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1
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Chen X, Zhang Z, Wang K. Lactate released by lung adenocarcinoma (LUAD) cells promotes M2 macrophage polarization via the GPR132/cAMP/PKA pathway. Genes Genomics 2025; 47:521-531. [PMID: 40053234 DOI: 10.1007/s13258-025-01622-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Accepted: 01/31/2025] [Indexed: 05/16/2025]
Abstract
BACKGROUND Increasing evidence suggests that lactate is an essential compound in the tumor microenvironment, and especially for macrophage cells. However, the mechanism by which lactate affects macrophages remains unclear. OBJECTIVE This study investigated whether and how lactate affects macrophage polarization in lung adenocarcinoma (LUAD). METHODS Clinical samples of LUAD and paracancerous tissue were obtained for evaluation of lactate dehydrogenase A (LDHA) expression. LUAD cell lines and THP-1 induced macrophages were used in this study. Quantitative real-time PCR (QPCR), western blotting, and immunohistochemical (IHC) staining were performed to detect gene expression. Flow cytometry and ELISA assays were used to detect the levels of M1 macrophage and M2 macrophage biomarkers. RESULTS LDHA was highly expressed in the LUAD tissues. Culture medium supernatants derived from LUAD cells (CM) promoted macrophage M2 polarization, and lactate levels were elevated in the CM. Inhibition of LDHA in LUAD cells decreased lactate levels and suppressed M2 macrophage polarization. Moreover, overexpression of GPR132 in macrophages promoted, while GPR132 knockdown in macrophages suppressed M2 macrophage polarization and cAMP (Cyclic Adenosine 3',5'-Monophosphate)/PKA (Protein Kinase) pathway activation induced by lactate. The effect of GPR132 overexpression was reversed by a PKA inhibitor (H-89). CONCLUSION Collectively, our results confirmed that lactate released by LUAD cells promoted M2 macrophage polarization via the GPR132/cAMP/PKA pathway.
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Affiliation(s)
- Xiao Chen
- Department of Geriatrics, The First Affiliated Hospital of Bengbu Medical University, Bengbu, China
| | - Zhongzheng Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Bengbu Medical University, 287 Chang Huai Road, Bengbu, 233000, Anhui, China
| | - Kangwu Wang
- Department of Thoracic Surgery, The First Affiliated Hospital of Bengbu Medical University, 287 Chang Huai Road, Bengbu, 233000, Anhui, China.
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2
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Deipenbrock A, Wilmes BE, Sommermann T, Abdo N, Moustakas K, Raasch M, Rennert K, Teusch NE. Modelling of the multicellular tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) on a fit-for-purpose biochip for preclinical drug discovery. LAB ON A CHIP 2025; 25:2168-2181. [PMID: 40018951 DOI: 10.1039/d4lc01016g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/01/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal form of pancreatic cancer. One major cause for a fast disease progression is the presence of a highly fibrotic tumor microenvironment (TME) mainly composed of cancer-associated fibroblasts (CAF), and various immune cells, especially tumor-associated macrophages (TAM). To conclusively evaluate drug efficacy, it is crucial to develop in vitro models that can recapitulate the cross talk between tumor cells and the surrounding stroma. Here, we constructed a fit-for-purpose biochip platform which allows the integration of PDAC spheroids (composed of PANC-1 cells and pancreatic stellate cells (PSC)). Additionally, the chip design enables dynamic administration of drugs or immune cells via a layer of human umbilical vein endothelial cells (HUVEC). As a proof-of-concept for drug administration, vorinostat, an FDA-approved histone deacetylase inhibitor for cutaneous T cell lymphoma (CTCL), subjected via continuous flow for 72 h, resulted in a significantly reduced viability of PDAC spheroids without affecting vascular integrity. Furthermore, dynamic perfusion with peripheral mononuclear blood cells (PBMC)-derived monocytes resulted in an immune cell migration through the endothelium into the spheroids. After 72 h of infiltration, monocytes differentiated into macrophages which polarized into the M2 phenotype. The polarization into M2 macrophages persisted for at least 168 h, verified by expression of the M2 marker CD163 which increased from 72 h to 168 h, while the M1 markers CD86 and HLA-DR were significantly downregulated. Overall, the described spheroid-on-chip model allows the evaluation of novel therapeutic strategies by mimicking and targeting the complex TME of PDAC.
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Affiliation(s)
- Alina Deipenbrock
- Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
| | - Ben Eric Wilmes
- Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
| | | | | | - Kyra Moustakas
- Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
| | | | | | - Nicole E Teusch
- Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
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3
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Yu L, Wu Q, Jiang S, Liu J, Liu J, Chen G. Controversial Roles of Regenerating Family Proteins in Tissue Repair and Tumor Development. Biomedicines 2024; 13:24. [PMID: 39857608 PMCID: PMC11762848 DOI: 10.3390/biomedicines13010024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 12/23/2024] [Accepted: 12/24/2024] [Indexed: 01/27/2025] Open
Abstract
Background: Over the past 40 years since the discovery of regenerating family proteins (Reg proteins), numerous studies have highlighted their biological functions in promoting cell proliferation and resisting cell apoptosis, particularly in the regeneration and repair of pancreatic islets and exocrine glands. Successively, short peptides derived from Reg3δ and Reg3α have been employed in clinical trials, showing favorable therapeutic effects in patients with type I and type II diabetes. However, continued reports have been limited, presumably attributed to the potential side effects. Methods: This review summarizes extensive research on Reg proteins over the past decade, combined with our own related studies, proposing that Reg proteins exhibit dimorphic effects. Results: The activity of Reg proteins is not as simplistic as previously perceived but shows auto-immunogenicity depending on different pathophysiological microenvironments. The immunogenicity of Reg proteins could recruit immune cells leading to an anti-tumor effect. Such functional diversity is correlated with their structural characteristics: the N-terminal region contributes to autoantigenicity, while the C-type lectin fragment near the C-terminal determines the trophic action. It should be noted that B-cell masking antigens might also reside within the C-type lectin domain. Conclusions: Reg proteins have dual functional roles under various physiological and pathological conditions. These theoretical foundations facilitate the subsequent development of diagnostic reagents and therapeutic drugs targeting Reg proteins.
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Affiliation(s)
- Luting Yu
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China; (L.Y.)
| | - Qingyun Wu
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China; (L.Y.)
| | - Shenglong Jiang
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China; (L.Y.)
| | - Jia Liu
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China; (L.Y.)
| | - Junli Liu
- MeDiC Program, The Research Institute of McGill University Health Centre, Montreal, QC H4A 3J1, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada
| | - Guoguang Chen
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China; (L.Y.)
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Tong W, Song C, Jin D, Li M, Cheng Z, Lu G, Yang B, Deng F. QSOX1 exerts anti-inflammatory effects in sepsis-induced acute lung injury: Regulation involving EGFR phosphorylation mediated M1 polarization of macrophages. Int J Biochem Cell Biol 2024; 176:106651. [PMID: 39251039 DOI: 10.1016/j.biocel.2024.106651] [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: 04/15/2024] [Revised: 08/29/2024] [Accepted: 09/04/2024] [Indexed: 09/11/2024]
Abstract
Sepsis is a systemic inflammatory response caused by an infection, which can easily lead to acute lung injury. Quiescin Q6 sulfhydryl oxidase 1 (QSOX1) is a sulfhydryl oxidase involved in oxidative stress and the inflammatory response. However, there are few reports on the role of QSOX1 in sepsis-induced acute lung injury (SALI). In this study, mice model of SALI was constructed by intraperitoneal injection with lipopolysaccharide (LPS). The increased inflammatory response and lactate dehydrogenase activity in bronchoalveolar lavage fluid (BALF) indicated successful modeling. Increased QSOX1 expression was both observed in lung tissues and lung macrophages of sepsis mice accompanied by increased polarization of M1-type macrophages. To explore the role of QSOX1 in the SALI, lentivirus containing QSOX1-specific overexpression or knockdown vectors were used to change QSOX1 expression in LPS-treated RAW264.7 cells. QSOX1 suppressed LPS-induced M1 polarization and further inhibited inflammatory response in RAW264.7 cells. Interestingly, the phosphorylation of epidermal growth factor receptor (EGFR), the promoter of M1 polarization in macrophages, was found to be downregulated upon QSOX1 overexpression in RAW264.7 cells. Mechanically, the binding of QSOX1 to EGFR protein promoted EGFR ubiquitination and degradation, thereby down-regulating EGFR phosphorylation. Moreover, inhibiting EGFR expression or its phosphorylation restored the impact of QSOX1 silencing on M1 polarization and inflammation in the LPS-treated RAW264.7 cells. In summary, QSOX1 may exert anti-inflammatory effects in SALI by inhibiting EGFR phosphorylation-mediated M1 macrophage polarization. This presented a potential target for the treatment and prevention of SALI.
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Affiliation(s)
- Wenjia Tong
- Department of Pediatric Nephrology, Children's Hospital of Anhui Medical University, Hefei, Anhui, China.; Department of Pediatric Nephrology, Anhui Provincial Children's Hospital, Hefei, Anhui, China
| | - Conglei Song
- Department of Pediatric Neurology, Children's Hospital of Anhui Medical University, Hefei, Anhui, China.; Department of Pediatric Neurology, Anhui Provincial Children's Hospital, Hefei, Anhui, China
| | - Danqun Jin
- Department of Pediatric Intensive Care Unit, Children's Hospital of Anhui Medical University, Hefei, Anhui, China.; Department of Pediatric Intensive Care Unit, Anhui Provincial Children's Hospital, Hefei, Anhui, China
| | - Min Li
- Department of Pediatric Nephrology, Children's Hospital of Anhui Medical University, Hefei, Anhui, China.; Department of Pediatric Nephrology, Anhui Provincial Children's Hospital, Hefei, Anhui, China
| | - Zimei Cheng
- Department of Pediatric Intensive Care Unit, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Guoping Lu
- Department of Pediatric Intensive Care Unit, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Bin Yang
- Department of Pediatric Neurology, Children's Hospital of Anhui Medical University, Hefei, Anhui, China.; Department of Pediatric Neurology, Anhui Provincial Children's Hospital, Hefei, Anhui, China..
| | - Fang Deng
- Department of Pediatric Nephrology, Children's Hospital of Anhui Medical University, Hefei, Anhui, China.; Department of Pediatric Nephrology, Anhui Provincial Children's Hospital, Hefei, Anhui, China..
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Xue JD, Gao J, Tang AF, Feng C. Shaping the immune landscape: Multidimensional environmental stimuli refine macrophage polarization and foster revolutionary approaches in tissue regeneration. Heliyon 2024; 10:e37192. [PMID: 39296009 PMCID: PMC11408064 DOI: 10.1016/j.heliyon.2024.e37192] [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: 05/10/2024] [Revised: 08/28/2024] [Accepted: 08/28/2024] [Indexed: 09/21/2024] Open
Abstract
In immunology, the role of macrophages extends far beyond their traditional classification as mere phagocytes; they emerge as pivotal architects of the immune response, with their function being significantly influenced by multidimensional environmental stimuli. This review investigates the nuanced mechanisms by which diverse external signals ranging from chemical cues to physical stress orchestrate macrophage polarization, a process that is crucial for the modulation of immune responses. By transitioning between pro-inflammatory (M1) and anti-inflammatory (M2) states, macrophages exhibit remarkable plasticity, enabling them to adapt to and influence their surroundings effectively. The exploration of macrophage polarization provides a compelling narrative on how these cells can be manipulated to foster an immune environment conducive to tissue repair and regeneration. Highlighting cutting-edge research, this review presents innovative strategies that leverage the dynamic interplay between macrophages and their environment, proposing novel therapeutic avenues that harness the potential of macrophages in regenerative medicine. Moreover, this review critically evaluates the current challenges and future prospects of translating macrophage-centered strategies from the laboratory to clinical applications.
