期刊
CANCER MEDICINE
卷 6, 期 2, 页码 463-470出版社
WILEY
DOI: 10.1002/cam4.993
关键词
Cancer-associated fibroblasts; Macrophage colony-stimulating factor ( MCSF); pancreatic adenocarcinoma; reactive oxygen species; tumor-associated macrophages
类别
资金
- Foundation for Innovative Research Groups of the National Natural Science Foundation of China [81421062]
- National Natural Science Foundation of China [81373160]
- Zhejiang Provincial Natural Science Foundation of China [LY12H16011]
- Key project of appropriate technological achievement transfer for primary medical care in the twelfth Five- Year Plan of Zhejiang province [2013T301-15]
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.
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