (M.U.); (V.B.); (L.T.); (V.H.K.); (M.T.); (P.D.); (J.B.); (S.C.)
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Hayasaka H, Yoshida J, Kuroda Y, Nishiguchi A, Matsusaki M, Kishimoto K, Nishimura H, Okada M, Shimomura Y, Kobayashi D, Shimazu Y, Taya Y, Akashi M, Miyasaka M. CXCL12 promotes CCR7 ligand-mediated breast cancer cell invasion and migration toward lymphatic vessels. Cancer Sci 2022; 113:1338-1351. [PMID: 35133060 PMCID: PMC8990860 DOI: 10.1111/cas.15293] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/20/2022] [Accepted: 01/25/2022] [Indexed: 12/03/2022] Open
Abstract
Chemokines are a family of cytokines that mediate leukocyte trafficking and are involved in tumor cell migration, growth, and progression. Although there is emerging evidence that multiple chemokines are expressed in tumor tissues and that each chemokine induces receptor‐mediated signaling, their collaboration to regulate tumor invasion and lymph node metastasis has not been fully elucidated. In this study, we examined the effect of CXCL12 on the CCR7‐dependent signaling in MDA‐MB‐231 human breast cancer cells to determine the role of CXCL12 and CCR7 ligand chemokines in breast cancer metastasis to lymph nodes. CXCL12 enhanced the CCR7‐dependent in vitro chemotaxis and cell invasion into collagen gels at suboptimal concentrations of CCL21. CXCL12 promoted CCR7 homodimer formation, ligand binding, CCR7 accumulation into membrane ruffles, and cell response at lower concentrations of CCL19. Immunohistochemistry of MDA‐MB‐231–derived xenograft tumors revealed that CXCL12 is primarily located in the pericellular matrix surrounding tumor cells, whereas the CCR7 ligand, CCL21, mainly associates with LYVE‐1+ intratumoral and peritumoral lymphatic vessels. In the three‐dimensional tumor invasion model with lymph networks, CXCL12 stimulation facilitates breast cancer cell migration to CCL21‐reconstituted lymphatic networks. These results indicate that CXCL12/CXCR4 signaling promotes breast cancer cell migration and invasion toward CCR7 ligand–expressing intratumoral lymphatic vessels and supports CCR7 signaling associated with lymph node metastasis.
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Affiliation(s)
- Haruko Hayasaka
- Faculty of Science & Engineering, Department of Science, Graduate School of Science and Engineering, Kindai University
| | - Junichi Yoshida
- Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University
| | - Yasutaka Kuroda
- Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University
| | - Akihiro Nishiguchi
- Department of Applied Chemistry, Graduate School of Engineering, Osaka University
| | - Michiya Matsusaki
- Department of Applied Chemistry, Graduate School of Engineering, Osaka University
| | - Kei Kishimoto
- Faculty of Science & Engineering, Department of Science, Graduate School of Science and Engineering, Kindai University
| | - Hitoshi Nishimura
- Faculty of Science & Engineering, Department of Science, Graduate School of Science and Engineering, Kindai University
| | - Mari Okada
- Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University
| | - Yuki Shimomura
- Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University
| | - Daichi Kobayashi
- Niigata University Graduate School of Medical and Dental Sciences
| | - Yoshihito Shimazu
- Department of Life and Food Science, School of Life and Environmental Science, Azabu University
| | - Yuji Taya
- Life Dentistry at Tokyo, The Nippon Dental University
| | - Mitsuru Akashi
- Department of Applied Chemistry, Graduate School of Engineering, Osaka University
| | - Masayuki Miyasaka
- Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University.,MediCity Research Laboratory, University of Turku, Finland
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19
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Kamel MG, Sroor FM, Othman AM, Mahrous KF, Saleh FM, Hassaneen HM, Abdallah TA, Abdelhamid IA, Teleb MAM. Structure-based design of novel pyrazolyl–chalcones as anti-cancer and antimicrobial agents: synthesis and in vitro studies. MONATSHEFTE FUR CHEMIE 2022. [DOI: 10.1007/s00706-021-02886-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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20
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Helmy MT, Sroor FM, Mahrous KF, Mahmoud K, Hassaneen HM, Saleh FM, Abdelhamid IA, Mohamed Teleb MA. Anticancer activity of novel 3-(furan-2-yl)pyrazolyl and 3-(thiophen-2-yl)pyrazolyl hybrid chalcones: Synthesis and in vitro studies. Arch Pharm (Weinheim) 2021; 355:e2100381. [PMID: 34939695 DOI: 10.1002/ardp.202100381] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/26/2021] [Accepted: 11/29/2021] [Indexed: 12/18/2022]
Abstract
Twelve novel chalcone derivatives were prepared using the Claisen-Schmidt condensation reaction. The reaction of 4-acetyl-5-furan/thiophene-pyrazole derivatives 5 with the corresponding aldehydes 6 afforded the targeted chalcone derivatives 7a-l in good yields. The newly synthesized chalcones were fully characterized by spectrometric and elemental analyses. The in vitro anticancer activities of the novel compounds 7a-l were evaluated against four human cancer cell lines: HepG2 (human hepatocellular carcinoma), MCF7 (human Caucasian breast adenocarcinoma), A549 (lung carcinoma), and BJ1 (normal skin fibroblasts). Compound 7g emerged as the most promising compound, with IC50 = 27.7 µg/ml against A549 cells compared to the reference drug doxorubicin (IC50 = 28.3 µg/ml), and IC50 = 26.6 µg/ml against HepG2 cells compared to the reference drug doxorubicin (IC50 = 21.6 µg/ml). The gene expression and DNA damage values and the DNA fragmentation percentages for compound 7g were determined on the lung and liver cell lines. The expression levels of the AMY2A and FOXG1 genes increased significantly (p < 0.01) in the negative samples of lung cancer cells compared with treated cells. Also, the expression values of the PKM and PSPH genes improved significantly (p < 0.01) in the negative samples compared with treated samples of liver cancer cells. The DNA damage values increased significantly (p < 0.01) in treated lung cell line samples (7g) and the positive control. The results showed a significant decrease (p < 0.05) in DNA damage values in the negative samples of liver cancer cells compared to those treated with 7g. However, the DNA fragmentation values increased significantly (p < 0.01) in the treated lung and liver cell line samples compared with the negative control.
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Affiliation(s)
- Mirna T Helmy
- Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
| | - Farid M Sroor
- Organometallic and Organometalloid Chemistry Department, National Research Centre, Cairo, Egypt.,Institut für Anorganische Chemie, Universität Göttingen, Göttingen, Germany
| | | | - Khaled Mahmoud
- Pharmacognosy Department, National Research Centre, Dokki, Egypt
| | - Hamdi M Hassaneen
- Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
| | - Fatma M Saleh
- Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
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21
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Tang S, Hang Y, Ding L, Tang W, Yu A, Zhang C, Sil D, Xie Y, Oupický D. Intraperitoneal siRNA Nanoparticles for Augmentation of Gemcitabine Efficacy in the Treatment of Pancreatic Cancer. Mol Pharm 2021; 18:4448-4458. [PMID: 34699242 PMCID: PMC9153288 DOI: 10.1021/acs.molpharmaceut.1c00653] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Pancreatic ductal adenocarcinoma is a deadly disease with limited treatment options due to late diagnosis and resistance to conventional chemotherapy. Among emerging therapeutic targets, the CXCR4 chemokine receptor and polo-like kinase 1 (PLK1) play critical roles in the progression, metastasis, and chemoresistance of pancreatic cancer. Here, we tested the hypothesis that combining CXCR4 inhibition by a polymeric CXCR4 antagonist PAMD-CHOL with PLK1 knockdown by siRNA will enhance the therapeutic effect of gemcitabine (GEM) in the orthotopic model of metastatic pancreatic cancer. We formulated nanoparticles with cholesterol-modified PAMD and siPLK1 and found strong synergism when combined with GEM treatment in vitro in both murine and human pancreatic cancer cell lines. The biodistribution of the nanoparticles in orthotopic pancreatic cancer models revealed strong accumulation in primary and metastatic tumors, with limited hepatic disposition. The cholesterol-containing nanoparticles showed not only increased tumor accumulation than the cholesterol-lacking control but also deeper penetration into the tumors. In a therapeutic study in vivo, the triple combination of PAMD-CHOL/siPLK1 and GEM showed superior anticancer activity when compared with single and dual combination controls. In conclusion, PAMD-CHOL/siPLK1 nanoparticles synergistically enhance anticancer activity of GEM in pancreatic cancer and represent a promising addition to the treatment arsenal.