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Affiliation(s)
- Jing-Dong Xue
- Department of Urology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - Jing Gao
- Department of Obstetrics and Gynecology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Ai-Fang Tang
- Department of Geratology, Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, 200233, China
| | - Chao Feng
- Department of Reproductive Medicine, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China
- Shanghai Key Laboratory of Embryo Original Disease, Shanghai 200030, China
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6
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Dong ZR, Zhang MY, Qu LX, Zou J, Yang YH, Ma YL, Yang CC, Cao XL, Wang LY, Zhang XL, Li T. Spatial resolved transcriptomics reveals distinct cross-talk between cancer cells and tumor-associated macrophages in intrahepatic cholangiocarcinoma. Biomark Res 2024; 12:100. [PMID: 39256888 PMCID: PMC11389341 DOI: 10.1186/s40364-024-00648-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Accepted: 08/31/2024] [Indexed: 09/12/2024] Open
Abstract
BACKGROUND Multiple studies have shown that tumor-associated macrophages (TAMs) promote cancer initiation and progression. However, the reprogramming of macrophages in the tumor microenvironment (TME) and the cross-talk between TAMs and malignant subclones in intrahepatic cholangiocarcinoma (iCCA) has not been fully characterized, especially in a spatially resolved manner. Deciphering the spatial architecture of variable tissue cellular components in iCCA could contribute to the positional context of gene expression containing information pathological changes and cellular variability. METHODS Here, we applied spatial transcriptomics (ST) and digital spatial profiler (DSP) technologies with tumor sections from patients with iCCA. RESULTS The results reveal that spatial inter- and intra-tumor heterogeneities feature iCCA malignancy, and tumor subclones are mainly driven by physical proximity. Tumor cells with TME components shaped the intra-sectional heterogenetic spatial architecture. Macrophages are the most infiltrated TME component in iCCA. The protein trefoil factor 3 (TFF3) secreted by the malignant subclone can induce macrophages to reprogram to a tumor-promoting state, which in turn contributes to an immune-suppressive environment and boosts tumor progression. CONCLUSIONS In conclusion, our description of the iCCA ecosystem in a spatially resolved manner provides novel insights into the spatial features and the immune suppressive landscapes of TME for iCCA.
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Affiliation(s)
- Zhao-Ru Dong
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, 250010, Shandong, China
| | - Meng-Ya Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Ling-Xin Qu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Jie Zou
- Department of Geriatrics, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China
| | - Yong-Heng Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Yun-Long Ma
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, 250010, Shandong, China
| | - Chun-Cheng Yang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, 250010, Shandong, China
| | - Xue-Lei Cao
- Department of Clinical Laboratory, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250010, Shandong, China
| | - Li-Yuan Wang
- Department of Hepatology, Cheeloo Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Xiao-Lu Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
| | - Tao Li
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, 250010, Shandong, China.
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7
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Ammarah U, Pereira‐Nunes A, Delfini M, Mazzone M. From monocyte-derived macrophages to resident macrophages-how metabolism leads their way in cancer. Mol Oncol 2024; 18:1739-1758. [PMID: 38411356 PMCID: PMC11223613 DOI: 10.1002/1878-0261.13618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 01/24/2024] [Accepted: 02/16/2024] [Indexed: 02/28/2024] Open
Abstract
Macrophages are innate immune cells that play key roles during both homeostasis and disease. Depending on the microenvironmental cues sensed in different tissues, macrophages are known to acquire specific phenotypes and exhibit unique features that, ultimately, orchestrate tissue homeostasis, defense, and repair. Within the tumor microenvironment, macrophages are referred to as tumor-associated macrophages (TAMs) and constitute a heterogeneous population. Like their tissue resident counterpart, TAMs are plastic and can switch function and phenotype according to the niche-derived stimuli sensed. While changes in TAM phenotype are known to be accompanied by adaptive alterations in their cell metabolism, it is reported that metabolic reprogramming of macrophages can dictate their activation state and function. In line with these observations, recent research efforts have been focused on defining the metabolic traits of TAM subsets in different tumor malignancies and understanding their role in cancer progression and metastasis formation. This knowledge will pave the way to novel therapeutic strategies tailored to cancer subtype-specific metabolic landscapes. This review outlines the metabolic characteristics of distinct TAM subsets and their implications in tumorigenesis across multiple cancer types.
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Affiliation(s)
- Ummi Ammarah
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer BiologyVIBLeuvenBelgium
- Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, Center for Cancer BiologyKU LeuvenBelgium
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology CentreUniversity of TorinoItaly
| | - Andreia Pereira‐Nunes
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer BiologyVIBLeuvenBelgium
- Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, Center for Cancer BiologyKU LeuvenBelgium
- Life and Health Sciences Research Institute (ICVS), School of MedicineUniversity of MinhoBragaPortugal
- ICVS/3B's‐PT Government Associate LaboratoryBraga/GuimarãesPortugal
| | - Marcello Delfini
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer BiologyVIBLeuvenBelgium
- Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, Center for Cancer BiologyKU LeuvenBelgium
| | - Massimiliano Mazzone
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer BiologyVIBLeuvenBelgium
- Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, Center for Cancer BiologyKU LeuvenBelgium
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Ahmadpour S, Habibi MA, Ghazi FS, Molazadeh M, Pashaie MR, Mohammadpour Y. The effects of tumor-derived supernatants (TDS) on cancer cell progression: A review and update on carcinogenesis and immunotherapy. Cancer Treat Res Commun 2024; 40:100823. [PMID: 38875884 DOI: 10.1016/j.ctarc.2024.100823] [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: 04/25/2024] [Revised: 05/26/2024] [Accepted: 05/27/2024] [Indexed: 06/16/2024]
Abstract
Tumors can produce bioactive substances called tumor-derived supernatants (TDS) that modify the immune response in the host body. This can result in immunosuppressive effects that promote the growth and spread of cancer. During tumorigenesis, the exudation of these substances can disrupt the function of immune sentinels in the host and reinforce the support for cancer cell growth. Tumor cells produce cytokines, growth factors, and proteins, which contribute to the progression of the tumor and the formation of premetastatic niches. By understanding how cancer cells influence the host immune system through the secretion of these factors, we can gain new insights into cancer diagnosis and therapy.
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Affiliation(s)
- Sajjad Ahmadpour
- Patient Safety Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Mohammad Amin Habibi
- Department of Neurosurgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mikaeil Molazadeh
- Department of Medical Physics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Reza Pashaie
- Patient Safety Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran; Department of Internal Medicine, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Yousef Mohammadpour
- Department of Medical Education, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
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9
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Ryu S, Lee EK. The Pivotal Role of Macrophages in the Pathogenesis of Pancreatic Diseases. Int J Mol Sci 2024; 25:5765. [PMID: 38891952 PMCID: PMC11171839 DOI: 10.3390/ijms25115765] [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: 04/25/2024] [Revised: 05/20/2024] [Accepted: 05/23/2024] [Indexed: 06/21/2024] Open
Abstract
The pancreas is an organ with both exocrine and endocrine functions, comprising a highly organized and complex tissue microenvironment composed of diverse cellular and non-cellular components. The impairment of microenvironmental homeostasis, mediated by the dysregulation of cell-to-cell crosstalk, can lead to pancreatic diseases such as pancreatitis, diabetes, and pancreatic cancer. Macrophages, key immune effector cells, can dynamically modulate their polarization status between pro-inflammatory (M1) and anti-inflammatory (M2) modes, critically influencing the homeostasis of the pancreatic microenvironment and thus playing a pivotal role in the pathogenesis of the pancreatic disease. This review aims to summarize current findings and provide detailed mechanistic insights into how alterations mediated by macrophage polarization contribute to the pathogenesis of pancreatic disorders. By analyzing current research comprehensively, this article endeavors to deepen our mechanistic understanding of regulatory molecules that affect macrophage polarity and the intricate crosstalk that regulates pancreatic function within the microenvironment, thereby facilitating the development of innovative therapeutic strategies that target perturbations in the pancreatic microenvironment.
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Affiliation(s)
- Seungyeon Ryu
- Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
- Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Eun Kyung Lee
- Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
- Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
- Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
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Guo Z, Ashrafizadeh M, Zhang W, Zou R, Sethi G, Zhang X. Molecular profile of metastasis, cell plasticity and EMT in pancreatic cancer: a pre-clinical connection to aggressiveness and drug resistance. Cancer Metastasis Rev 2024; 43:29-53. [PMID: 37453022 DOI: 10.1007/s10555-023-10125-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 07/07/2023] [Indexed: 07/18/2023]
Abstract
The metastasis is a multistep process in which a small proportion of cancer cells are detached from the colony to enter into blood cells for obtaining a new place for metastasis and proliferation. The metastasis and cell plasticity are considered major causes of cancer-related deaths since they improve the malignancy of cancer cells and provide poor prognosis for patients. Furthermore, enhancement in the aggressiveness of cancer cells has been related to the development of drug resistance. Metastasis of pancreatic cancer (PC) cells has been considered one of the major causes of death in patients and their undesirable prognosis. PC is among the most malignant tumors of the gastrointestinal tract and in addition to lifestyle, smoking, and other factors, genomic changes play a key role in its progression. The stimulation of EMT in PC cells occurs as a result of changes in molecular interaction, and in addition to increasing metastasis, EMT participates in the development of chemoresistance. The epithelial, mesenchymal, and acinar cell plasticity can occur and determines the progression of PC. The major molecular pathways including STAT3, PTEN, PI3K/Akt, and Wnt participate in regulating the metastasis of PC cells. The communication in tumor microenvironment can provide by exosomes in determining PC metastasis. The components of tumor microenvironment including macrophages, neutrophils, and cancer-associated fibroblasts can modulate PC progression and the response of cancer cells to chemotherapy.
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Affiliation(s)
- Zhenli Guo
- Department of Oncology, First Affiliated Hospital, Gannan Medical University, 128 Jinling Road, Ganzhou City, Jiangxi Province, 341000, China
| | - Milad Ashrafizadeh
- Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, 518055, Guangdong, China.
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Wei Zhang
- Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, 518055, Guangdong, China
| | - Rongjun Zou
- Department of Cardiovascular Surgery, Guangdong Provincial Hospital of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, Guangdong, China
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
| | - Gautam Sethi
- Department of Pharmacology, National University of Singapore, 16 Medical Drive, Singapore, 117600, Singapore.
| | - Xianbin Zhang
- Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, 518055, Guangdong, China.
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11
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Sun Y, Wang X, Yao L, He R, Man C, Fan Y. Construction and validation of a RARRES3-based prognostic signature related to the specific immune microenvironment of pancreatic cancer. Front Oncol 2024; 14:1246308. [PMID: 38375157 PMCID: PMC10876156 DOI: 10.3389/fonc.2024.1246308] [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: 06/24/2023] [Accepted: 01/16/2024] [Indexed: 02/21/2024] Open
Abstract
Background Tumor immune microenvironment (TiME) is prognostically instructive in Pancreatic adenocarcinoma (PAAD). However, the potential value of TiME-related genes in the individualized immunotherapy of PAAD has not been clarified. Methods Correlation between Immune-Related Genes (IRGs) and immune-related transcription factors (TFs) was performed to prove the immune correlation of selected genes. Immune-related molecular subtypes were identified by consensus clustering. The TiME-score, an immune microenvironment-related prognostic signature for PAAD, was constructed using minimum absolute contraction and selection operator regression (Lasso-Cox). The International Cancer Genome Consortium (ICGC) dataset validated the reliability of TiME-score as external validation. Single-cell samples from GSE197177 confirmed microenvironment differences of TiME-score hub genes between tumor and its paracancer tissues. Then, RARRES3, a hub gene in TiME-score, was further analyzed about its upstream TP53 mutation and the specific immune landscape of itself in transcriptome and Single-cell level. Eventually, TiME-score were validated in different therapeutic cohorts of PAAD mice models. Results A 14-genes PAAD immune-related risk signature, TiME-score, was constructed based on IRGs. The differences of TiME-score hub genes in single-cell samples of PAAD cancer tissues and adjacent tissues were consistent with the transcriptome. Single-cell samples of cancer tissues showed more pronounced immune cell infiltration. The upstream mutation factor TP53 of RARRES3 was significantly enriched in immune-related biological processes. High RARRES3 expression was correlated with a worse prognosis and high macrophages M1 infiltration. Additionally, the immunohistochemistry of hub genes AGT, DEFB1, GH1, IL20RB, and TRAF3 in different treatment cohorts of mice PAAD models were consistent with the predicted results. The combination of immunotherapy, chemotherapy and targeted therapy has shown significantly better therapeutic effects than single drug therapy in PAAD. Conclusion TiME-score, as a prognostic signature related to PAAD-specific immune microenvironment constructed based on RARRES3, has predictive value for prognosis and the potential to guide individualized immunotherapy for PAAD patients.
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Affiliation(s)
- Yimeng Sun
- Cancer Institute, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Xiaoyan Wang
- Department of Gastroenterology, Suqian First People’s Hospital, Suqian, Jiangsu, China
| | - Lin Yao
- Cancer Institute, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Rong He
- Cancer Institute, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Changfeng Man
- Cancer Institute, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yu Fan
- Cancer Institute, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
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12
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Stinson MW, Liu S, Laurenson AJ, Rotty JD. Macrophage migration is differentially regulated by fibronectin and laminin through altered adhesion and myosin II localization. Mol Biol Cell 2024; 35:ar22. [PMID: 38088893 PMCID: PMC10881148 DOI: 10.1091/mbc.e23-04-0137] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 10/30/2023] [Accepted: 11/28/2023] [Indexed: 12/26/2023] Open
Abstract
Macrophages are indispensable for proper immune surveillance and inflammatory regulation. They also exhibit dramatic phenotypic plasticity and are highly responsive to their local microenvironment, which includes the extracellular matrix (ECM). This work demonstrates that two fibrous ECM glycoproteins, fibronectin (FN) and laminin (LAM), elicit distinct morphological and migratory responses from macrophages in two-dimensional environments. LAM 111 inhibits macrophage cell spreading, but drives them to migrate rapidly and less persistently compared with cells on FN. Differential integrin engagement and ROCK/myosin II organization helps explain why macrophages alter their morphology and migration character on these two ECM components. This study also demonstrates that LAM 111 exerts a suppressive effect toward FN, as macrophages plated on a LAM/FN mixture adopt a morphology and migratory character almost identical to LAM alone. This suggests that distinct responses can be initiated downstream of receptor-ECM engagement, and that one component of the microenvironment may affect the cell's ability to sense another. Overall, macrophages appear intrinsically poised to rapidly switch between distinct migratory characters based on their ECM environments. The role of ECM composition in dictating motile and inflammatory responses in three-dimensional and in vivo contexts warrants further study.
