IGFBP2 promotes tumor progression by inducing alternative polarization of macrophages in pancreatic ductal adenocarcinoma through the STAT3 pathway
Autor: | Huamin Wang, Elizabeth Forbes, Jason B. Fleming, Zhixiang Zhang, Weijun Tian, Longhao Sun, Boris Pasche, Ya'an Kang, Qianqian Song, Xuebin Zhang, Wei Zhang, Liang Liu |
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Rok vydání: | 2021 |
Předmět: |
STAT3 Transcription Factor
0301 basic medicine Cancer Research endocrine system diseases medicine.medical_treatment Adenocarcinoma Article Mice 03 medical and health sciences 0302 clinical medicine In vivo Cell Line Tumor Tumor-Associated Macrophages medicine Animals Humans STAT3 Cell Proliferation biology Chemistry Growth factor Cell Polarity M2 Macrophage Phenotype Insulin-Like Growth Factor Binding Protein 2 030104 developmental biology Oncology Tumor progression 030220 oncology & carcinogenesis Disease Progression biology.protein Cancer research STAT protein Heterografts Signal transduction Carcinoma Pancreatic Ductal Signal Transduction |
Zdroj: | Cancer Lett |
ISSN: | 0304-3835 |
Popis: | Tumor-associated macrophages (TAMs) represent the M2-like phenotype with potent immunosuppressive activity, and play a pro-tumor role in pancreatic ductal adenocarcinoma (PDAC) biology. In this study, we investigated the role of the insulin-like growth factor binding protein 2 (IGFBP2) as a determinant of TAM polarity. Clinical data revealed that the levels of IGFBP2 correlated with M2 TAMs accumulation and disease progression in human PDAC. In vivo mouse model experiments showed that IGFBP2 promoted an immunosuppressive microenvironment and tumor growth in a macrophage dependent manner. Bioinformatics analysis of PDAC transcriptomes revealed a significant association between IGFBP2 expression and M2 macrophage polarization and signal transducer and activator of transcription 3 (STAT3) activation. Mechanistic investigations demonstrated that IGFBP2 augmented the expression and secretion of IL-10 through STAT3 activation in PDAC cells, which induced TAM polarization toward an M2 phenotype. IGFBP2-polarized M2 macrophages significantly increased Tregs infiltration and impaired antitumor T-cell immunity in a mouse model. Thus, our investigations have illuminated the IGFBP2 signaling pathway that contributes to the macrophage-based immunosuppressive microenvironment in PDAC, suggesting that blocking the IGFBP2 axis constitutes a potential treatment strategy to reset TAM polarization toward an antitumor state in PDAC. |
Databáze: | OpenAIRE |
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