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Affiliation(s)
- Siyuan Tang
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Yu Hang
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Ling Ding
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Weimin Tang
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Ao Yu
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Chuhan Zhang
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Diptesh Sil
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Ying Xie
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - David Oupický
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA
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Ji R, Ji Y, Ma L, Ge S, Chen J, Wu S, Huang T, Sheng Y, Wang L, Yi N, Liu Z. Keratin 17 upregulation promotes cell metastasis and angiogenesis in colon adenocarcinoma. Bioengineered 2021; 12:12598-12611. [PMID: 34935584 PMCID: PMC8809968 DOI: 10.1080/21655979.2021.2010393] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 11/16/2021] [Accepted: 11/17/2021] [Indexed: 01/05/2023] Open
Abstract
Colon adenocarcinoma (COAD), having high malignancy and poor prognosis, is the main pathological type of colon cancer. Previous studies show that Keratin 17 (KRT17) plays an important role in the development of many malignant tumors. However, its role and the molecular mechanism underlying COAD remain unclear. Using TCGA and ONCOMINE databases, as well as immunohistochemistry, we found that the expression of KRT17 was higher in COAD tissues as compared to that in the adjacent normal tissues. Cell- and animal-based experiments showed that overexpression of KRT17 promoted the invasion and metastasis of colon cancer cells while knocking down KRT17 reversed these processes both in vitro and in vivo. In addition, we also showed that KRT17 promoted the formation of new blood vessels. Mechanistically, KRT17 could regulate the WNT/β-catenin signaling pathway, and APC may be involved in this process by interacting with KRT17. In summary, these findings suggested that high expression of KRT17 could promote cell metastasis and angiogenesis of colon cancer cells by regulating the WNT/β-catenin signaling pathway. Thus, KRT17 could be a potential therapeutic target for COAD treatment.
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Affiliation(s)
- Ran Ji
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Yifei Ji
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
| | - Lin Ma
- Department of Gastroenterology, Affiliated Haian Hospital of Nantong University, Nantong, China
| | - Sijia Ge
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Jing Chen
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Shuzhen Wu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Tianxin Huang
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Yu Sheng
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Liyang Wang
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Nan Yi
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
| | - Zhaoxiu Liu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
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Braga M, Leow CH, Gil JH, Teh JH, Carroll L, Long NJ, Tang MX, Aboagye EO. Investigating CXCR4 expression of tumor cells and the vascular compartment: A multimodal approach. PLoS One 2021; 16:e0260186. [PMID: 34793563 PMCID: PMC8601444 DOI: 10.1371/journal.pone.0260186] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 11/03/2021] [Indexed: 11/19/2022] Open
Abstract
The C-X-C chemokine receptor 4 (CXCR4) is G protein-coupled receptor that upon binding to its cognate ligand, can lead to tumor progression. Several CXCR4-targeted therapies are currently under investigation, and with it comes the need for imaging agents capable of accurate depiction of CXCR4 for therapeutic stratification and monitoring. PET agents enjoy the most success, but more cost-effective and radiation-free approaches such as ultrasound (US) imaging could represent an attractive alternative. In this work, we developed a targeted microbubble (MB) for imaging of vascular CXCR4 expression in cancer. A CXCR4-targeted MB was developed through incorporation of the T140 peptide into the MB shell. Binding properties of the T140-MB and control, non-targeted MB (NT-MB) were evaluated in MDA-MB-231 cells where CXCR4 expression was knocked-down (via shRNA) through optical imaging, and in the lymphoma tumor models U2932 and SuDHL8 (high and low CXCR4 expression, respectively) by US imaging. PET imaging of [18F]MCFB, a tumor-penetrating CXCR4-targeted small molecule, was used to provide whole-tumor CXCR4 readouts. CXCR4 expression and microvessel density were performed by immunohistochemistry analysis and western blot. T140-MB were formed with similar properties to NT-MB and accumulated sensitively and specifically in cells according to their CXCR4 expression. In NOD SCID mice, T140-MB persisted longer in tumors than NT-MB, indicative of target interaction, but showed no difference between U2932 and SuDHL8. In contrast, PET imaging with [18F]MCFB showed a marked difference in tumor uptake at 40-60 min post-injection between the two tumor models (p<0.05). Ex vivo analysis revealed that the large differences in CXCR4 expression between the two models are not reflected in the vascular compartment, where the MB are restricted; in fact, microvessel density and CXCR4 expression in the vasculature was comparable between U2932 and SuDHL8 tumors. In conclusion, we successfully developed a T140-MB that can be used for imaging CXCR4 expression in the tumor vasculature.
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Affiliation(s)
- Marta Braga
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Chee Hau Leow
- Department of Bioengineering, Faculty of Engineering, Imperial College London, London, United Kingdom
| | - Javier Hernandez Gil
- Department of Chemistry, Faculty of Natural Sciences, Imperial College London, London, United Kingdom
| | - Jin H. Teh
- Department of Chemistry, Faculty of Natural Sciences, Imperial College London, London, United Kingdom
| | - Laurence Carroll
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Nicholas J. Long
- Department of Chemistry, Faculty of Natural Sciences, Imperial College London, London, United Kingdom
| | - Meng-Xing Tang
- Department of Bioengineering, Faculty of Engineering, Imperial College London, London, United Kingdom
| | - Eric O. Aboagye
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom
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CXCR4 intracellular protein promotes drug resistance and tumorigenic potential by inversely regulating the expression of Death Receptor 5. Cell Death Dis 2021; 12:464. [PMID: 33966046 PMCID: PMC8106681 DOI: 10.1038/s41419-021-03730-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 04/06/2021] [Accepted: 04/12/2021] [Indexed: 12/24/2022]
Abstract
Chemokine receptor CXCR4 overexpression in solid tumors has been strongly associated with poor prognosis and adverse clinical outcome. However, blockade of CXCL12-CXCR4 signaling axis by inhibitors like Nox-A12, FDA approved CXCR4 inhibitor drug AMD3100 have shown limited clinical success in cancer treatment. Therefore, exclusive contribution of CXCR4-CXCL12 signaling in pro-tumorigenic function is questionable. In our pursuit to understand the impact of chemokine signaling in carcinogenesis, we reveal that instead of CXCR4-CXCL12 signaling, presence of CXCR4 intracellular protein augments paclitaxel resistance and pro-tumorigenic functions. In search of pro-apoptotic mechanisms for CXCR4 mediated drug resistance; we discover that DR5 is a new selective target of CXCR4 in breast and colon cancer. Further, we detect that CXCR4 directs the differential recruitment of transcription factors p53 and YY1 to the promoter of DR5 in course of its transcriptional repression. Remarkably, inhibiting CXCR4-ligand-mediated signals completely fails to block the above phenotype. Overexpression of different mutant versions of CXCR4 lacking signal transduction capabilities also result in marked downregulation of DR5 expression in colon cancer indeed confirms the reverse relationship between DR5 and intracellular CXCR4 protein expression. Irrespective of CXCR4 surface expression, by utilizing stable gain and loss of function approaches, we observe that intracellular CXCR4 protein selectively resists and sensitizes colon cancer cells against paclitaxel therapy in vitro and in vivo. Finally, performing TCGA data mining and using human breast cancer patient samples, we demonstrate that expression of CXCR4 and DR5 are inversely regulated. Together, our data suggest that targeting CXCR4 intracellular protein may be critical to dampen the pro-tumorigenic functions of CXCR4.