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Affiliation(s)
- Matthew W. Stinson
- Uniformed Services University of the Health Sciences, Department of Biochemistry, Bethesda, MD 20814
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817
| | - Sophia Liu
- Uniformed Services University of the Health Sciences, Department of Biochemistry, Bethesda, MD 20814
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817
| | - Alexander J. Laurenson
- Uniformed Services University of the Health Sciences, Department of Biochemistry, Bethesda, MD 20814
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817
| | - Jeremy D. Rotty
- Uniformed Services University of the Health Sciences, Department of Biochemistry, Bethesda, MD 20814
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13
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Zhang CY, Zhang R, Zhang L, Wang ZM, Sun HZ, Cui ZG, Zheng HC. Regenerating gene 4 promotes chemoresistance of colorectal cancer by affecting lipid droplet synthesis and assembly. World J Gastroenterol 2023; 29:5104-5124. [PMID: 37744296 PMCID: PMC10514755 DOI: 10.3748/wjg.v29.i35.5104] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 08/10/2023] [Accepted: 08/25/2023] [Indexed: 09/14/2023] Open
Abstract
BACKGROUND Regenerating gene 4 (REG4) has been proved to be carcinogenic in some cancers, but its manifestation and possible carcinogenic mechanisms in colorectal cancer (CRC) have not yet been elucidated. Our previous study found that the drug resistance of CRC cells may be closely linked to their fat metabolism. AIM To explore the role of REG4 in CRC and its association with lipid droplet formation and chemoresistance. METHODS We conducted a meta-analysis and bioinformatics and pathological analyses of REG4 expression in CRC. The effects of REG4 on the phenotypes and related protein expression were also investigated in CRC cells. We detected the impacts of REG4 on the chemoresistance and lipid droplet formation in CRC cells. Finally, we analyzed how REG4 regulated the transcription and proteasomal degradation of lipogenic enzymes in CRC cells. RESULTS Compared to normal mucosa, REG4 mRNA expression was high in CRC (P < 0.05) but protein expression was low. An inverse correlation existed between lymph node and distant metastases, tumor-node-metastasis staging or short overall survival and REG4 mRNA overexpression (P < 0.05), but vice versa for REG4 protein expression. REG4-related genes included: Chemokine activity; taste receptors; protein-DNA and DNA packing complexes; nucleosomes and chromatin; generation of second messenger molecules; programmed cell death signals; epigenetic regulation and DNA methylation; transcription repression and activation by DNA binding; insulin signaling pathway; sugar metabolism and transfer; and neurotransmitter receptors (P < 0.05). REG4 exposure or overexpression promoted proliferation, antiapoptosis, migration, and invasion of DLD-1 cells in an autocrine or paracrine manner by activating the epidermal growth factor receptor-phosphoinositide 3-kinase-Akt-nuclear factor-κB pathway. REG4 was involved in chemoresistance not through de novo lipogenesis, but lipid droplet assembly. REG4 inhibited the transcription of acetyl-CoA carboxylase 1 (ACC1) and ATP-citrate lyase (ACLY) by disassociating the complex formation of anti-acetyl (AC)-acetyl-histone 3-AC-histone 4-inhibitor of growth protein-5-si histone deacetylase;-sterol-regulatory element binding protein 1 in their promoters and induced proteasomal degradation of ACC1 or ACLY. CONCLUSION REG4 may be involved in chemoresistance through lipid droplet assembly. REG4 reduces expression of de novo lipid synthesis key enzymes by inhibiting transcription and promoting ubiquitination-mediated proteasomal degradation.
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Affiliation(s)
- Cong-Yu Zhang
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
| | - Rui Zhang
- Department of Colorectal Surgery, Liaoning Cancer Hospital, Shenyang 110042, Liaoning Province, China
| | - Li Zhang
- Department of Oncology, The Affiliated Hospital of Chengde Medical University, Chengde 067000, Hebei Province, China
| | - Zi-Mo Wang
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
| | - Hong-Zhi Sun
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
| | - Zheng-Guo Cui
- Department of Environmental Health, University of Fukui School of Medical Sciences, Fukui 910-1193, Japan
| | - Hua-Chuan Zheng
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
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14
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Gao H, Ma L, Zou Q, Hu B, Cai K, Sun Y, Lu L, Ren D. Unraveling dynamic interactions between tumor-associated macrophages and consensus molecular subtypes in colorectal cancer: An integrative analysis of single-cell and bulk RNA transcriptome. Heliyon 2023; 9:e19224. [PMID: 37662758 PMCID: PMC10470276 DOI: 10.1016/j.heliyon.2023.e19224] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 08/14/2023] [Accepted: 08/16/2023] [Indexed: 09/05/2023] Open
Abstract
Background Accumulating research substantiated that tumor-associated macrophages (TAMs) have a significant impact on the tumorigenesis, progression, and distant metastasis, representing a novel target for various cancers. However, the underlying dynamic changes and interactions between TAMs and tumor cells remain largely elusive in colorectal cancer (CRC). Methods We depicted the dynamic changes of macrophages using sing-cell RNA-seq data and extracted TAM differentiation-related genes. Next, we utilized the weighted gene co-expression network analysis (WGCNA) to acquire CMS-related modular genes using bulk RNA-seq data. Finally, we utilized univariate Cox and Lasso Cox regression analyses to identify TAM differentiation-related biomarkers and established a novel risk signature model. We employed quantitative real-time polymerase chain reaction (qRT-PCR) on CRC tissue samples and used immunohistochemistry (IHC) data frome the HPA database to validate the mRNA and protein expression of prognostic genes. The interaction of TAMs and each consensus molecular subtype (CMS) subpopulation was analyzed at the cellular level. Results A total of 47,285 cells from single-cell dataset and 1197 CRC patients from bulk dataset were obtained. Among those, 6400 myeloid cells were re-clustered and annotated. RNASE1, F13A1, DAPK1, CLEC10A, RPN2, REG4 and RGS19 were identified as prognostic genes and the risk signature model was established based on the above genes. The qRT-PCR analysis indicated that the expression of RNASE1 and DAPK1 were significantly up-regulated in CRC tumor tissues. The cell-cell communication analysis demonstrated complex interactions between TAMs and CMS malignant cell subpopulations. Conclusion This study presents an in-depth dissection of the dynamic features of TAMs in the tumor microenvironment and provides promising therapeutic targets for CRC.
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Affiliation(s)
- Han Gao
- Department of Coloproctology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Linyun Ma
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qi Zou
- Department of Coloproctology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Bang Hu
- Department of Coloproctology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Keyu Cai
- Department of Coloproctology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yi Sun
- Kingmed Pathology Center, Guangzhou, China
| | - Li Lu
- Department of Coloproctology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Donglin Ren
- Department of Coloproctology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Lin HJ, Liu Y, Caroland K, Lin J. Polarization of Cancer-Associated Macrophages Maneuver Neoplastic Attributes of Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2023; 15:3507. [PMID: 37444617 DOI: 10.3390/cancers15133507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/01/2023] [Accepted: 07/03/2023] [Indexed: 07/15/2023] Open
Abstract
Mounting evidence links the phenomenon of enhanced recruitment of tumor-associated macrophages towards cancer bulks to neoplastic growth, invasion, metastasis, immune escape, matrix remodeling, and therapeutic resistance. In the context of cancer progression, naïve macrophages are polarized into M1 or M2 subtypes according to their differentiation status, gene signatures, and functional roles. While the former render proinflammatory and anticancer effects, the latter subpopulation elicits an opposite impact on pancreatic ductal adenocarcinoma. M2 macrophages have gained increasing attention as they are largely responsible for molding an immune-suppressive landscape. Through positive feedback circuits involving a paracrine manner, M2 macrophages can be amplified by and synergized with neighboring neoplastic cells, fibroblasts, endothelial cells, and non-cell autonomous constituents in the microenvironmental niche to promote an advanced disease state. This review delineates the molecular cues expanding M2 populations that subsequently convey notorious clinical outcomes. Future therapeutic regimens shall comprise protocols attempting to abolish environmental niches favoring M2 polarization; weaken cancer growth typically assisted by M2; promote the recruitment of tumoricidal CD8+ T lymphocytes and dendritic cells; and boost susceptibility towards gemcitabine as well as other chemotherapeutic agents.
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Affiliation(s)
- Huey-Jen Lin
- Department of Medical & Molecular Sciences, University of Delaware, Willard Hall Education Building, 16 West Main Street, Newark, DE 19716, USA
| | - Yingguang Liu
- Department of Molecular and Cellular Sciences, College of Osteopathic Medicine, Liberty University, 306 Liberty View Lane, Lynchburg, VA 24502, USA
| | - Kailey Caroland
- Department of Biochemistry and Molecular Biology, Molecular Medicine Graduate Program, Greenebaum Comprehensive Cancer Center, School of Medicine, University of Maryland, 108 N. Greene Street, Baltimore, MD 21201, USA
| | - Jiayuh Lin
- Department of Biochemistry and Molecular Biology, Molecular Medicine Graduate Program, Greenebaum Comprehensive Cancer Center, School of Medicine, University of Maryland, 108 N. Greene Street, Baltimore, MD 21201, USA
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16
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Kang H, Yang S, Lee J. Tauroursodeoxycholic Acid Enhances Osteogenic Differentiation through EGFR/p-Akt/CREB1 Pathway in Mesenchymal Stem Cells. Cells 2023; 12:1463. [PMID: 37296585 PMCID: PMC10252885 DOI: 10.3390/cells12111463] [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: 04/18/2023] [Revised: 05/12/2023] [Accepted: 05/22/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are pluripotent stromal cells that are among the most appealing candidates for regenerative medicine and may aid in the repair and regeneration of skeletal disorders through multiple mechanisms, including angiogenesis, differentiation, and response to inflammatory conditions. Tauroursodeoxycholic acid (TUDCA) has recently been used in various cell types as one of these drugs. The mechanism of osteogenic differentiation by TUDCA in hMSCs remains unknown. METHODS Cell proliferation was performed by the WST-1 method, and alkaline phosphatase activity and alizarin red-sulfate staining were used to confirm the osteogenic differentiation indicator. Expression of genes related to bone differentiation and specific genes related to signaling pathways was confirmed by quantitative real-time polymerase chain reaction. RESULTS We found that cell proliferation was higher as the concentration increased, and showed that the induction of osteogenic differentiation was significantly enhanced. We also show that osteogenic differentiation genes were upregulated, with the expression of the epidermal growth factor receptor (EGFR) and cAMP responsive element binding protein 1 (CREB1) being specifically high. To confirm the participation of the EGFR signaling pathway, the osteogenic differentiation index and expression of osteogenic differentiation genes were determined after using an EGFR inhibitor. As a result, EGFR expression was remarkably low, and that of CREB1, cyclin D1, and cyclin E1 was also significantly low. CONCLUSIONS Therefore, we suggest that TUDCA-induced osteogenic differentiation of human MSCs is enhanced through the EGFR/p-Akt/CREB1 pathway.
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Affiliation(s)
- Hyojin Kang
- Department of Oral and Maxillofacial Surgery, College of Dentistry, Wonkwang University, 77 Dunsan-ro, Seo-gu, Daejeon 35233, Republic of Korea;
| | - Sunsik Yang
- Bonecell Biotech Inc., 77 Dunsan-dong, Seo-gu, Daejeon 35233, Republic of Korea;
| | - Jun Lee
- Department of Oral and Maxillofacial Surgery, College of Dentistry, Wonkwang University, 77 Dunsan-ro, Seo-gu, Daejeon 35233, Republic of Korea;
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17
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Stinson MW, Laurenson AJ, Rotty JD. Macrophage migration is differentially regulated by distinct ECM components. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.27.538597. [PMID: 37162935 PMCID: PMC10168351 DOI: 10.1101/2023.04.27.538597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
Macrophages are indispensable for proper immune surveillance and inflammatory regulation. They also exhibit dramatic phenotypic plasticity and are highly responsive to their local microenvironment, which includes the extracellular matrix (ECM). The present work demonstrates that two fibrous ECM glycoproteins, fibronectin (FN) and laminin (LAM), elicit distinct morphological and migratory responses to macrophages in 2D environments. Laminin 111 inhibits macrophage cell spreading, but drives them to migrate rapidly and less persistently compared to cells on fibronectin. Differential integrin engagement and ROCK/myosin II organization helps explain why macrophages alter their morphology and migration character on these two ECM components. The present study also demonstrates that laminin 111 exerts a suppressive effect toward fibronectin, as macrophages plated on a LAM/FN mixture adopt a morphology and migratory character almost identical to LAM alone. This suggests that distinct responses can be initiated downstream of receptor-ECM engagement, and that one component of the microenvironment may affect the cell's ability to sense another. Overall, macrophages appear intrinsically poised to rapidly switch between distinct migratory modes based on their ECM environments. The role of ECM composition in dictating motile and inflammatory responses in 3D and in vivo contexts warrants further study.
