title: Cancer-associated fibroblasts promote M2 polarization of macrophages in pancreatic ductal adenocarcinoma.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is characterized by remarkable desmoplasia with infiltration of distinct cellular components. Cancer-associated fibroblasts (CAFs) has been shown to be among the most prominent cells and played a significant role in shaping the tumor microenvironment by interacting with other type of cells. Here, we aimed to investigate the effect of CAFs in modulating phenotype of tumor-associated macrophages (TAM). Under treatment of CAFs conditioned medium (CM) or direct co-culture with CAFs, monocytes exhibited enhanced expression of CD206 and CD163 compared with control group (P < 0.01). The induction of M2 polarization was mediated by increased reactive oxygen species (ROS) production in monocytes as ROS elimination abolished the effect of CAFs (P < 0.05). The supernatant analysis showed that pancreatic CAFs produced increased macrophage colony-stimulating factor (M-CSF). Upon treatment of M-CSF neutralizing antibody, the ROS generation and M2 polarization of CAFs CM-stimulated monocytes were significantly inhibited (P < 0.05). In addition, the CAFs-induced M2 macrophages significantly enhanced pancreatic tumor cell growth, migration, and invasion. Collectively, our data revealed that pancreatic CAFs were able to induce a tumor-promoting TAM phenotype partly through secreted M-CSF and enhanced ROS production in monocytes, indicating possible treatment strategies by targeting stromal cell interaction within PDAC microenvironment.
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China.|Key Laboratory of Organ Transplantation, Hangzhou, China.|Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China.
authors.forename: Aibin
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China.|Key Laboratory of Organ Transplantation, Hangzhou, China.|Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China.
authors.forename: Yigang
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China.|Key Laboratory of Organ Transplantation, Hangzhou, China.|Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China.|Key Laboratory of Organ Transplantation, Hangzhou, China.|Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China.
authors.forename: Haiyong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China.|Key Laboratory of Organ Transplantation, Hangzhou, China.|Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Xie
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China.|Key Laboratory of Organ Transplantation, Hangzhou, China.|Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China.|Key Laboratory of Organ Transplantation, Hangzhou, China.|Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China.|Key Laboratory of Organ Transplantation, Hangzhou, China.|Collaborative innovation center for Diagnosis treatment of infectious diseases, Hangzhou, China.
authors.forename: Shusen
authors.initials: S
authors.lastname: Zheng
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism / Q000473:pathology*; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D016764:Cell Polarity; D049109:Cell Proliferation; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D017077:Culture Media, Conditioned; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D016173:Macrophage Colony-Stimulating Factor
keywords: Cancer-associated fibroblasts; Macrophage colony-stimulating factor (M-CSF); pancreatic adenocarcinoma; reactive oxygen species; tumor-associated macrophages