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25
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Chang CY, Lin CC. Hydrogel Models with Stiffness Gradients for Interrogating Pancreatic Cancer Cell Fate. Bioengineering (Basel) 2021; 8:37. [PMID: 33805737 PMCID: PMC8002168 DOI: 10.3390/bioengineering8030037] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/24/2021] [Accepted: 03/09/2021] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and has seen only modest improvements in patient survival rate over the past few decades. PDAC is highly aggressive and resistant to chemotherapy, owing to the presence of a dense and hypovascularized fibrotic tissue, which is composed of stromal cells and extracellular matrices. Increase deposition and crosslinking of matrices by stromal cells lead to a heterogeneous microenvironment that aids in PDAC development. In the past decade, various hydrogel-based, in vitro tumor models have been developed to mimic and recapitulate aspects of the tumor microenvironment in PDAC. Advances in hydrogel chemistry and engineering should provide a venue for discovering new insights regarding how matrix properties govern PDAC cell growth, migration, invasion, and drug resistance. These engineered hydrogels are ideal for understanding how variation in matrix properties contributes to the progressiveness of cancer cells, including durotaxis, the directional migration of cells in response to a stiffness gradient. This review surveys the various hydrogel-based, in vitro tumor models and the methods to generate gradient stiffness for studying migration and other cancer cell fate processes in PDAC.
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Affiliation(s)
- Chun-Yi Chang
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA;
| | - Chien-Chi Lin
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA;
- Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA
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26
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Tsubaki M, Genno S, Takeda T, Matsuda T, Kimura N, Yamashita Y, Morii Y, Shimomura K, Nishida S. Rhosin Suppressed Tumor Cell Metastasis through Inhibition of Rho/YAP Pathway and Expression of RHAMM and CXCR4 in Melanoma and Breast Cancer Cells. Biomedicines 2021; 9:biomedicines9010035. [PMID: 33406809 PMCID: PMC7824767 DOI: 10.3390/biomedicines9010035] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 12/29/2020] [Indexed: 11/24/2022] Open
Abstract
The high mortality rate of cancer is strongly correlated with the development of distant metastases at secondary sites. Although Rho GTPases, such as RhoA, RhoB, RhoC, and RhoE, promote tumor metastasis, the main roles of Rho GTPases remain unidentified. It is also unclear whether rhosin, a Rho inhibitor, acts by suppressing metastasis by a downstream inhibition of Rho. In this study, we investigated this mechanism of metastasis in highly metastatic melanoma and breast cancer cells, and the mechanism of inhibition of metastasis by rhosin. We found that rhosin suppressed the RhoA and RhoC activation, the nuclear localization of YAP, but did not affect ERK1/2, Akt, or NF-κB activation in the highly metastatic cell lines B16BL6 and 4T1. High expression of YAP was associated with poor overall and recurrence-free survival in patients with breast cancer or melanoma. Treatment with rhosin inhibited lung metastasis in vivo. Moreover, rhosin inhibited tumor cell adhesion to the extracellular matrix via suppression of RHAMM expression, and inhibited SDF-1-induced cell migration and invasion by decreasing CXCR4 expression in B16BL6 and 4T1 cells. These results suggest that the inhibition of RhoA/C-YAP pathway by rhosin could be an extremely useful therapeutic approach in patients with melanoma and breast cancer.
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Affiliation(s)
- Masanobu Tsubaki
- Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Kowakae, Higashi-Osaka 577-8502, Japan; (M.T.); (S.G.); (T.T.); (T.M.); (N.K.); (Y.Y.); (Y.M.)
| | - Shuuji Genno
- Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Kowakae, Higashi-Osaka 577-8502, Japan; (M.T.); (S.G.); (T.T.); (T.M.); (N.K.); (Y.Y.); (Y.M.)
| | - Tomoya Takeda
- Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Kowakae, Higashi-Osaka 577-8502, Japan; (M.T.); (S.G.); (T.T.); (T.M.); (N.K.); (Y.Y.); (Y.M.)
| | - Takuya Matsuda
- Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Kowakae, Higashi-Osaka 577-8502, Japan; (M.T.); (S.G.); (T.T.); (T.M.); (N.K.); (Y.Y.); (Y.M.)
| | - Naoto Kimura
- Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Kowakae, Higashi-Osaka 577-8502, Japan; (M.T.); (S.G.); (T.T.); (T.M.); (N.K.); (Y.Y.); (Y.M.)
| | - Yuuma Yamashita
- Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Kowakae, Higashi-Osaka 577-8502, Japan; (M.T.); (S.G.); (T.T.); (T.M.); (N.K.); (Y.Y.); (Y.M.)
| | - Yuusuke Morii
- Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Kowakae, Higashi-Osaka 577-8502, Japan; (M.T.); (S.G.); (T.T.); (T.M.); (N.K.); (Y.Y.); (Y.M.)
- Department of Phamacy, Municipal Ikeda Hospital, Ikeda, Osaka 563-0025, Japan;
| | - Kazunori Shimomura
- Department of Phamacy, Municipal Ikeda Hospital, Ikeda, Osaka 563-0025, Japan;
| | - Shozo Nishida
- Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Kowakae, Higashi-Osaka 577-8502, Japan; (M.T.); (S.G.); (T.T.); (T.M.); (N.K.); (Y.Y.); (Y.M.)
- Correspondence: ; Tel.: +81-6-6721-2332
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Stock C. Circulating Tumor Cells: Does Ion Transport Contribute to Intravascular Survival, Adhesion, Extravasation, and Metastatic Organotropism? Rev Physiol Biochem Pharmacol 2021; 182:139-175. [DOI: 10.1007/112_2021_68] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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28
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Litman-Zawadzka A, Łukaszewicz-Zając M, Gryko M, Kulczyńska-Przybik A, Kędra B, Mroczko B. Specific Receptors for the Chemokines CXCR2 and CXCR4 in Pancreatic Cancer. Int J Mol Sci 2020; 21:ijms21176193. [PMID: 32867211 PMCID: PMC7504436 DOI: 10.3390/ijms21176193] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 08/25/2020] [Indexed: 12/16/2022] Open
Abstract
Background: The mortality rate of pancreatic cancer (PC) is equal to its incidence and the majority of PC patients die within a few months of diagnosis. Therefore, a search for new biomarkers useful in the diagnosis and prognosis of PC is ongoing. Objectives: The aim of our study was to compare the utility of CXCR2 and CXCR4 in the diagnosis and prediction of PC with classical tumor marker (carcinoembryonic antigen, CEA) and marker of inflammation–C-reactive protein (CRP). Patients and Methods: The study comprised 64 subjects — 32 PC patients and 32 healthy volunteers. Serum concentrations of tested proteins were analysed using immunological methods. Results: Serum CXCR2 and CXCR4 concentrations, similarly to those of CEA and CRP, were significantly elevated in PC patients compared to healthy controls. Moreover, concentrations of CXCR4 were significantly correlated with CXCR2 and CRP levels, while CRP concentrations were correlated with CXCR2 and CEA levels. The diagnostic sensitivity and the predictive value for negative (PV−ve) results for CXCR4 were similar to those of CEA and higher than those of CXCR2 and CRP, while the area under the ROC curve (AUC) for CXCR4 was the highest among all tested proteins (CXCR2, CEA, CRP). Moreover, serum CXCR2 was found to be a significant predictor of PC risk. Conclusions: CXCR4 is a better candidate for a tumor marker than CXCR2 in the diagnosis of PC, while serum CXCR2 is a significant predictor of PC risk.
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Affiliation(s)
- Ala Litman-Zawadzka
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland; (A.K.-P.); (B.M.)
- Correspondence: ; Tel.: +48-85-8318785; Fax: +48-85-8318585
| | - Marta Łukaszewicz-Zając
- Department of Biochemical Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland;
| | - Mariusz Gryko
- Second Department of General Surgery, Medical University of Bialystok, 15-276 Bialystok, Poland; (M.G.); (B.K.)
| | - Agnieszka Kulczyńska-Przybik
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland; (A.K.-P.); (B.M.)
| | - Bogusław Kędra
- Second Department of General Surgery, Medical University of Bialystok, 15-276 Bialystok, Poland; (M.G.); (B.K.)
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland; (A.K.-P.); (B.M.)