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18
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Anwar MM, Albanese C, Hamdy NM, Sultan AS. Rise of the natural red pigment 'prodigiosin' as an immunomodulator in cancer. Cancer Cell Int 2022; 22:419. [PMID: 36577970 PMCID: PMC9798661 DOI: 10.1186/s12935-022-02815-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 11/29/2022] [Indexed: 12/29/2022] Open
Abstract
Cancer is a heterogeneous disease with multifaceted drug resistance mechanisms (e.g., tumour microenvironment [TME], tumour heterogeneity, and immune evasion). Natural products are interesting repository of bioactive molecules, especially those with anticancer activities. Prodigiosin, a red pigment produced by Serratia marcescens, possesses inherent anticancer characteristics, showing interesting antitumour activities in different cancers (e.g., breast, gastric) with low or without harmful effects on normal cells. The present review discusses the potential role of prodigiosin in modulating and reprogramming the metabolism of the various immune cells in the TME, such as T and B lymphocytes, tumour-associated macrophages (TAMs), natural killer (NK) cells, and tumour-associated dendritic cells (TADCs), and myeloid-derived suppressor cells (MDSCs) which in turn might introduce as an immunomodulator in cancer therapy.
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Affiliation(s)
- Mohammed Moustapha Anwar
- grid.7155.60000 0001 2260 6941Department of Biotechnology, Institute of Graduate Studies and Research (IGSR), Alexandria University, Alexandria, Egypt
| | - Chris Albanese
- grid.516085.f0000 0004 0606 3221Oncology and Radiology Departments, Lombardi Comprehensive Cancer Center, Washington, D.C. USA
| | - Nadia M. Hamdy
- Department of Biochemistry, Ain Shams Faculty of Pharmacy, Cairo, Egypt
| | - Ahmed S. Sultan
- grid.7155.60000 0001 2260 6941Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
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19
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Wang K, Xuan Z, Liu X, Zheng M, Yang C, Wang H. Immunomodulatory role of metalloproteinase ADAM17 in tumor development. Front Immunol 2022; 13:1059376. [PMID: 36466812 PMCID: PMC9715963 DOI: 10.3389/fimmu.2022.1059376] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 11/03/2022] [Indexed: 12/25/2023] Open
Abstract
ADAM17 is a member of the a disintegrin and metalloproteinase (ADAM) family of transmembrane proteases involved in the shedding of some cell membrane proteins and regulating various signaling pathways. More than 90 substrates are regulated by ADAM17, some of which are closely relevant to tumor formation and development. Besides, ADAM17 is also responsible for immune regulation and its substrate-mediated signal transduction. Recently, ADAM17 has been considered as a major target for the treatment of tumors and yet its immunomodulatory roles and mechanisms remain unclear. In this paper, we summarized the recent understanding of structure and several regulatory roles of ADAM17. Importantly, we highlighted the immunomodulatory roles of ADAM17 in tumor development, as well as small molecule inhibitors and monoclonal antibodies targeting ADAM17.
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Affiliation(s)
- Kai Wang
- Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, China
| | - Zixue Xuan
- Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China
| | - Xiaoyan Liu
- Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, China
| | - Meiling Zheng
- Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, China
| | - Chao Yang
- National Engineering Research Center for Marine Aquaculture, Institute of Innovation & Application, Zhejiang Ocean University, Zhoushan, China
| | - Haiyong Wang
- Department of Internal Medicine Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
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20
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Zheng HC, Xue H, Zhang CY. REG4 promotes the proliferation and anti-apoptosis of cancer. Front Cell Dev Biol 2022; 10:1012193. [PMID: 36172286 PMCID: PMC9511136 DOI: 10.3389/fcell.2022.1012193] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 08/26/2022] [Indexed: 11/27/2022] Open
Abstract
Regenerating islet-derived 4 (REG4) gene was discovered by high-throughput sequencing of ulcerative colitis cDNA libraries. REG4 is involved in infection and inflammation by enhancing macrophage polarization to M2, via activation of epidermal growth factor receptor (EGFR)/Akt/cAMP-responsive element binding and the killing inflammatory Escherichia coli, and closely linked to tumorigenesis. Its expression was transcriptionally activated by caudal type homeobox 2, GATA binding protein 6, GLI family zinc finger 1, SRY-box transcription factor 9, CD44 intracytoplasmic domain, activating transcription factor 2, and specificity protein 1, and translationally activated by miR-24. REG4 can interact with transmembrane CD44, G protein-coupled receptor 37, mannan and heparin on cancer cells. Its overexpression was observed in gastric, colorectal, pancreatic, gallbladder, ovarian and urothelial cancers, and is closely linked to their aggressive behaviors and a poor prognosis. Additionally, REG4 expression and recombinant REG4 aggravated such cellular phenotypes as tumorigenesis, proliferation, anti-apoptosis, chemoradioresistance, migration, invasion, peritoneal dissemination, tumor growth, and cancer stemness via EGFR/Akt/activator protein-1 and Akt/glycogen synthase kinase three β/β-catenin/transcription factor 4 pathways. Sorted REG4-positive deep crypt secretory cells promote organoid formation of single Lgr5 (+) colon stem cells by Notch inhibition and Wnt activation. Histologically, REG4 protein is specifically expressed in neuroendocrine tumors and signet ring cell carcinomas of the gastrointestinal tract, pancreas, ovary, and lung. It might support the histogenesis of gastric intestinal–metaplasia–globoid dysplasia–signet ring cell carcinoma. In this review, we summarized the structure, biological functions, and effects of REG4 on inflammation and cancer. We conclude that REG4 may be employed as a biomarker of tumorigenesis, subsequent progression and poor prognosis of cancer, and may be a useful target for gene therapy.
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Affiliation(s)
- Hua-Chuan Zheng
- Department of Oncology and Central Laboratory, The Affiliated Hospital of Chengde Medical University, Chengde, China
- *Correspondence: Hua-Chuan Zheng,
| | - Hang Xue
- Department of Oncology and Central Laboratory, The Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Cong-Yu Zhang
- Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
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Targeting PI3K/AKT/mTOR Signaling Pathway in Pancreatic Cancer: From Molecular to Clinical Aspects. Int J Mol Sci 2022; 23:ijms231710132. [PMID: 36077529 PMCID: PMC9456549 DOI: 10.3390/ijms231710132] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/01/2022] [Accepted: 09/01/2022] [Indexed: 02/06/2023] Open
Abstract
Although pancreatic cancer (PC) was considered in the past an orphan cancer type due to its low incidence, it may become in the future one of the leading causes of cancer death. Pancreatic ductal adenocarcinoma (PDAC) is the most frequent type of PC, being a highly aggressive malignancy and having a 5-year survival rate of less than 10%. Non-modifiable (family history, age, genetic susceptibility) and modifiable (smoking, alcohol, acute and chronic pancreatitis, diabetes mellitus, intestinal microbiota) risk factors are involved in PC pathogenesis. Chronic inflammation induced by various factors plays crucial roles in PC development from initiation to metastasis. In multiple malignant conditions such as PC, cytokines, chemokines, and growth factors activate the class I phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) (PI3K/AKT/mTOR) signaling pathway, which plays key roles in cell growth, survival, proliferation, metabolism, and motility. Currently, mTOR, AKT, and PI3K inhibitors are used in clinical studies. Moreover, PI3K/mTOR dual inhibitors are being tested in vitro and in vivo with promising results for PC patients. The main aim of this review is to present PC incidence, risk factors, tumor microenvironment development, and PI3K/AKT/mTOR dysregulation and inhibitors used in clinical, in vivo, and in vitro studies.
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22
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Wang X, Li W, Jiang H, Ma C, Huang M, Wei X, Wang W, Jing L. Zebrafish Xenograft Model for Studying Pancreatic Cancer-Instructed Innate Immune Microenvironment. Int J Mol Sci 2022; 23:6442. [PMID: 35742884 PMCID: PMC9224329 DOI: 10.3390/ijms23126442] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 06/06/2022] [Accepted: 06/07/2022] [Indexed: 12/10/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has up to half the tumor mass of tumor-associated myeloid cells. Myeloid innate immune cells play important roles in regulating cancer cell recognition and tumor growth. PDAC cells often mold myeloid cells into pro-tumoral state to fuel cancer growth and induce immune suppression. However, how tumor cells educate the innate immune responses remains largely unknown. In this study, we used four different human PDAC cell lines (PANC1, BxPC3, AsPC1, and CFPAC1) to establish the zebrafish xenograft model and investigated the interaction between pancreatic cancer and innate immune cells. The primary tumor-derived cancer cells PANC1 and BxPC3 activated innate immune anti-tumoral responses efficiently, while cancer cells from metastatic tissues AsPC1 and CFPAC1 induced an innate immune suppression and educated innate immune cells towards pro-tumoral state. Chemical conversion of innate immune cells to anti-tumoral state inhibited tumor growth for AsPC1 and CFPAC1. Moreover, genetic and pharmacological inhibition of macrophages also significantly reduced tumor growth, supporting the important roles of macrophages in innate immune suppression. REG4 expression is high in AsPC1 and CFPAC1. Knockdown of REG4 induced innate immune activation and reduced tumor growth in the xenografts, indicating that REG4 is a beneficial target for PDAC therapy. Our study provides a fast in-vivo model to study PDAC-innate immune interaction and their plasticity that could be used to study the related mechanism as well as identify new drugs to enhance immunotherapy.
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Affiliation(s)
| | | | | | | | | | | | | | - Lili Jing
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; (X.W.); (W.L.); (H.J.); (C.M.); (M.H.); (X.W.); (W.W.)
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23
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Guo Y, Li G, Xu M, Peng B. A lncRNA signature of tumor-infiltrating macrophages is associated with prognosis and tumor immunity in lung adenocarcinoma. Comput Biol Med 2022; 148:105655. [PMID: 35715263 DOI: 10.1016/j.compbiomed.2022.105655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/05/2022] [Accepted: 05/18/2022] [Indexed: 12/09/2022]
Abstract
Accumulating evidence suggests that long noncoding RNAs (lncRNAs) play a critical role in regulating cancer immunity and the tumor microenvironment. Tumor-infiltrating macrophages are one of the most abundant constituents of many tumors. However, the functions and clinical significance of lncRNAs in tumor-associated macrophages have not been systematically elucidated. In this study, we analyzed the tumor immune microenvironment and lncRNA expression level differences based on The Cancer Genome Atlas (TCGA) and immune cell transcriptome profiles using lung adenocarcinoma microarray datasets GSE3141, GSE51210, GSE37745, and the RNA sequencing data of GSE81089. We then identified a macrophage infiltration-related lncRNA signature (MILnc) including LINC00240, MCF2L-AS1, SFTA3, MIR497HG, FAM215A, UCA1, MIR155HG, and TLRB-AS1 from a list of 147 macrophage-specific lncRNAs. The MILnc was capable of predicting overall survival differences in TCGA and several external validation datasets with a favorable performance. Functional analysis revealed that MILnc was associated with tumor progression and negatively correlated with immune checkpoints. Additionally, MILnc was positively correlated with tumor mutational burden and could predict the immunotherapy response of patients receiving anti-PD-1 or anti-CTLA4 therapy. In summary, our study highlighted the value of MILnc, which revealed the immune environment status and immunotherapy response of lung adenocarcinoma. A robust and powerful MILnc risk model could aid exploration of treatment decisions and mechanisms of macrophage-infiltrating lncRNAs.
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Affiliation(s)
- Yanhua Guo
- Department of Thoracic Surgery, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), 518020, Shenzhen, China
| | - Guofeng Li
- Department of Thoracic Surgery, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), 518020, Shenzhen, China
| | - Mingming Xu
- Department of Thoracic Surgery, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), 518020, Shenzhen, China
| | - Bin Peng
- Department of Thoracic Surgery, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), 518020, Shenzhen, China.