- Department of Biochemical Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland;
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Wang J, Tannous BA, Poznansky MC, Chen H. CXCR4 antagonist AMD3100 (plerixafor): From an impurity to a therapeutic agent. Pharmacol Res 2020; 159:105010. [PMID: 32544428 DOI: 10.1016/j.phrs.2020.105010] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 05/22/2020] [Accepted: 06/07/2020] [Indexed: 02/07/2023]
Abstract
AMD3100 (plerixafor), a CXCR4 antagonist, has opened a variety of avenues for potential therapeutic approaches in different refractory diseases. The CXCL12/CXCR4 axis and its signaling pathways are involved in diverse disorders including HIV-1 infection, tumor development, non-Hodgkin lymphoma, multiple myeloma, WHIM Syndrome, and so on. The mechanisms of action of AMD3100 may relate to mobilizing hematopoietic stem cells, blocking infection of X4 HIV-1, increasing circulating neutrophils, lymphocytes and monocytes, reducing myeloid-derived suppressor cells, and enhancing cytotoxic T-cell infiltration in tumors. Here, we first revisit the pharmacological discovery of AMD3100. We then review monotherapy of AMD3100 and combination use of AMD3100 with other agents in various diseases. Among those, we highlight the perspective of AMD3100 as an immunomodulator to regulate immune responses particularly in the tumor microenvironment and synergize with other therapeutics. All the pre-clinical studies support the clinical testing of the monotherapy and combination therapies with AMD3100 and further development for use in humans.
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Affiliation(s)
- Jingzhe Wang
- Jiangsu Key Laboratory of Clinical Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Bakhos A Tannous
- Experimental Therapeutics and Molecular Imaging Laboratory, Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA; Harvard Medical School, Boston, MA, 02115, USA
| | - Mark C Poznansky
- Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA; Harvard Medical School, Boston, MA, 02115, USA
| | - Huabiao Chen
- Experimental Therapeutics and Molecular Imaging Laboratory, Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA; Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA; Harvard Medical School, Boston, MA, 02115, USA.
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30
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Garcia PL, Miller AL, Yoon KJ. Patient-Derived Xenograft Models of Pancreatic Cancer: Overview and Comparison with Other Types of Models. Cancers (Basel) 2020; 12:E1327. [PMID: 32456018 PMCID: PMC7281668 DOI: 10.3390/cancers12051327] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 05/11/2020] [Accepted: 05/19/2020] [Indexed: 12/19/2022] Open
Abstract
Pancreatic cancer (PC) is anticipated to be second only to lung cancer as the leading cause of cancer-related deaths in the United States by 2030. Surgery remains the only potentially curative treatment for patients with pancreatic ductal adenocarcinoma (PDAC), the most common form of PC. Multiple recent preclinical studies focus on identifying effective treatments for PDAC, but the models available for these studies often fail to reproduce the heterogeneity of this tumor type. Data generated with such models are of unknown clinical relevance. Patient-derived xenograft (PDX) models offer several advantages over human cell line-based in vitro and in vivo models and models of non-human origin. PDX models retain genetic characteristics of the human tumor specimens from which they were derived, have intact stromal components, and are more predictive of patient response than traditional models. This review briefly describes the advantages and disadvantages of 2D cultures, organoids and genetically engineered mouse (GEM) models of PDAC, and focuses on the applications, characteristics, advantages, limitations, and the future potential of PDX models for improving the management of PDAC.
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Affiliation(s)
| | | | - Karina J. Yoon
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (P.L.G.); (A.L.M.)
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Khan MA, Srivastava SK, Zubair H, Patel GK, Arora S, Khushman M, Carter JE, Gorman GS, Singh S, Singh AP. Co-targeting of CXCR4 and hedgehog pathways disrupts tumor-stromal crosstalk and improves chemotherapeutic efficacy in pancreatic cancer. J Biol Chem 2020; 295:8413-8424. [PMID: 32358063 DOI: 10.1074/jbc.ra119.011748] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 04/17/2020] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer (PC) remains a therapeutic challenge because of its intrinsic and extrinsic chemoresistance mechanisms. Here, we report that C-X-C motif chemokine receptor 4 (CXCR4) and hedgehog pathways cooperate in PC chemoresistance via bidirectional tumor-stromal crosstalk. We show that when PC cells are co-cultured with pancreatic stellate cells (PSCs) they are significantly more resistant to gemcitabine toxicity than those grown in monoculture. We also demonstrate that this co-culture-induced chemoresistance is abrogated by inhibition of the CXCR4 and hedgehog pathways. Similarly, the co-culture-induced altered expression of genes in PC cells associated with gemcitabine metabolism, antioxidant defense, and cancer stemness is also reversed upon CXCR4 and hedgehog inhibition. We have confirmed the functional impact of these genetic alterations by measuring gemcitabine metabolites, reactive oxygen species production, and sphere formation in vehicle- or gemcitabine-treated monocultures and co-cultured PC cells. Treatment of orthotopic pancreatic tumor-bearing mice with gemcitabine alone or in combination with a CXCR4 antagonist (AMD3100) or hedgehog inhibitor (GDC-0449) displays reduced tumor growth. Notably, we show that the triple combination treatment is the most effective, resulting in nearly complete suppression of tumor growth. Immunohistochemical analysis of Ki67 and cleaved caspase-3 confirm these findings from in vivo imaging and tumor measurements. Our findings provide preclinical and mechanistic evidence that a combination of gemcitabine treatment with targeted inhibition of both the CXCR4 and hedgehog pathways improves outcomes in a PC mouse model.
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Affiliation(s)
- Mohammad Aslam Khan
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama.,Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama
| | - Sanjeev Kumar Srivastava
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama.,Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama
| | - Haseeb Zubair
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama.,Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama
| | - Girijesh Kumar Patel
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama
| | - Sumit Arora
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama
| | - Moh'd Khushman
- Department of Medical Oncology, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama
| | - James Elliot Carter
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama
| | | | - Seema Singh
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama.,Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.,Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama
| | - Ajay Pratap Singh
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama .,Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.,Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama
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32
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Rizeq B, Malki MI. The Role of CCL21/CCR7 Chemokine Axis in Breast Cancer Progression. Cancers (Basel) 2020; 12:E1036. [PMID: 32340161 PMCID: PMC7226115 DOI: 10.3390/cancers12041036] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 04/01/2020] [Accepted: 04/11/2020] [Indexed: 12/14/2022] Open
Abstract
Breast cancer is a leading cause of cancer-related deaths worldwide, predominantly caused by metastasis. It is generally accepted that the pattern of breast cancer metastasis is largely determined by the interaction between the chemokine receptors on cancer cells and the chemokines expressed at the sites of metastatic disease. Chemokine receptors belong to the G-protein-coupled receptors (GPCRs) family that appear to be implicated in inflammatory diseases, tumor growth and metastasis. One of its members, C-C Chemokine receptor 7 (CCR7), binds chemokines CCL19 and CCL21, which are important for tissue homeostasis, immune surveillance and tumorigenesis. These receptors have been shown to induce the pathobiology of breast cancer due to their ability to induce cellular proliferation and migration upon the binding of the cognate chemokine receptors. The underlying signaling pathways and exact cellular interactions within this biological system are not fully understood and need further insights. Thus, in this review, we summarize the essential roles of CCR7 and its receptors in breast cancer progression. Furthermore, we discuss the mechanisms of regulation that may lead to novel opportunities for therapeutic intervention. Despite the enormous advances in our knowledge of the nature of the chemokines in breast cancer metastasis, research about the involvement of CCR7 in cancer progression is still limited. Therefore, further studies are essential to illustrate the distinct roles of CCR7 in cancer progression and validate its potential as a preventive bio-factor for human breast cancer metastasis by targeting chemokine receptor genes.
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Affiliation(s)
| | - Mohammed Imad Malki
- College of Medicine, QU Health, Qatar University, P. O. Box. 2713, Doha, Qatar;
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33
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Xie Y, Hang Y, Wang Y, Sleightholm R, Prajapati DR, Bader J, Yu A, Tang W, Jaramillo L, Li J, Singh RK, Oupický D. Stromal Modulation and Treatment of Metastatic Pancreatic Cancer with Local Intraperitoneal Triple miRNA/siRNA Nanotherapy. ACS NANO 2020; 14:255-271. [PMID: 31927946 PMCID: PMC7041410 DOI: 10.1021/acsnano.9b03978] [Citation(s) in RCA: 113] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
Nanomedicines achieve tumor-targeted delivery mainly through enhanced permeability and retention (EPR) effect following intravenous (IV) administration. Unfortunately, the EPR effect is severely compromised in pancreatic cancer due to hypovascularity and dense desmoplastic stroma. Intraperitoneal (IP) administration may be an effective EPR-independent local delivery approach to target peritoneal tumors. Besides improved delivery, effective combination delivery strategies are needed to improve pancreatic cancer therapy by targeting both cancer cells and cellular interactions within the tumor stroma. Here, we described simple cholesterol-modified polymeric CXCR4 antagonist (PCX) nanoparticles (to block cancer-stroma interactions) for codelivery of anti-miR-210 (to inactivate stroma-producing pancreatic stellate cells (PSCs)) and siKRASG12D (to kill pancreatic cancer cells). IP administration delivered the nanoparticles to an orthotopic syngeneic pancreatic tumors as a result of preferential localization to the tumors and metastases with disrupted mesothelium and effective tumor penetration. The local IP delivery resulted in nearly 15-fold higher tumor accumulation than delivery by IV injection. Through antagonism of CXCR4 and downregulation of miR-210/KRASG12D, the triple-action nanoparticles favorably modulated desmoplastic tumor microenvironment via inactivating PSCs and promoting the infiltration of cytotoxic T cells. The combined therapy displayed improved therapeutic effect when compared with individual therapies as documented by the delayed tumor growth, depletion of stroma, reduction of immunosuppression, inhibition of metastasis, and prolonged survival. Overall, we present data that a local IP delivery of a miRNA/siRNA combination holds the potential to improve pancreatic cancer therapy.
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Affiliation(s)
- Ying Xie
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
| | - Yu Hang
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
| | - Yazhe Wang
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
| | - Richard Sleightholm
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
| | - Dipakkumar R Prajapati
- Department of Pathology and Microbiology , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
| | - Johannes Bader
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
- Department of Pharmacy, Pharmaceutical Technology and Biopharmacy , Ludwig-Maximilians-Universität München , 81337 Munich , Germany
| | - Ao Yu
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
| | - Weimin Tang
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
| | - Lee Jaramillo
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
- Bohemica Pharmaceuticals, LLC , La Vista , Nebraska 68128 , United States
| | - Jing Li
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
| | - Rakesh K Singh
- Department of Pathology and Microbiology , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
| | - David Oupický
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States
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34
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Mardani A, Gheytanchi E, Mousavie SH, Madjd Jabari Z, Shooshtarizadeh T. Clinical Significance of Cancer Stem Cell Markers CD133 and CXCR4 in Osteosarcomas. Asian Pac J Cancer Prev 2020; 21:67-73. [PMID: 31983166 PMCID: PMC7294029 DOI: 10.31557/apjcp.2020.21.1.67] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Indexed: 12/16/2022] Open
Abstract
Objective: Osteosarcomas (OS) is one the most common primary bone malignancy in humans with the lungs metastasis in most cases. Metastasis and recurrence of OS is attributed to cancer stem cells (CSCs). Our study aimed to evaluate the clinical significance of CD133 and C-X-C chemokine receptor type 4 (CXCR4) as the frequently applied markers for CSCs in OS patients. Methods: In this cross-sectional, a total of 50 tissue samples from the patients with primary OS were immunohistochemically examined to detect the expression of CD133 and CXCR4. The associations of the relative expression and clinical significance of each marker were also evaluated. Results: High level expression of CD133 was detected in 26% of OS patient tissues. Of the 12 patients who showed lung metastasis, 5 cases showed high expression of CD133 with marginal trend correlation (P=0.06). No significant correlation was observed between CD133 expression and clinicopathological factors. Only 36% of cases showed CXCR4 expression which was not significantly correlated with gender, age, tumor size, necrosis, stage and metastasis (P>0.05). Clinically, patients with concomitant CD133/CXCR4 expression had significant association with lung metastasis (P=0.05). Conclusion: Our findings showed that concomitant expression of CSC markers CD133/CXCR4 might had a synergistic effect on the OS poor prognosis. These markers could be considered as potential therapeutic candidates of OS targeted therapy.
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Affiliation(s)
- Azam Mardani
- Department of Pathology, Iran University of Medical Science, Tehran, Iran
| | - Elmira Gheytanchi
- Oncopathology Research Center, Iran University of Medical Science, Tehran, Iran
| | - Seyed Hamzeh Mousavie
- Department of Surgery, Rasool-Akram Hospital, Iran University of Medical Science, Tehran, Iran
| | - Zahra Madjd Jabari
- Oncopathology Research Center, Iran University of Medical Science, Tehran, Iran
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35
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Tan HX, Gong WZ, Zhou K, Xiao ZG, Hou FT, Huang T, Zhang L, Dong HY, Zhang WL, Liu Y, Huang ZC. CXCR4/TGF-β1 mediated hepatic stellate cells differentiation into carcinoma-associated fibroblasts and promoted liver metastasis of colon cancer. Cancer Biol Ther 2019; 21:258-268. [PMID: 31825725 DOI: 10.1080/15384047.2019.1685157] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Background: Liver metastasis of colon cancer is strongly affected by the tumor microenvironment (TME), with interactions between tumor cells and cancer-associated fibroblasts (CAFs) in particular. TGF-β is well known for its ability to mediate the CAF phenotype, and CXCR4 expression is closely correlated to poor prognosis in CRC. The relationship between these two signaling pathways remains to be delineated in liver metastasis of colon cancer.Methods: Immunohistochemistry was employed to investigate CXCR4 expression in 45 human specimens of primary colorectal cancer (CRC) and liver metastasis. The functions of SDF-1 released by hepatic stellate cells (HSCs) on CXCR4 and TGF-β1 in CRC cells were investigated in vitro. The effects of CRC on HSCs differentiation into CAFs were confirmed using co-culture technology and expression analysis of CAFs markers by qPCR, western blot and immunofluorescence. The involvement of CXCR4 and TGF-β1 was verified with addition of CXCR4 inhibitor AMD3100 and TGF-β1 inhibitor cyclophosphamide (Cy) both in vitro and in vivo.Results: There were more CXCR4-positive cells at the liver metastatic tissues compared to the primary sites. CRC cells activated and transformed HSCs to CAFs after co-cultivating with HSCs. Activated HSCs stimulated TGF-β1 secretion from CRC cells after co-culture with CRC cells in vitro. Moreover, the expression of CAFs markers was increasing in the activated HSCs. In a mouse hepatic metastasis model, treated with AMD3100 or Cy blocked the metastatic potential of HCT116 cells and the hepatic CAFs differentiation.Conclusions: These results indicated that CXCR4/TGF-β1 axis plays an important role in CRC liver metastasis through mediating HSCs differentiation into CAFs, providing preclinical evidences that blockade of the axis might be beneficial for anti-metastasis therapy in CRC.
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Affiliation(s)
- Hao-Xiang Tan
- Department of General Surgery, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, P.R.China.,Department of General Surgery, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, P.R.China
| | - Wei-Zhi Gong
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, P.R.China
| | - Kai Zhou
- Department of Emergency, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, P.R.China
| | - Zhi-Gang Xiao
- Department of General Surgery, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, P.R.China
| | - Fu-Tao Hou
- Department of General Surgery, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, P.R.China
| | - Tao Huang
- Department of General Surgery, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, P.R.China
| | - Ling Zhang
- Department of General Surgery, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, P.R.China
| | - Hong-Yu Dong
- Department of General Surgery, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, P.R.China
| | - Wei-Lin Zhang
- Department of General Surgery, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, P.R.China
| | - Yu Liu
- Department of General Surgery, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, P.R.China
| | - Zhong-Cheng Huang
- Department of General Surgery, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, P.R.China
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36
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Clinicopathological significance and prognostic role of chemokine receptor CXCR4 expression in pancreatic ductal adenocarcinoma, a meta-analysis and literature review. Int J Surg 2019; 65:32-38. [DOI: 10.1016/j.ijsu.2019.03.009] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 02/12/2019] [Accepted: 03/11/2019] [Indexed: 12/18/2022]
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37
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The Contributions of Prostate Cancer Stem Cells in Prostate Cancer Initiation and Metastasis. Cancers (Basel) 2019; 11:cancers11040434. [PMID: 30934773 PMCID: PMC6521153 DOI: 10.3390/cancers11040434] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 03/15/2019] [Accepted: 03/21/2019] [Indexed: 12/13/2022] Open
Abstract
Research in the last decade has clearly revealed a critical role of prostate cancer stem cells (PCSCs) in prostate cancer (PC). Prostate stem cells (PSCs) reside in both basal and luminal layers, and are the target cells of oncogenic transformation, suggesting a role of PCSCs in PC initiation. Mutations in PTEN, TP53, and RB1 commonly occur in PC, particularly in metastasis and castration-resistant PC. The loss of PTEN together with Ras activation induces partial epithelial–mesenchymal transition (EMT), which is a major mechanism that confers plasticity to cancer stem cells (CSCs) and PCSCs, which contributes to metastasis. While PTEN inactivation leads to PC, it is not sufficient for metastasis, the loss of PTEN concurrently with the inactivation of both TP53 and RB1 empower lineage plasticity in PC cells, which substantially promotes PC metastasis and the conversion to PC adenocarcinoma to neuroendocrine PC (NEPC), demonstrating the essential function of TP53 and RB1 in the suppression of PCSCs. TP53 and RB1 suppress lineage plasticity through the inhibition of SOX2 expression. In this review, we will discuss the current evidence supporting a major role of PCSCs in PC initiation and metastasis, as well as the underlying mechanisms regulating PCSCs. These discussions will be developed along with the cancer stem cell (CSC) knowledge in other cancer types.