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24
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Wang J, Saung MT, Li K, Fu J, Fujiwara K, Niu N, Muth S, Wang J, Xu Y, Rozich N, Zlomke H, Chen S, Espinoza B, Henderson M, Funes V, Herbst B, Ding D, Twyman-Saint Victor C, Zhao Q, Narang A, He J, Zheng L. CCR2/CCR5 inhibitor permits the radiation-induced effector T cell infiltration in pancreatic adenocarcinoma. J Exp Med 2022; 219:e20211631. [PMID: 35404390 PMCID: PMC9006312 DOI: 10.1084/jem.20211631] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 01/10/2022] [Accepted: 03/07/2022] [Indexed: 12/26/2022] Open
Abstract
The resistance of pancreatic ductal adenocarcinoma (PDAC) to immune checkpoint inhibitors (ICIs) is attributed to the immune-quiescent and -suppressive tumor microenvironment (TME). We recently found that CCR2 and CCR5 were induced in PDAC following treatment with anti-PD-1 antibody (αPD-1); thus, we examined PDAC vaccine or radiation therapy (RT) as T cell priming mechanisms together with BMS-687681, a dual antagonist of CCR2 and CCR5 (CCR2/5i), in combination with αPD-1 as new treatment strategies. Using PDAC mouse models, we demonstrated that RT followed by αPD-1 and prolonged treatment with CCR2/5i conferred better antitumor efficacy than other combination treatments tested. The combination of RT + αPD-1 + CCR2/5i enhanced intratumoral effector and memory T cell infiltration but suppressed regulatory T cell, M2-like tumor-associated macrophage, and myeloid-derived suppressive cell infiltration. RNA sequencing showed that CCR2/5i partially inhibited RT-induced TLR2/4 and RAGE signaling, leading to decreased expression of immunosuppressive cytokines including CCL2/CCL5, but increased expression of effector T cell chemokines such as CCL17/CCL22. This study thus supports the clinical development of CCR2/5i in combination with RT and ICIs for PDAC treatment.
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Affiliation(s)
- Jianxin Wang
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
- Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD
| | - May Tun Saung
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
- Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Keyu Li
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
- Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Juan Fu
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
- Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Kenji Fujiwara
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
- Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Nan Niu
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
- Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Stephen Muth
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
- Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Junke Wang
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
- Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Yao Xu
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
- Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Noah Rozich
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
- Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Haley Zlomke
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
- Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Sophia Chen
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
- Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Birginia Espinoza
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
- Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD
| | - MacKenzie Henderson
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
- Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Vanessa Funes
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
- Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Brian Herbst
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
- Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ding Ding
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
- Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD
| | | | | | - Amol Narang
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
- Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Jin He
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
- Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Lei Zheng
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
- Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD
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25
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Bishnupuri KS, Sainathan SK, Ciorba MA, Houchen CW, Dieckgraefe BK. Reg4 Interacts with CD44 to Regulate Proliferation and Stemness of Colorectal and Pancreatic Cancer Cells. Mol Cancer Res 2022; 20:387-399. [PMID: 34753802 DOI: 10.1158/1541-7786.mcr-21-0224] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 09/08/2021] [Accepted: 11/01/2021] [Indexed: 11/16/2022]
Abstract
Regenerating Gene 4 (Reg4) is highly upregulated in gastrointestinal (GI) malignancies including colorectal and pancreatic cancers. Numerous studies demonstrated an association between higher Reg4 expression and tumor aggressiveness, intrinsic resistance to apoptotic death, and poor outcomes from GI malignancies. However, the precise receptor and underlying signaling mechanism have remained unknown. Although we previously reported a Reg4-mediated induction of EGFR activity in colorectal cancer cells, a direct interaction between Reg4 and EGFR was not observed. This study is focused on identifying the cell surface binding partner of Reg4 and dissecting its role in colorectal cancer and pancreatic cancer growth and stem cell survival. In vitro models of human colorectal cancer and pancreatic cancer were used to evaluate the results. Results of this study find: (i) Reg4 interacts with CD44, a transmembrane protein expressed by a population of colorectal cancer and pancreatic cancer cells; (ii) Reg4 activates regulated intramembrane proteolysis of CD44 resulting in γ-secretase-mediated cleavage and release of the CD44 intracytoplasmic domain (CD44ICD) that functions as a transcriptional activator of D-type cyclins involved in the regulation of cancer cell proliferation and Klf4 and Sox2 expression involved in regulating pluripotency of cancer stem cells; and (iii) Reg4 significantly increases colorectal cancer and pancreatic cancer cell proliferation and their clonogenic potential in stem cell assays. IMPLICATIONS These results suggest that pro-proliferative and pro-stemness effects of Reg4 are mediated through γ-secretase-mediated CD44/CD44ICD signaling, hence strategies to disrupt Reg4-CD44-γ-secretase-CD44ICD signaling axis may increase cancer cell susceptibility to chemo- and radiotherapeutics.
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Affiliation(s)
- Kumar S Bishnupuri
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri
- Veteran Affair St Louis Health Care System, St Louis, Missouri
| | - Satheesh K Sainathan
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri
| | - Matthew A Ciorba
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri
| | - Courtney W Houchen
- Section of Digestive Disease and Nutrition, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma
| | - Brian K Dieckgraefe
- Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri
- Veteran Affair St Louis Health Care System, St Louis, Missouri
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26
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Dynamic increase of M2 macrophages is associated with disease progression of colorectal cancers following cetuximab-based treatment. Sci Rep 2022; 12:1678. [PMID: 35102212 PMCID: PMC8803829 DOI: 10.1038/s41598-022-05694-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 01/11/2022] [Indexed: 02/07/2023] Open
Abstract
We aimed to investigate the dynamic changes of gene expression profiles and immune microenvironment linked to resistance to cetuximab-based treatments in patients with metastatic colorectal cancer (mCRC). A total of 106 patients with RAS-wild type mCRC who were treated with cetuximab-based treatments were included as the study population. RNA-sequencing and multiplexed immunohistochemistry were performed using paired or unpaired pre-treatment and post-treatment tumor tissues. Differentially expressed gene analysis of paired pre-treatment and post-treatment tumor tissues that develop acquired resistance (AR) identified the AR signature. Gene ontology analysis of the AR signature indicated enrichment of immune-related pathway genes. Among the immune subsets whose abundance was estimated by CIBERSORT, M2 macrophages showed the most prominent positive correlation with the expression of the AR signature. Among the post-treatment samples, progressive disease (PD) tumors showed a significantly higher abundance of M2 macrophages compared to non-PD tumors. These findings were validated by multiplexed immunohistochemistry analysis: the density of CD68+CD206+ M2 macrophages significantly increased at the time of PD following cetuximab-based treatment, whereas it did not consistently change in the tumor pairs of non-PD. In conclusion, a dynamic increase of M2 macrophages is associated with disease progression during cetuximab-based treatment of mCRCs. Targeting M2 macrophages is a promising immunotherapeutic strategy in this clinical context.
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27
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Dai J, He Y, Jiang M, Niu M, Li B, Wu Z, Bao J, Wen L, Wang X, Hu G. Reg4 regulates pancreatic regeneration following pancreatitis via modulating the Notch signaling. J Cell Physiol 2021; 236:7565-7577. [PMID: 33899235 DOI: 10.1002/jcp.30397] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 03/25/2021] [Accepted: 04/05/2021] [Indexed: 12/12/2022]
Abstract
Pancreatic regeneration after acute pancreatitis is critical in the normal restoration of pancreatic exocrine function, the inhibition of which can cause severe complications including pancreatic exocrine insufficiency. However, the regulators of pancreatic regeneration and the underlying mechanisms remain uncovered. Here, using the inducible Tet-on system, we found that regenerating family member 4 (Reg4) knockdown significantly impaired pancreatic regeneration after pancreatitis. Both acinar-to-ductal metaplasia and the resolution of pancreatitis during regeneration were affected by Reg4 knockdown. Further investigations confirmed that Reg4 exerted its function through regulating Notch activation both in vitro and in vivo. Our study revealed Reg4 as a new regulator and potential therapeutic target for pancreatic regeneration.
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Affiliation(s)
- Juanjuan Dai
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Intensive Care Unit, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yan He
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mingjie Jiang
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Head and Neck, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Mengya Niu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bin Li
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zengkai Wu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jingpiao Bao
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Wen
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xingpeng Wang
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guoyong Hu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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28
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Chen Z, Song H, Zeng X, Quan M, Gao Y. Screening and discrimination of optimal prognostic genes for pancreatic cancer based on a prognostic prediction model. G3 (BETHESDA, MD.) 2021; 11:6355586. [PMID: 34499727 PMCID: PMC8527504 DOI: 10.1093/g3journal/jkab296] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 07/14/2021] [Indexed: 02/06/2023]
Abstract
The prognosis of pancreatic cancer is poor because patients are usually asymptomatic in the early stage and the early diagnostic rate is low. Therefore, in this study, we aimed to identify potential prognosis-related genes in pancreatic cancer to improve diagnosis and the outcome of patients. The mRNA expression profile data from The Cancer Genome Atlas database and GSE79668, GSE62452, and GSE28735 datasets from Gene Expression Omnibus were downloaded. The prognosis-relevant genes and clinical factors were analyzed using Cox regression analysis and the optimal gene sets were screened using the Cox proportional model. Next, the Kaplan-Meier survival analysis was used to evaluate the relationship between risk grouping and patient prognosis. Finally, an optimal gene-based prognosis prediction model was constructed and validated using a test dataset to discriminate the model accuracy and reliability. The results showed that 325 expression variable genes were identified, and 48 prognosis-relevant genes and three clinical factors, including lymph node stage (pathologic N), new tumor, and targeted molecular therapy were preliminarily obtained. In addition, a gene set containing 16 optimal genes was identified and included FABP6, MAL, KIF19, and REG4, which were significantly associated with the prognosis of pancreatic cancer. Moreover, a prognosis prediction model was constructed and validated to be relatively accurate and reliable. In conclusion, a gene set consisting of 16 prognosis-related genes was identified and a prognosis prediction model was constructed, which is expected to be applicable in the clinical diagnosis and treatment guidance of pancreatic cancer in the future.
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Affiliation(s)
| | | | | | - Ming Quan
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China
| | - Yong Gao
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China
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Pan L, Niu Z, Gao Y, Wang L, Liu Z, Liu J, Sun J, Pei H. Silencing of CREB Inhibits HDAC2/TLR4/NF-κB Cascade to Relieve Severe Acute Pancreatitis-Induced Myocardial Injury. Inflammation 2021; 44:1565-1580. [PMID: 33725236 DOI: 10.1007/s10753-021-01441-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 02/06/2021] [Accepted: 02/19/2021] [Indexed: 02/08/2023]
Abstract
The purpose of the present study is to investigate the role of CREB in cardiomyocytes proliferation in regulation of HDAC2-dependent TLR4/NF-κB pathway in severe acute pancreatitis (SAP)-induced myocardial injury. The SAP rat model was developed by injecting sodium touracholate into SD rats and then infected with lentivirus vectors expressing sh-CREB in the presence/absence of LPS. The pathological alterations of rat pancreatic and cardiac tissues were observed by HE staining. TUNEL assay was used to study apoptosis of cardiomyocytes. Next, the loss- and gain-function assay was conducted in LPS-induced myocardial injury cardiomyocytes to define the roles of CREB, HDAC2, and TLR4 in cardiomyocyte proliferation, apoptosis, inflammation, and myocardial injury in vitro. ChIP assay was used to study the enrichment of CREB bound to HDAC2 promoter. RT-qPCR and Western blot analysis were used to detect the expressions of related mRNA and proteins in the NF-κB pathway, respectively. CREB was found to be overexpressed in both SAP tissues and cells. CREB directly bound to the promoter of HDAC2 and activated its expression. Overexpressed CREB or HDAC2 inhibited proliferation and promoted apoptosis of cardiomyocytes. Suppression of CREB inhibited the HDAC2/TLR4/NF-κB cascade to promote proliferation and inhibit apoptosis of cardiomyocytes. The in vitro results were validated in vivo experiments. Coherently, suppression of CREB can inhibit HDAC2/TLR4/NF-κB cascade to promote cardiomyocyte proliferation, thus ameliorating SAP-induced myocardial injury.
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Affiliation(s)
- Longfei Pan
- Department of Emergency, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xincheng District, 710004, Xi'an, Shaanxi Province, People's Republic of China.
| | - Zequn Niu
- Department of Emergency, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xincheng District, 710004, Xi'an, Shaanxi Province, People's Republic of China
| | - Yanxia Gao
- Department of Emergency, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xincheng District, 710004, Xi'an, Shaanxi Province, People's Republic of China
| | - Liming Wang
- Department of Emergency, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xincheng District, 710004, Xi'an, Shaanxi Province, People's Republic of China
| | - Zhong Liu
- Department of Emergency, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xincheng District, 710004, Xi'an, Shaanxi Province, People's Republic of China
| | - Jie Liu
- Department of Emergency, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xincheng District, 710004, Xi'an, Shaanxi Province, People's Republic of China
| | - Jiangli Sun
- Department of Emergency, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xincheng District, 710004, Xi'an, Shaanxi Province, People's Republic of China
| | - Honghong Pei
- Department of Emergency, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xincheng District, 710004, Xi'an, Shaanxi Province, People's Republic of China
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30
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Yang HH, Liu JW, Lee JH, Harn HJ, Chiou TW. Pancreatic Adenocarcinoma Therapeutics Targeting RTK and TGF Beta Receptor. Int J Mol Sci 2021; 22:ijms22158125. [PMID: 34360896 PMCID: PMC8348294 DOI: 10.3390/ijms22158125] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/28/2021] [Accepted: 07/26/2021] [Indexed: 12/21/2022] Open
Abstract
Despite the improved overall survival rates in most cancers, pancreatic cancer remains one of the deadliest cancers in this decade. The rigid microenvironment, which majorly comprises cancer-associated fibroblasts (CAFs), plays an important role in the obstruction of pancreatic cancer therapy. To overcome this predicament, the signaling of receptor tyrosine kinases (RTKs) and TGF beta receptor (TGFβR) in both pancreatic cancer cell and supporting CAF should be considered as the therapeutic target. The activation of receptors has been reported to be aberrant to cell cycle regulation, and signal transduction pathways, such as growth-factor induced proliferation, and can also influence the apoptotic sensitivity of tumor cells. In this article, the regulation of RTKs/TGFβR between pancreatic ductal adenocarcinoma (PDAC) and CAFs, as well as the RTKs/TGFβR inhibitor-based clinical trials on pancreatic cancer are reviewed.
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Affiliation(s)
- Hsin-Han Yang
- Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien 974, Taiwan;
| | - Jen-Wei Liu
- Everfront Biotech Inc., New Taipei City 221, Taiwan; (J.-W.L.); (J.-H.L.)
| | - Jui-Hao Lee
- Everfront Biotech Inc., New Taipei City 221, Taiwan; (J.-W.L.); (J.-H.L.)
| | - Horng-Jyh Harn
- Bioinnovation Center, Tzu Chi Foundation, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien 970, Taiwan
- Department of Pathology, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien 970, Taiwan
- Correspondence: (H.-J.H.); (T.-W.C.)
| | - Tzyy-Wen Chiou
- Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien 974, Taiwan;
- Correspondence: (H.-J.H.); (T.-W.C.)
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31
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Poddighe D. Autoimmune pancreatitis and pancreatic cancer: Epidemiological aspects and immunological considerations. World J Gastroenterol 2021; 27:3825-3836. [PMID: 34321847 PMCID: PMC8291014 DOI: 10.3748/wjg.v27.i25.3825] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/13/2021] [Accepted: 05/20/2021] [Indexed: 02/06/2023] Open
Abstract
Ordinary chronic pancreatitis is a well-known risk factor for pancreatic cancer, whereas such an association with autoimmune pancreatitis (AIP) is widely debated. Due to the rarity of the latter disorder, there are few specific clinical and epidemiological studies investigating the relation between AIP and pancreatic cancer, which do not seem to support it. However, these studies are affected by several limitations and, therefore, a link between AIP (and, specifically, type 1 AIP) and pancreatic cancer cannot be ruled out definitively on this basis. Moreover, several immunopathological aspects of type 1 AIP and, in general, immunoglobulin G4-related disease can create an immunological context that may impair the tumoral immunosurveillance and promote the pancreatic carcinogenesis and its progression. In detail, Th2 immunological dominance, type 2 macrophage polarization and basophil infiltration observed in type 1 AIP, may play a permissive role in creating a favorable immunological environment for pancreatic carcinogenesis, in addition to the immunosuppressive therapies that can be used in these patients.
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Affiliation(s)
- Dimitri Poddighe
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan 010000, Kazakhstan
- Department of Pediatrics, National Research Institute for Maternal and Child Health (NRCMCH), University Medical Center (UMC) Nur-Sultan 010000, Kazakhstan
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32
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Kwiatkowska I, Hermanowicz JM, Przybyszewska-Podstawka A, Pawlak D. Not Only Immune Escape-The Confusing Role of the TRP Metabolic Pathway in Carcinogenesis. Cancers (Basel) 2021; 13:2667. [PMID: 34071442 PMCID: PMC8198784 DOI: 10.3390/cancers13112667] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/20/2021] [Accepted: 05/26/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The recently discovered phenomenon that cancer cells can avoid immune response has gained scientists' interest. One of the pathways involved in this process is tryptophan (TRP) metabolism through the kynurenine pathway (KP). Individual components involved in TRP conversion seem to contribute to cancerogenesis both through a direct impact on cancer cells and the modulation of immune cell functionality. Due to this fact, this pathway may serve as a target for immunotherapy and attempts are being made to create novel compounds effective in cancer treatment. However, the results obtained from clinical trials are not satisfactory, which raises questions about the exact role of KP elements in tumorigenesis. An increasing number of experiments reveal that TRP metabolites may either be tumor promoters and suppressors and this is why further research in this field is highly needed. The aim of this study is to present KP as a modulator of cancer development through multiple mechanisms and to point to its ambiguity, which may be a reason for failures in treatment based on the inhibition of tryptophan metabolism.
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Affiliation(s)
- Iwona Kwiatkowska
- Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland; (J.M.H.); (D.P.)
| | - Justyna Magdalena Hermanowicz
- Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland; (J.M.H.); (D.P.)
- Department of Clinical Pharmacy, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland
| | | | - Dariusz Pawlak
- Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland; (J.M.H.); (D.P.)
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33
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Review of clinical and emerging biomarkers for early diagnosis and treatment management of pancreatic cancer: towards personalised medicine. JOURNAL OF RADIOTHERAPY IN PRACTICE 2021. [DOI: 10.1017/s1460396921000182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Abstract
Background:
Pancreatic cancer is the 12th most commonly diagnosed cancer and the 3rd leading cause of cancer mortality and accounts for approximately 2·7% of all newly diagnosed cancer cases and 6·4% of all cancer mortalities in Canada. It has a very poor survival rate mainly due to the difficulty of detecting the disease at an early stage. Consequently, in the advancement of disease management towards the concept of precision medicine that takes individual patient variabilities into account, several investigators have focused on the identification of effective clinical biomarkers with high specificity and sensitivity, capable of early diagnosis of symptomatic patients and early detection of the disease in asymptomatic individuals at high risk for developing pancreatic cancer.
Materials and methods:
We searched several databases from August to December 2020 for relevant studies published in English between 2000 and 2020 and reporting on biomarkers for the management of pancreatic cancer. In this narrative review paper, we describe 13 clinical and emerging biomarkers for pancreatic cancers used in screening for early detection and diagnosis, to identify patients’ risk for metastatic disease and subsequent relapse, to monitor patient response to specific treatment and to provide clinicians the possibility of prospectively identifying groups of patients who will benefit from a particular treatment.
Conclusions:
Current and emerging biomarkers for pancreatic cancer with high specificity and sensitivity has the potential to account for individual patient variabilities, for early detection of disease before the onset of metastasis to improve treatment outcome and patients’ survival, help screen high-risk populations, predict prognosis, provide accurate information of patient response to specific treatment and improve patients monitoring during treatment. Thus, the future holds promise for the use of effective clinical biomarkers or a panel of biomarkers for personalised patient-specific targeted medicine for pancreatic cancer.
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34
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Yang S, Liu Q, Liao Q. Tumor-Associated Macrophages in Pancreatic Ductal Adenocarcinoma: Origin, Polarization, Function, and Reprogramming. Front Cell Dev Biol 2021; 8:607209. [PMID: 33505964 PMCID: PMC7829544 DOI: 10.3389/fcell.2020.607209] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 11/19/2020] [Indexed: 12/19/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy. PDAC is only cured by surgical resection in its early stage, but there remains a relatively high possibility of recurrence. The development of PDAC is closely associated with the tumor microenvironment. Tumor-associated macrophages (TAMs) are one of the most abundant immune cell populations in the pancreatic tumor stroma. TAMs are inclined to M2 deviation in the tumor microenvironment, which promotes and supports tumor behaviors, including tumorigenesis, immune escape, metastasis, and chemotherapeutic resistance. Herein, we comprehensively reviewed the latest researches on the origin, polarization, functions, and reprogramming of TAMs in PDAC.
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Affiliation(s)
- Sen Yang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Qiaofei Liu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Quan Liao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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35
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Zhang J, Zhu Z, Miao Z, Huang X, Sun Z, Xu H, Wang Z. The Clinical Significance and Mechanisms of REG4 in Human Cancers. Front Oncol 2021; 10:559230. [PMID: 33489872 PMCID: PMC7819868 DOI: 10.3389/fonc.2020.559230] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 11/23/2020] [Indexed: 11/13/2022] Open
Abstract
Regenerating islet-derived type 4 (REG4), a member of the calcium-dependent lectin gene superfamily, is abnormally expressed in various cancers, such as colorectal, gastric, gallbladder, pancreatic, ovarian, prostate, and lung cancer. REG4 is associated with a relatively unfavorable prognosis and clinicopathologic features in cancers, including advanced tumor and nodal stage, histological differentiation, and liver and peritoneal metastasis. Moreover, REG4-positive cancer cells show more frequent resistance to chemoradiotherapy, especially 5-FU-based chemotherapy. REG4 participates in many aspects of carcinogenesis, including cell proliferation, apoptosis, cell cycle, invasion, metastasis, and drug resistance. The underlying mechanisms are complex and involve a series of signaling mediators and multiple pathways. Thus, REG4 may be a potential diagnostic and prognostic biomarker as well as a candidate therapeutic target in cancer patients. In this review, we systematically summarize the advances about the clinical significance, biological functions, and mechanisms underlying REG4 in cancer to provide new directions for future cancer research.
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Affiliation(s)
- Junyan Zhang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhi Zhu
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhifeng Miao
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xuanzhang Huang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhe Sun
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Huimian Xu
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
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36
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Wang H, Ren R, Yang Z, Cai J, Du S, Shen X. The COL11A1/Akt/CREB signaling axis enables mitochondrial-mediated apoptotic evasion to promote chemoresistance in pancreatic cancer cells through modulating BAX/BCL-2 function. J Cancer 2021; 12:1406-1420. [PMID: 33531986 PMCID: PMC7847647 DOI: 10.7150/jca.47032] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Accepted: 12/05/2020] [Indexed: 12/27/2022] Open
Abstract
Collagen XI, a member of the collagen family, is present in the extracellular matrix (ECM), and high collagen XI/αI (COL11A1) expression in tumor tissue is reportedly correlated with the clinicopathological parameters of pancreatic ductal adenocarcinoma (PDAC). However, the function of COL11A1 in the development of pancreatic cancer cells remains unclear. In the current study, we assessed mRNA expression of COL11A1 and its receptors and created a testing-model of both a COL11A1-overexpressing tumor microenvironment and/or altered-COL11A1 expression in pancreatic cancer cell lines. Next, we investigated the mechanism by which COL11A1 affects growth, gemcitabine (GEM) resistance and apoptosis in pancreatic cancer cells. We demonstrated that COL11A1 phosphorylated AktSer473, promoting proliferation of cancer cells and inhibiting their apoptosis. Additionally, our data showed that COL11A1/Akt/CREB altered the balance between BCL-2 and BAX and mediated their mitochondrial translocation in pancreatic cancer cells. The COL11A1/Akt axis induced disruption of mitochondrial transmembrane function, enabling mitochondria-mediated apoptotic evasion to promote chemoresistance. We also explored the regulatory effect of COL11A1/Akt on molecular signaling in the mitochondria-mediated apoptotic program. COL11A1/Akt disturbed the BCL-2/BAX balance, inhibiting cytochrome c (Cyt-C) release and binding of Apaf-1/procaspase-9/Cyt-C, which suppressed the apoptotic program and induced GEM resistance in pancreatic cancer cells. In conclusion, COL11A1 modulates apoptotic inhibition and chemoresistance in pancreatic cancer cells by activating the Akt/CREB/BCL-2/BAX signaling pathway. COL11A1 may represent a distinct prognostic indicator and may be an attractive therapeutic target for PDAC.