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38
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Eckert F, Schilbach K, Klumpp L, Bardoscia L, Sezgin EC, Schwab M, Zips D, Huber SM. Potential Role of CXCR4 Targeting in the Context of Radiotherapy and Immunotherapy of Cancer. Front Immunol 2018; 9:3018. [PMID: 30622535 PMCID: PMC6308162 DOI: 10.3389/fimmu.2018.03018] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 12/06/2018] [Indexed: 12/28/2022] Open
Abstract
Cancer immunotherapy has been established as standard of care in different tumor entities. After the first reports on synergistic effects with radiotherapy and the induction of abscopal effects-tumor shrinkage outside the irradiated volume attributed to immunological effects of radiotherapy-several treatment combinations have been evaluated. Different immunotherapy strategies (e.g., immune checkpoint inhibition, vaccination, cytokine based therapies) have been combined with local tumor irradiation in preclinical models. Clinical trials are ongoing in different cancer entities with a broad range of immunotherapeutics and radiation schedules. SDF-1 (CXCL12)/CXCR4 signaling has been described to play a major role in tumor biology, especially in hypoxia adaptation, metastasis and migration. Local tumor irradiation is a known inducer of SDF-1 expression and release. CXCR4 also plays a major role in immunological processes. CXCR4 antagonists have been approved for the use of hematopoietic stem cell mobilization from the bone marrow. In addition, several groups reported an influence of the SDF-1/CXCR4 axis on intratumoral immune cell subsets and anti-tumor immune response. The aim of this review is to merge the knowledge on the role of SDF-1/CXCR4 in tumor biology, radiotherapy and immunotherapy of cancer and in combinatorial approaches.
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Affiliation(s)
- Franziska Eckert
- Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany
| | - Karin Schilbach
- Department of General Pediatrics/Pediatric Oncology, University Hospital Tuebingen, Tuebingen, Germany
| | - Lukas Klumpp
- Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany.,Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany
| | - Lilia Bardoscia
- Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany.,Department of Radiation Oncology, University of Brescia, Brescia, Italy
| | - Efe Cumhur Sezgin
- Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany
| | - Matthias Schwab
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.,Departments of Clinical Pharmacology, Pharmacy and Biochemistry, University Hospital and University Tuebingen, Tuebingen, Germany
| | - Daniel Zips
- Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany
| | - Stephan M Huber
- Department of Radiation Oncology, University Hospital Tuebingen, Tuebingen, Germany
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39
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Doiron B, DeFronzo RA. A novel experimental model for human mixed acinar-ductal pancreatic cancer. Carcinogenesis 2018; 39:180-190. [PMID: 29106450 PMCID: PMC5862347 DOI: 10.1093/carcin/bgx119] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 10/27/2017] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer has remained refractory to treatment. In large part, this results from the lack of an animal model that mimics pancreatic cancer in man. We describe a novel experimental model of pancreatic cancer that shares the genetic background, histologic features and natural history of human mixed acinar–ductal carcinoma. Adult wild-type mice received an injection into the pancreatic duct of lentivirus coding two molecules, KrasG12D mutation and shRNA p53, which recapitulate the mechanisms of pancreatic cancer in humans. The lentivirus constructs also co-expressed the luciferase gene for in vivo imaging by bioluminescence using the Xenogen IVIS imaging system. Weeks post-injection wild-type mice develop pancreatic cancer with the same histologic characteristics and metastases observed with human pancreatic mixed acinar–ductal carcinoma. This novel approach represents the first pancreatic cancer model that does not involve alterations of embryonic development, which is inherent with transgenic mice or knockout mice models. This novel experimental human pancreatic cancer model can be used to more effectively test new anti-cancer drug to inhibit tumor progression in situ and to retard metastases. Furthermore, our method of injecting lentivirus containing oncogenes and molecules implicated in the development of pancreatic can be employed in diabetic and obese mice, two common metabolic conditions characterized by an increased incidence of pancreatic cancer.
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Affiliation(s)
- Bruno Doiron
- Diabetes Division, University of Texas Health Science Center at San Antonio, USA
| | - Ralph A DeFronzo
- Diabetes Division, University of Texas Health Science Center at San Antonio, USA
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40
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Bisht S, Feldmann G. Novel Targets in Pancreatic Cancer Therapy - Current Status and Ongoing Translational Efforts. Oncol Res Treat 2018; 41:596-602. [PMID: 30269126 DOI: 10.1159/000493437] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 09/03/2018] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC, pancreatic cancer) carries one of the poorest overall prognoses of all human malignancies known to date. Despite the introduction of novel therapeutic regimens, the outcome has not markedly improved over the past decades, the incidence rates are almost identical to the mortality rates, and PDAC is projected to soon become the second most common cause of cancer-related mortality in Western countries. Despite this clear medical need to develop novel therapeutic strategies against this dire malady, this need has so far not been addressed with sufficient institutional attention and support in terms of research funding and strategical programs. Given the still growing life expectancy and projected demographic changes with a growing proportion of senior citizens in many European societies, this discrepancy is likely to become even more pressing in the future. This article provides a brief overview of ongoing preclinical efforts to identify novel targets and, based on this, to develop novel strategies to treat advanced pancreatic cancer and improve survival and the quality of life of patients suffering from this malignancy.
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41
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Łukaszewicz-Zając M, Gryko M, Mroczko B. The role of selected chemokines and their specific receptors in pancreatic cancer. Int J Biol Markers 2018; 33:141-147. [PMID: 29799354 DOI: 10.1177/1724600817753094] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Pancreatic carcinoma is a highly malignant disease associated with an extremely poor prognosis, which is caused by late presentation, aggressive invasion and metastases, as well as the detection of pancreatic carcinoma in its advanced stages. Thus, better understanding of the tumour biology of this malignancy is sorely needed to improve the clinical outcome. A great challenge for the medical practice is finding a new biomarker of pancreatic carcinoma that will be helpful in diagnosis, in prognosis and in making clinical decisions, including the assessment of patients' response to therapy. It is suggested that selected chemokines and their specific receptors play an important role in tumour progression, such as tumour growth, angiogenesis, proliferation and development of metastasis. In the present review, general characteristics of chemokines and their specific receptors as well as the significance of these molecules in tumour development are described. The crucial issue of this review is to summarise the importance of various chemokines and their specific receptors in pancreatic carcinoma. Understanding the role of chemokines in the pathogenesis of pancreatic carcinoma is extremely important since these proteins may be used as a potential tool in the diagnosis and prognosis of pancreatic carcinoma patients.