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Affiliation(s)
- Hui Wang
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Runling Ren
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Zizhong Yang
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Jun Cai
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Shaoxia Du
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Xiaohong Shen
- School of Medicine, Nankai University, Tianjin 300071, China
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37
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Cruz AF, Rohban R, Esni F. Macrophages in the pancreas: Villains by circumstances, not necessarily by actions. IMMUNITY INFLAMMATION AND DISEASE 2020; 8:807-824. [PMID: 32885589 PMCID: PMC7654401 DOI: 10.1002/iid3.345] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/13/2020] [Accepted: 08/19/2020] [Indexed: 12/17/2022]
Abstract
Introduction Mounting evidence suggest that macrophages play crucial roles in disease and tissue regeneration. However, despite much efforts during the past decade, our knowledge about the extent of macrophages' contribution to adult pancreatic regeneration after injury or during pancreatic disease progression is still limited. Nevertheless, it is generally accepted that some macrophage features that normally would contribute to healing and regeneration may be detrimental in pancreatic cancer. Altogether, the current literature contains conflicting reports on whether macrophages act as friends or foe in these conditions. Methods and Results In this review, we briefly review the origins of tissue resident and infiltrating macrophages and the importance of cellular crosstalking between macrophages and other resident cells in tissue regeneration. The primary objective of this review is to summarize our knowledge of the distinct roles of tissue resident and infiltrating macrophages, the impact of M1 and M2 macrophage phenotypes, and emerging evidence on macrophage crosstalking in pancreatic injury, regeneration, and disease. Conclusion Macrophages are involved with various stages of pancreatic cancer development, pancreatitis, and diabetes. Elucidating their role in these conditions will aid the development of targeted therapeutic treatments.
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Affiliation(s)
- Andrea F Cruz
- Division of Pediatric General and Thoracic Surgery, Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Rokhsareh Rohban
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Farzad Esni
- Division of Pediatric General and Thoracic Surgery, Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.,Department of Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.,University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
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38
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Malekghasemi S, Majidi J, Baghbanzadeh A, Abdolalizadeh J, Baradaran B, Aghebati-Maleki L. Tumor-Associated Macrophages: Protumoral Macrophages in Inflammatory Tumor Microenvironment. Adv Pharm Bull 2020; 10:556-565. [PMID: 33062602 PMCID: PMC7539304 DOI: 10.34172/apb.2020.066] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 02/01/2020] [Accepted: 02/02/2020] [Indexed: 12/13/2022] Open
Abstract
Tumor microenvironment consists of malignant and non-malignant cells. The interaction of these dynamic and different cells is responsible for tumor progression at different levels. The non-malignant cells in TME contain cells such as tumor-associated macrophages (TAMs), cancer associated fibroblasts, pericytes, adipocytes, T cells, B cells, myeloid-derived suppressor cells (MDSCs), tumor-associated neutrophils (TANs), dendritic cells (DCs) and Vascular endothelial cells. TAMs are abundant in most human and murine cancers and their presence are associated with poor prognosis. The major event in tumor microenvironment is macrophage polarization into tumor-suppressive M1 or tumor-promoting M2 types. Although much evidence suggests that TAMS are primarily M2-like macrophages, the mechanism responsible for polarization into M1 and M2 macrophages remain unclear. TAM contributes cancer cell motility, invasion, metastases and angiogenesis. The relationship between TAM and tumor cells lead to used them as a diagnostic marker, therapeutic target and prognosis of cancer. This review presents the origin, polarization, role of TAMs in inflammation, metastasis, immune evasion and angiogenesis as well as they can be used as therapeutic target in variety of cancer cells. It is obvious that additional substantial and preclinical research is needed to support the effectiveness and applicability of this new and promising strategy for cancer treatment.
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Affiliation(s)
- Somaiyeh Malekghasemi
- Department of Basic Oncology, Oncology Institute, Hacettepe University, Sihhiye, Ankara, TR-06100, Turkey
| | - Jafar Majidi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Baghbanzadeh
- Department of Basic Oncology, Oncology Institute, Hacettepe University, Sihhiye, Ankara, TR-06100, Turkey
| | - Jalal Abdolalizadeh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leili Aghebati-Maleki
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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39
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Zhang XQ, Yu LT, Du P, Yin TQ, Zhang ZY, Xu Y, Li X, Li YJ, Wang M, Luo C. Single-chain Antibody Against Reg4 Suppresses Gastric Cancer Cell Growth and Enhances 5-FU-induced Cell Death in vitro. Anticancer Agents Med Chem 2020; 19:610-619. [PMID: 30465515 DOI: 10.2174/1871520619666181122104720] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 08/15/2018] [Accepted: 11/13/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Regenerating islet-derived gene family member 4 (Reg4), a well-investigated growth factor in the regenerative pancreas, has recently been reported to be highly associated with a majority of gastrointestinal cancers. Pathological hyper-expression or artificial over-expression of Reg4 causes acceleration of tumor growth, migration, and resistance to chemotherapeutic 5-Fluorouracil (5-FU). Until now, no method has been successfully established for eliminating the effects of Reg4 protein. METHODS This study reports the production of an engineered immunoglobin, a single-chain variable fragment (scFv-Reg4), to specifically bind Reg4 and block the bioactivity. The complementary-determining regions (CDRs) against Reg4 were assigned using MOE and ZDOCK servers. The binding affinity (KD) was determined by bio-layer interferometry (BLI). MKN45 and AGS cell proliferation was determined by Thiazolyl blue tetrazolium bromide (MTT) method and the cell apoptosis was detected by flow cytometry assay. RESULTS The KD of scFv-Reg4 to Reg4 was determined to be 1.91×10-8. In MKN45 and AGS cell lines, scFv- Reg4 depressed Reg4-stimulated cell proliferation and the inhibitory rates were 27.7±1.5% and 17.3±2.6%, respectively. Furthermore, scFv significantly enhanced 5-FU-induced cell death, from 23.0±1.0% to 28.4±1.2% in MKN45 and 28.2±0.7% to 36.6±0.6% in AGS cells. Treatment with scFv alone could lyse cancer cells to a certain extent, but no significance has been observed. CONCLUSION The single-chain antibody (scFv-Reg4) significantly inhibited gastric cancer cell proliferation and synergistically enhanced the lethal effect of 5-FU. Thus, traditional chemo-/radio- therapeutics supplemented with scFv-Reg4 may provide advances in the strategy for gastrointestinal cancer treatment.
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Affiliation(s)
- Xue-Qing Zhang
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - Lu-Ting Yu
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China.,Fraser Laboratories for Diabetes Research, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada
| | - Pei Du
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - Tian-Qi Yin
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - Zhi-Yuan Zhang
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - Ying Xu
- Jiangsu Celtec Biotechnology Co. Ltd, Jiangsu, China
| | - Xiang Li
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - You-Jie Li
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China
| | - Min Wang
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China.,State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing, China
| | - Chen Luo
- School of Life Science & Technology, China Pharmaceutical University, Nanjing, China.,State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing, China
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40
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Chen Z, Downing S, Tzanakakis ES. Four Decades After the Discovery of Regenerating Islet-Derived (Reg) Proteins: Current Understanding and Challenges. Front Cell Dev Biol 2019; 7:235. [PMID: 31696115 PMCID: PMC6817481 DOI: 10.3389/fcell.2019.00235] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 09/30/2019] [Indexed: 12/15/2022] Open
Abstract
Regenerating islet-derived (Reg) proteins have emerged as multifunctional agents with pro-proliferative, anti-apoptotic, differentiation-inducing and bactericidal properties. Over the last 40 years since first discovered, Reg proteins have been implicated in a gamut of maladies including diabetes, various types of cancer of the digestive tract, and Alzheimer disease. Surprisingly though, a consensus is still absent on the regulation of their expression, and molecular underpinning of their function. Here, we provide a critical appraisal of recent findings in the field of Reg protein biology. Specifically, the structural characteristics are reviewed particularly in connection with established or purported functions of different members of the Reg family. Moreover, Reg expression patterns in different tissues both under normal and pathophysiological conditions are summarized. Putative receptors and cascades reported to relay Reg signaling inciting cellular responses are presented aiming at a better appreciation of the biological activities of the distinct Reg moieties. Challenges are also discussed that have hampered thus far the rapid progress in this field such as the use of non-standard nomenclature for Reg molecules among various research groups, the existence of multiple Reg members with significant degree of homology and possibly compensatory modes of action, and the need for common assays with robust readouts of Reg activity. Coordinated research is warranted going forward, given that several research groups have independently linked Reg proteins to diseased states and raised the possibility that these biomolecules can serve as therapeutic targets and biomarkers.
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Affiliation(s)
- Zijing Chen
- Department of Chemical and Biological Engineering, Tufts University, Medford, MA, United States
| | - Shawna Downing
- Clinical and Translational Science Institute, Tufts Medical Center, Boston, MA, United States
| | - Emmanuel S Tzanakakis
- Department of Chemical and Biological Engineering, Tufts University, Medford, MA, United States.,Clinical and Translational Science Institute, Tufts Medical Center, Boston, MA, United States
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41
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Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. J Hematol Oncol 2019; 12:76. [PMID: 31300030 PMCID: PMC6626377 DOI: 10.1186/s13045-019-0760-3] [Citation(s) in RCA: 952] [Impact Index Per Article: 158.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Accepted: 06/25/2019] [Indexed: 12/12/2022] Open
Abstract
Tumor metastasis is a major contributor to the death of cancer patients. It is driven not only by the intrinsic alterations in tumor cells, but also by the implicated cross-talk between cancer cells and their altered microenvironment components. Tumor-associated macrophages (TAMs) are the key cells that create an immunosuppressive tumor microenvironment (TME) by producing cytokines, chemokines, growth factors, and triggering the inhibitory immune checkpoint proteins release in T cells. In doing so, TAMs exhibit important functions in facilitating a metastatic cascade of cancer cells and, meanwhile, provide multiple targets of certain checkpoint blockade immunotherapies for opposing tumor progression. In this article, we summarize the regulating networks of TAM polarization and the mechanisms underlying TAM-facilitated metastasis. Based on the overview of current experimental evidence dissecting the critical roles of TAMs in tumor metastasis, we discuss and prospect the potential applications of TAM-focused therapeutic strategies in clinical cancer treatment at present and in the future.
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42
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Lin Y, Xu J, Lan H. Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. J Hematol Oncol 2019. [PMID: 31300030 DOI: 10.1186/s13045-019-0760-3.pmid:31300030;pmcid:pmc6626377] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/09/2023] Open
Abstract
Tumor metastasis is a major contributor to the death of cancer patients. It is driven not only by the intrinsic alterations in tumor cells, but also by the implicated cross-talk between cancer cells and their altered microenvironment components. Tumor-associated macrophages (TAMs) are the key cells that create an immunosuppressive tumor microenvironment (TME) by producing cytokines, chemokines, growth factors, and triggering the inhibitory immune checkpoint proteins release in T cells. In doing so, TAMs exhibit important functions in facilitating a metastatic cascade of cancer cells and, meanwhile, provide multiple targets of certain checkpoint blockade immunotherapies for opposing tumor progression. In this article, we summarize the regulating networks of TAM polarization and the mechanisms underlying TAM-facilitated metastasis. Based on the overview of current experimental evidence dissecting the critical roles of TAMs in tumor metastasis, we discuss and prospect the potential applications of TAM-focused therapeutic strategies in clinical cancer treatment at present and in the future.
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Affiliation(s)
- Yuxin Lin
- Department of Oncology, Hospital of Chinese Medicine of Changxing County, Huzhou, 313100, China
| | - Jianxin Xu
- Department of Oncology, Hospital of Chinese Medicine of Changxing County, Huzhou, 313100, China.
| | - Huiyin Lan
- Department of Radiation Oncology, Zhejiang Key Lab of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, China.
- Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, MS-1, 1301 Catherine Street, Ann Arbor, MI, 48109, USA.
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43
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The Formation and Therapeutic Update of Tumor-Associated Macrophages in Cervical Cancer. Int J Mol Sci 2019; 20:ijms20133310. [PMID: 31284453 PMCID: PMC6651300 DOI: 10.3390/ijms20133310] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 07/01/2019] [Accepted: 07/03/2019] [Indexed: 12/15/2022] Open
Abstract
Both clinicopathological and experimental studies have suggested that tumor-associated macrophages (TAMs) play a key role in cervical cancer progression and are associated with poor prognosis in the respects of tumor cell proliferation, invasion, angiogenesis, and immunosuppression. Therefore, having a clear understanding of TAMs is essential in treating this disease. In this review, we will discuss the origins and categories of macrophages, the molecules responsible for forming and reeducating TAMs in cervical cancer (CC), the biomarkers of macrophages and the therapy development targeting TAMs in CC research.
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44
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Lankadasari MB, Mukhopadhyay P, Mohammed S, Harikumar KB. TAMing pancreatic cancer: combat with a double edged sword. Mol Cancer 2019; 18:48. [PMID: 30925924 PMCID: PMC6441154 DOI: 10.1186/s12943-019-0966-6] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 02/21/2019] [Indexed: 12/11/2022] Open
Abstract
Among all the deadly cancers, pancreatic cancer ranks seventh in mortality. The absence of any grave symptoms coupled with the unavailability of early prognostic and diagnostic markers make the disease incurable in most of the cases. This leads to a late diagnosis, where the disease would have aggravated and thus, incurable. Only around 20% of the cases present the early disease diagnosis. Surgical resection is the prime option available for curative local disease but in the case of advanced cancer, chemotherapy is the standard treatment modality although the patients end up with drug resistance and severe side effects. Desmoplasia plays a very important role in chemoresistance associated with pancreatic cancer and consists of a thick scar tissue around the tumor comprised of different cell populations. The interplay between this heterogenous population in the tumor microenvironment results in sustained tumor growth and metastasis. Accumulating evidences expose the crucial role played by the tumor-associated macrophages in pancreatic cancer and this review briefly presents the origin from their parent lineage and the importance in maintaining tumor hallmarks. Finally we have tried to address their role in imparting chemoresistance and the therapeutic interventions leading to reduced tumor burden.