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Affiliation(s)
- Marta Łukaszewicz-Zając
- 1 Department of Biochemical Diagnostics, Medical University of Bialystok, Bialystok - Poland
| | - Mariusz Gryko
- 2 Second Department of General Surgery, Medical University of Bialystok, Bialystok - Poland
| | - Barbara Mroczko
- 3 Department of Neurodegeneration Diagnostics, Medical University of Bialystok, Bialystok - Poland
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42
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Wu J, Li L, Liu J, Wang Y, Wang Z, Wang Y, Liu W, Zhou Z, Chen C, Liu R, Yang R. CC chemokine receptor 7 promotes triple-negative breast cancer growth and metastasis. Acta Biochim Biophys Sin (Shanghai) 2018; 50:835-842. [PMID: 30032244 DOI: 10.1093/abbs/gmy077] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 03/20/2018] [Indexed: 01/11/2023] Open
Abstract
Metastasis is the leading cause of breast cancer-related death. Chemokine (C-C motif) receptor 7 (CCR7) plays important roles in breast cancer metastasis. However, the role of CCR7 in triple-negative breast cancer (TNBC) has not been fully elucidated. In this study, we found that CCR7 is highly expressed in both TNBC cell lines and breast cancer tissues. CCR7 was knocked down by shRNA in 4T1 and MDA-MB-231, two TNBC cell lines, and we found that the depletion of CCR7 significantly decreased TNBC cell proliferation, migration and invasion in vitro. Furthermore, we confirmed that the knockdown of CCR7 reduced the distant metastasis of 4T1 cells in an orthotopic mouse model. Proteomic analysis in 4T1 cells indicated that several signaling pathways such as epithelial cell adhesion molecule might contribute to CCR7's function in breast cancer metastasis. Our results suggest that CCR7 promotes TNBC metastasis and may serve as a target for breast cancer diagnosis and treatment.
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Affiliation(s)
- Jiao Wu
- Second Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Lu Li
- 2014 Grade of Queen Mary College of Medicine, Nanchang University, Nanchang, China
| | - Jianing Liu
- 2014 Grade of Queen Mary College of Medicine, Nanchang University, Nanchang, China
| | - Yang Wang
- Third Department of Internal Medicine, The Fifth People's Hospital of Puyang, Puyang, China
| | - Zehua Wang
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Yangdan Wang
- Department of Oncology, The First Affiliated Hospital of Dali University, Dali, China
| | - Wenjing Liu
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Zhongmei Zhou
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Rong Liu
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Runxiang Yang
- Second Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
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43
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Houg DS, Bijlsma MF. The hepatic pre-metastatic niche in pancreatic ductal adenocarcinoma. Mol Cancer 2018; 17:95. [PMID: 29903049 PMCID: PMC6003100 DOI: 10.1186/s12943-018-0842-9] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 05/31/2018] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies to date, largely because it is associated with high metastatic risk. Pancreatic tumors have a characteristic tendency to metastasize preferentially to the liver. Over the past two decades, it has become evident that the otherwise hostile milieu of the liver is selectively preconditioned at an early stage to render it more conducive to the engraftment and growth of disseminated cancer cells, a concept defined as pre-metastatic niche (PMN) formation. Pancreatic cancer cells exploit components of the tumor microenvironment to facilitate their migration out of the primary tumor, which often involves conversion of pancreatic cancer cells from an epithelial to a mesenchymal phenotype via the epithelial-to-mesenchymal transition. Pancreatic stellate cells and matrix stiffness have been put forward as major drivers of invasiveness in PDAC. Even before the onset of pancreatic cancer cell dissemination, soluble factors and extracellular vesicles secreted by the primary tumor, and possibly even premalignant lesions, help shape a supportive niche in the liver by providing vascular docking sites for circulating tumor cells, enhancing vascular permeability, remodeling the extracellular matrix and recruiting immunosuppressive inflammatory cells. Emerging evidence suggests that some of these tumor-derived factors may represent powerful diagnostic or prognostic biomarkers. Though our understanding of the mechanisms driving PMN formation in PDAC has expanded considerably, many outstanding questions and challenges remain. Further studies dissecting the molecular and cellular events involved in hepatic PMN formation in PDAC will likely improve diagnosis and open new avenues from a therapeutic standpoint.
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Affiliation(s)
- Demi S Houg
- Laboratory for Experimental Oncology and Radiobiology, Center of Experimental and Molecular Medicine, Cancer Center Amsterdam and Academic Medical Center, Amsterdam, the Netherlands
| | - Maarten F Bijlsma
- Laboratory for Experimental Oncology and Radiobiology, Center of Experimental and Molecular Medicine, Cancer Center Amsterdam and Academic Medical Center, Amsterdam, the Netherlands. .,Oncode Institute, Academic Medical Center, Amsterdam, the Netherlands.
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44
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δ-Tocotrienol, a natural form of vitamin E, inhibits pancreatic cancer stem-like cells and prevents pancreatic cancer metastasis. Oncotarget 2018; 8:31554-31567. [PMID: 28404939 PMCID: PMC5458229 DOI: 10.18632/oncotarget.15767] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 01/27/2017] [Indexed: 01/06/2023] Open
Abstract
The growth, metastasis, and chemotherapy resistance of pancreatic ductal adenocarcinoma (PDAC) is characterized by the activation and growth of tumor-initiating cells in distant organs that have stem-like properties. Thus, inhibiting growth of these cells may prevent PDAC growth and metastases. We have demonstrated that δ-tocotrienol, a natural form of vitamin E (VEDT), is bioactive against cancer, delays progression, and prevents metastases in transgenic mouse models of PDAC. In this report, we provide the first evidence that VEDT selectively inhibits PDAC stem-like cells. VEDT inhibited the viability, survival, self-renewal, and expression of Oct4 and Sox2 transcription factors in 3 models of PDAC stem-like cells. In addition, VEDT inhibited the migration, invasion, and several biomarkers of epithelial-to-mesenchymal transition and angiogenesis in PDAC cells and tumors. These processes are critical for tumor metastases. Furthermore, in the L3.6pl orthotopic model of PDAC metastases, VEDT significantly inhibited growth and metastases of these cells. Finally, in an orthotopic xenograft model of human PDAC stem-like cells, we showed that VEDT significantly retarded the growth and metastases of gemcitabine-resistant PDAC human stem-like cells. Because VEDT has been shown to be safe and to reach bioactive levels in humans, this work supports investigating VEDT for chemoprevention of PDAC metastases.
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Johnson BA, Yarchoan M, Lee V, Laheru DA, Jaffee EM. Strategies for Increasing Pancreatic Tumor Immunogenicity. Clin Cancer Res 2018; 23:1656-1669. [PMID: 28373364 DOI: 10.1158/1078-0432.ccr-16-2318] [Citation(s) in RCA: 132] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 01/23/2017] [Accepted: 01/27/2017] [Indexed: 12/15/2022]
Abstract
Immunotherapy has changed the standard of care for multiple deadly cancers, including lung, head and neck, gastric, and some colorectal cancers. However, single-agent immunotherapy has had little effect in pancreatic ductal adenocarcinoma (PDAC). Increasing evidence suggests that the PDAC microenvironment is comprised of an intricate network of signals between immune cells, PDAC cells, and stroma, resulting in an immunosuppressive environment resistant to single-agent immunotherapies. In this review, we discuss differences between immunotherapy-sensitive cancers and PDAC, the complex interactions between PDAC stroma and suppressive tumor-infiltrating cells that facilitate PDAC development and progression, the immunologic targets within these complex networks that are druggable, and data supporting combination drug approaches that modulate multiple PDAC signals, which should lead to improved clinical outcomes. Clin Cancer Res; 23(7); 1656-69. ©2017 AACRSee all articles in this CCR Focus section, "Pancreatic Cancer: Challenge and Inspiration."