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Affiliation(s)
- Manendra Babu Lankadasari
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, Kerala State, 695014, India.,Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Pramiti Mukhopadhyay
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, Kerala State, 695014, India.,Present address: Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Sabira Mohammed
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, Kerala State, 695014, India.,Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Kuzhuvelil B Harikumar
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, Kerala State, 695014, India.
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45
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Resolution of Gastric Cancer-Promoting Inflammation: A Novel Strategy for Anti-cancer Therapy. Curr Top Microbiol Immunol 2019; 421:319-359. [PMID: 31123895 DOI: 10.1007/978-3-030-15138-6_13] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The connection between inflammation and cancer was initially recognized by Rudolf Virchow in the nineteenth century. During the last decades, a large body of evidence has provided support to his hypothesis, and now inflammation is recognized as one of the hallmarks of cancer, both in etiopathogenesis and ongoing tumor growth. Infection with the pathogen Helicobacter pylori is the primary causal factor in 90% of gastric cancer (GC) cases. As we increase our understanding of how chronic inflammation develops in the stomach and contributes to carcinogenesis, there is increasing interest in targeting cancer-promoting inflammation as a strategy to treat GC. Moreover, once cancer develops and anti-cancer immune responses are suppressed, there is evidence of a substantial shift in the microenvironment and new targets for immune therapy emerge. In this chapter, we provide insight into inflammation-related factors, including T lymphocytes, macrophages, pro-inflammatory chemokines, and cytokines, which promote H. pylori-associated GC initiation and growth. While intervening with chronic inflammation is not a new practice in rheumatology or gastroenterology, this approach has not been fully explored for its potential to prevent carcinogenesis or to contribute to the treatment of GC. This review highlights current and possible strategies for therapeutic intervention including (i) targeting pro-inflammatory mediators, (ii) targeting growth factors and pathways involved in angiogenesis in the gastric tumor microenvironment, and (iii) enhancing anti-tumor immunity. In addition, we highlight a significant number of clinical trials and discuss the importance of individual tumor characterization toward offering personalized immune-related therapy.
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46
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Zhou J, Liu M, Chen Y, Xu S, Guo Y, Zhao L. Cucurbitacin B suppresses proliferation of pancreatic cancer cells by ceRNA: Effect of miR-146b-5p and lncRNA-AFAP1-AS1. J Cell Physiol 2018; 234:4655-4667. [PMID: 30206930 DOI: 10.1002/jcp.27264] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 07/24/2018] [Indexed: 12/22/2022]
Abstract
Cucurbitacin B (CuB) is a natural tetracyclic triterpene product that displays antitumor activity against a wide variety of cancers. In this study, we explored the antipancreatic cancer activity of CuB via the inhibition of expression of the cancer-related long noncoding RNA, actin filament-associated protein 1-antisense RNA 1 (AFAP1-AS1). CuB arrested pancreatic cancer (PC) cells in the G2/M cell cycle phase by suppressing the expression of AFAP1-AS1. Insights into the mechanisms of competing endogenous RNAs (ceRNAs) gained from bioinformatics analysis and luciferase activity assays showed that the epidermal growth factor receptor (EGFR) and AFAP1-AS1 directly compete for miR-146b-5p binding. CuB-induced high miR-146b-5p expression and inhibited the expression of AFAP1-AS1. In summary, reducing the expression of endogenous AFAP1-AS1 effectively increased the available concentration of miR-146b-5p in PC, whereas miR-146b-5p overexpression prevented the expression of endogenous AFAP1-AS1. In particular, we hypothesized that AFAP1-AS1 might act as a ceRNA, effectively becoming a sponge for miR-146b-5p, thereby activating the expression of the EGFR. Thus, CuB suppresses the proliferation, in vitro and in vivo, of PC cells through the ceRNA effect of AFAP1-AS1 on miR-146b-5p.
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Affiliation(s)
- Jingkai Zhou
- Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, China
| | - Mei Liu
- Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
| | - Yanan Chen
- Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, China
| | - Shansen Xu
- Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yingjie Guo
- National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, Jilin
| | - Limei Zhao
- Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, China
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47
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Saukkonen K, Hagström J, Mustonen H, Lehtinen L, Carpen O, Andersson LC, Seppänen H, Haglund C. Prognostic and diagnostic value of REG4 serum and tissue expression in pancreatic ductal adenocarcinoma. Tumour Biol 2018. [PMID: 29542402 DOI: 10.1177/1010428318761494] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Expression of regenerating islet-derived protein 4 (REG4), a secretory protein involved in cell differentiation and proliferation, is upregulated in inflammatory bowel diseases and in many gastrointestinal malignancies. The prognostic significance of its expression in pancreatic ductal adenocarcinoma is unknown. Our aim was to investigate tumor tissue and serum REG4 expression in pancreatic ductal adenocarcinoma patients. We also evaluated as a control the diagnostic value of serum REG4 level in patients with chronic pancreatitis. Immunohistochemical expression of REG4 was evaluated in 154 surgical specimens and serum REG4 level in 130 samples from pancreatic ductal adenocarcinoma patients treated at Helsinki University Hospital, Finland, in 2000-2011. REG4 tissue and serum expression was assessed in relation to clinicopathological parameters and patient survival. A chronic pancreatitis control group comprised 34 patients who underwent pancreatic resection because of suspicion of malignancy. Significant survival differences were detectable in subgroups: in tumor stages IA-IIA, high serum REG4 level predicted worse survival (p=0.046). In patients with grade I tumor, positive tissue REG4 expression predicted better survival (p=0.006). In multivariate analysis, neither tissue nor serum REG4 expression was independent prognostic factors. Serum REG4 levels were higher in pancreatic ductal adenocarcinoma than in chronic pancreatitis (p=0.002), with diagnostic sensitivity of 45% and specificity of 91%. In logistic regression analysis, a multivariate model with REG4, CA19-9, and age provided sensitivity of 82% and specificity of 79%. REG4 tissue expression is a prognostic marker in subgroups of pancreatic ductal adenocarcinoma patients. Serum REG4 level might be useful in differential diagnosis between pancreatic ductal adenocarcinoma and chronic pancreatitis.
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Affiliation(s)
- Kapo Saukkonen
- 1 Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,2 Translational Cancer Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Jaana Hagström
- 2 Translational Cancer Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.,3 Department of Pathology, Haartman Institute and HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Harri Mustonen
- 1 Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Laura Lehtinen
- 4 Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland
| | - Olli Carpen
- 3 Department of Pathology, Haartman Institute and HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,4 Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland.,5 Genome Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Leif C Andersson
- 3 Department of Pathology, Haartman Institute and HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Hanna Seppänen
- 1 Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Caj Haglund
- 1 Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,2 Translational Cancer Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
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48
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Dai JJ, Jiang MJ, Wang XP, Tian L. Inflammation-Related Pancreatic Carcinogenesis: Mechanisms and Clinical Potentials in Advances. Pancreas 2017; 46:973-985. [PMID: 28796135 DOI: 10.1097/mpa.0000000000000886] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Chronic inflammation has long been considered critical in pancreatic carcinogenesis, and recently studies showed that some anti-inflammatory agents such as aspirin could potentially be used to attenuate pancreatic carcinogenesis. Several inflammation-related critical transcription factors and pathways such as NF-κB (nuclear factor κ-light-chain enhancer of activated B cells) and reactive oxygen species have been confirmed to be involved in carcinogenesis. However, its underlying mechanisms are far from clear, which largely limits further development of potential anticarcinogenesis drugs. As a result, it is of great importance for us to better understand and gain a better perspective in inflammation-related pancreatic carcinogenesis. In this review, we systematically analyzed recent advances concerning inflammation-related pancreatic carcinogenesis and brought out the possible underlying mechanisms. Potential preventive and therapeutic strategies based on anti-inflammatory agents have also been further discussed.
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Affiliation(s)
- Juan-Juan Dai
- From the *Shanghai Key Laboratory of Pancreatic Diseases, †Institute of Translational Medicine, and ‡Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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49
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Fan HH, Li L, Zhang YM, Yang J, Li MC, Zeng FY, Deng F. PKCζ in prostate cancer cells represses the recruitment and M2 polarization of macrophages in the prostate cancer microenvironment. Tumour Biol 2017. [PMID: 28631559 DOI: 10.1177/1010428317701442] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Tumor-associated macrophages are key regulators of the complex interplay between tumor and tumor microenvironment. M2 Macrophages, one type of tumor-associated macrophages, are involved in prostate cancer growth and progression. Protein kinase C zeta has been shown to suppress prostate cancer cell growth, invasion, and metastasis as a tumor suppressor; however, its role in chemotaxis and activation of tumor-associated macrophages remains unclear. Here, we investigated the role of protein kinase C zeta of prostate cancer cells in regulation of macrophage chemotaxis and M2 phenotype activation. Immunohistochemistry was performed to analyze the expression of protein kinase C zeta and the number of CD206+ M2 macrophages in human prostate tissue. Macrophage chemotaxis and polarization were examined using Transwell migration assays and a co-culture system. Quantitative real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay were used to detect M2 markers, protein kinase C zeta, interleukin-4, and interleukin-10 expression. We found the expression of protein kinase C zeta increased in prostate cancer tissues, especially in the early stage, and was negatively associated with tumor grade and the number of CD206+ macrophages. Inhibition of protein kinase C zeta expression in prostate cancer cells promoted chemotaxis of peripheral macrophages and acquisition of M2 phenotypic features. These results were further supported by the finding that silencing of endogenous protein kinase C zeta promoted the expression of prostate cancer cell-derived interleukin-4 and interleukin-10. These results suggest that protein kinase C zeta plays an important role in reducing infiltration of tumor-associated macrophages and activation of a pro-tumor M2 phenotype, which may constitute an important mechanism by which protein kinase C zeta represses cancer progression.
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Affiliation(s)
- Hui-Hui Fan
- 1 Department of Clinical Laboratory, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ling Li
- 2 Department of Clinical Laboratory, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Yu-Ming Zhang
- 3 Department of Clinical Laboratory, Hospital of Integrated Chinese and Western Medicine, Southern Medical University, Guangzhou, China
| | - Jie Yang
- 1 Department of Clinical Laboratory, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Mao-Cheng Li
- 1 Department of Clinical Laboratory, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Fang-Yin Zeng
- 2 Department of Clinical Laboratory, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Fan Deng
- 4 Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
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50
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Zhang W, Chen L, Ma K, Zhao Y, Liu X, Wang Y, Liu M, Liang S, Zhu H, Xu N. Polarization of macrophages in the tumor microenvironment is influenced by EGFR signaling within colon cancer cells. Oncotarget 2016; 7:75366-75378. [PMID: 27683110 PMCID: PMC5342747 DOI: 10.18632/oncotarget.12207] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 09/13/2016] [Indexed: 02/05/2023] Open
Abstract
Epidermal growth factor receptor (EGFR) is a target of colon cancer therapy, but the effects of this therapy on the tumor microenvironment remain poorly understood. Our in vivo studies showed that cetuximab, an anti-EGFR monoclonal antibody, effectively inhibited AOM/DSS-induced, colitis-associated tumorigenesis, downregulated M2-related markers, and decreased F4/80+/CD206+ macrophage populations. Treatment with conditioned medium of colon cancer cells increased macrophage expression of the M2-related markers arginase-1 (Arg1), CCL17, CCL22, IL-10 and IL-4. By contrast, conditioned medium of EGFR knockout colon cancer cells inhibited expression of these M2-related markers and induced macrophage expression of the M1-related markers inducible nitric oxide synthase (iNOS), IL-12, TNF-α and CCR7. EGFR knockout in colon cancer cells inhibited macrophage-induced promotion of xenograft tumor growth. Moreover, colon cancer-derived insulin-like growth factor-1 (IGF-1) increased Arg1 expression, and treatment with the IGF1R inhibitor AG1024 inhibited that increase. These results suggest that inhibition of EGFR signaling in colon cancer cells modulates cytokine secretion (e.g. IGF-1) and prevents M1-to-M2 macrophage polarization, thereby inhibiting cancer cell growth.
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Affiliation(s)
- Weina Zhang
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Lechuang Chen
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Kai Ma
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Yahui Zhao
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Xianghe Liu
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Yu Wang
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Mei Liu
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Shufang Liang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, P.R. China
| | - Hongxia Zhu
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Ningzhi Xu
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, P.R. China
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