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Affiliation(s)
- Burles A Johnson
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland
| | - Mark Yarchoan
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland
| | - Valerie Lee
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland
| | - Daniel A Laheru
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland
| | - Elizabeth M Jaffee
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland. .,Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland
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46
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BK K+ channel blockade inhibits radiation-induced migration/brain infiltration of glioblastoma cells. Oncotarget 2017; 7:14259-78. [PMID: 26893360 PMCID: PMC4924713 DOI: 10.18632/oncotarget.7423] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Accepted: 01/29/2016] [Indexed: 12/14/2022] Open
Abstract
Infiltration of the brain by glioblastoma cells reportedly requires Ca2+ signals and BK K+ channels that program and drive glioblastoma cell migration, respectively. Ionizing radiation (IR) has been shown to induce expression of the chemokine SDF-1, to alter the Ca2+ signaling, and to stimulate cell migration of glioblastoma cells. Here, we quantified fractionated IR-induced migration/brain infiltration of human glioblastoma cells in vitro and in an orthotopic mouse model and analyzed the role of SDF-1/CXCR4 signaling and BK channels. To this end, the radiation-induced migratory phenotypes of human T98G and far-red fluorescent U-87MG-Katushka glioblastoma cells were characterized by mRNA and protein expression, fura-2 Ca2+ imaging, BK patch-clamp recording and transfilter migration assay. In addition, U-87MG-Katushka cells were grown to solid glioblastomas in the right hemispheres of immunocompromised mice, fractionated irradiated (6 MV photons) with 5 × 0 or 5 × 2 Gy, and SDF-1, CXCR4, and BK protein expression by the tumor as well as glioblastoma brain infiltration was analyzed in dependence on BK channel targeting by systemic paxilline application concomitant to IR. As a result, IR stimulated SDF-1 signaling and induced migration of glioblastoma cells in vitro and in vivo. Importantly, paxilline blocked IR-induced migration in vivo. Collectively, our data demonstrate that fractionated IR of glioblastoma stimulates and BK K+ channel targeting mitigates migration and brain infiltration of glioblastoma cells in vivo. This suggests that BK channel targeting might represent a novel approach to overcome radiation-induced spreading of malignant brain tumors during radiotherapy.
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47
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Inflammatory Cytokine Signaling during Development of Pancreatic and Prostate Cancers. J Immunol Res 2017; 2017:7979637. [PMID: 29379802 PMCID: PMC5742898 DOI: 10.1155/2017/7979637] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 10/31/2017] [Accepted: 11/08/2017] [Indexed: 02/07/2023] Open
Abstract
Inflammation is essential for many diseases including cancer. Activation and recruitment of immune cells during inflammation result in a cytokine- and chemokine-enriched cell environment, which affects cancer development. Since each type of cancer has its unique tumor environment, effects of cytokines from different sources such as tumor-infiltrating immune cells, stromal cells, endothelial cells, and cancer cells on cancer development can be quite complex. In this review, how immune cells contribute to tumorigenesis of pancreatic and prostate cancers through their secreted cytokines is discussed. In addition, the cytokine signaling that tumor cells of pancreatic and prostate cancers utilize to benefit their own survival is delineated.
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48
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Gao Y, Lin P, Lydon JP, Li Q. Conditional abrogation of transforming growth factor-β receptor 1 in PTEN-inactivated endometrium promotes endometrial cancer progression in mice. J Pathol 2017; 243:89-99. [PMID: 28657664 DOI: 10.1002/path.4930] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 05/10/2017] [Accepted: 05/28/2017] [Indexed: 12/16/2022]
Abstract
Although a putative role for transforming growth factor-β (TGFB) signalling in the pathogenesis of human endometrial cancer has long been proposed, the precise function of TGFB signalling in the development and progression of endometrial cancer remains elusive. Depletion of phosphatase and tensin homologue (PTEN) in the mouse uterus causes endometrial cancer. To identify the potential role of TGFB signalling in endometrial cancer, we simultaneously deleted TGFB receptor 1 (Tgfbr1) and Pten in the mouse uterus by using Cre-recombinase driven by the progesterone receptor (termed Ptend/d ;Tgfbr1d/d ). We found that Ptend/d ;Tgfbr1d/d mice developed severe endometrial lesions that progressed more rapidly than those resulting from conditional deletion of Pten alone, suggesting that TGFB signalling synergizes with PTEN to suppress endometrial cancer progression. Remarkably, Ptend/d ;Tgfbr1d/d mice developed distant pulmonary metastases, leading to a significantly reduced lifespan. The development of metastasis and accelerated tumour progression in Ptend/d ;Tgfbr1d/d mice are associated with increased production of proinflammatory chemokines, enhanced cancer cell motility, as shown by myometrial invasion and disruption, and an altered tumour microenvironment characterized by recruitment of tumour-associated macrophages. Thus, conditional deletion of Tgfbr1 in PTEN-inactivated endometrium leads to a disease that recapitulates invasive and lethal human endometrial cancer. This mouse model may be valuable for preclinical testing of new cancer therapies, particularly those targeting metastasis, one of the hallmarks of cancer and a major cause of death in endometrial cancer patients. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Yang Gao
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, TX, USA
| | - Pengfei Lin
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, TX, USA.,Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, PR China
| | - John P Lydon
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Qinglei Li
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, TX, USA
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49
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Drug-eluting scaffold inhibited in vivo pancreatic tumorigenesis by engaging murine CCR4 +CD8 + T cells. Colloids Surf B Biointerfaces 2017; 158:469-473. [PMID: 28732312 DOI: 10.1016/j.colsurfb.2017.07.021] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2017] [Revised: 07/02/2017] [Accepted: 07/07/2017] [Indexed: 01/08/2023]
Abstract
CCL17 is well known for its ability to engage CCR4+CD8+ T cells, which have been shown to play a critical role in preventing tumorigenesis. In this study, we attempted to inhibit in vivo pancreatic tumorigenesis by engaging murine CCR4+CD8+ T cells through a drug-eluting scaffold with a payload of CCL17. The drug-eluting scaffold was fabricated by electrospinning polyglyconate and porcine gelatin. The electrospun scaffold featured randomly distributed non-woven fibers with diameters ranging from 1μm to 4μm. The in vitro study confirmed that scaffolding materials were non-cytotoxic to pancreatic cancer cells. The in vivo study showed an increased presence of murine CCR4+CD8+ T cells into the tumor mass treated with drug-eluting scaffold compared to those with non-eluting scaffold or the control groups. The weights of tumor masses were 132.04mg±12.25mg in the control group, 158.12mg±18.98mg in the NES group and 96.22mg±14.56mg in the DES group, respectively. The volumes of tumor masses were 1035.21mm3±128.97mm3 in the control group, 978.56mm3±110.19mm3 in the NES group and 634.35mm3±87.12mm3 in the DES group, respectively. Further study showed that the increased presence of CCR4+CD8+ T cells also inhibited the hepatic metastasis of pancreatic cancer cells. Our study shed a new light on the post-operative treatment of pancreatic cancer to prevent the recurrence.
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50
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Sleightholm RL, Neilsen BK, Li J, Steele MM, Singh RK, Hollingsworth MA, Oupicky D. Emerging roles of the CXCL12/CXCR4 axis in pancreatic cancer progression and therapy. Pharmacol Ther 2017; 179:158-170. [PMID: 28549596 DOI: 10.1016/j.pharmthera.2017.05.012] [Citation(s) in RCA: 121] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Chemokine networks regulate a variety of cellular, physiological, and immune processes. These normal functions can become appropriated by cancer cells to facilitate a more hospitable niche for aberrant cells by enhancing growth, proliferation, and metastasis. This is especially true in pancreatic cancer, where chemokine signaling is a vital component in the development of the supportive tumor microenvironment and the signaling between the cancer cells and surrounding stromal cells. Although expression patterns vary among cancer types, the chemokine receptor CXCR4 has been implicated in nearly every major malignancy and plays a prominent role in pancreatic cancer development and progression. This receptor, in conjunction with its primary chemokine ligand CXCL12, promotes pancreatic cancer development, invasion, and metastasis through the management of the tumor microenvironment via complex crosstalk with other pathways. Thus, CXCR4 likely contributes to the poor prognoses observed in patients afflicted with this malignancy. Recent exploration of combination therapies with CXCR4 antagonists have demonstrated improved outcomes, and abolishing the contribution of this pathway may prove crucial to effectively treat pancreatic cancer at both the primary tumor and metastases.
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Affiliation(s)
- Richard L Sleightholm
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE, USA
| | - Beth K Neilsen
- Eppley Institute, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, NE, USA
| | - Jing Li
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE, USA
| | - Maria M Steele
- Eppley Institute, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, NE, USA
| | - Rakesh K Singh
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, USA
| | - Michael A Hollingsworth
- Eppley Institute, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, NE, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, USA
| | - David Oupicky
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE, USA.
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