期刊
ONCOTARGETS AND THERAPY
卷 12, 期 -, 页码 3051-3063出版社
DOVE MEDICAL PRESS LTD
DOI: 10.2147/OTT.S198126
关键词
M2 macrophages; colorectal cancer; 5-fluorouracil; chemotherapy resistance; CCL22
资金
- National Natural Science Foundation of China [81572874]
- National Natural Science Fund Youth Fund of China [81702411]
- Zhongnan Hospital of Wuhan University, Technology and Innovation Seed Found [znpy 2016058]
Background: M2 macrophages are crucial components of tumor microenvironment that frequently associated with the resistance of therapeutic treatments in human cancers, but their role in the chemosensitivity of colorectal cancer (CRC) to 5-fluorouracil (5-FU) is still obscure. Methods: In our study, we clarified the biological functions of M2 macrophages and their mechanism on the chemosensitivity of CRC cells to 5-FU. Then, we analyzed the correlation between CCL22 and CD68(+) and CD163(+) tumor-associated macrophages (TAMs), and further elucidated the prognostic value of CCL22 and CD163(+) M2 macrophages in clinical CRC samples. Results: M2 macrophages decreased the inhibitory effect of 5-FU on CRC cells migration and invasion by secreting CCL22, and declined the apoptosis induced by 5-FU. Treated with a neutralizing anti-CCL22 antibody destroyed these effects. We further illuminated that M2 macrophages regulated 5-FU resistance of CRC cells through epithelial-mesenchymal transition (EMT) program, PI3K/AKT pathway, and caspase-mediated apoptosis. Clinically, CCL22 was found to have elevated expression in CRC tissue samples, and was positively associated with CD163(+) TAMs. Furthermore, the patients with higher CD163(+) M2 macrophages and higher expression of CCL22 in CRC tissues had a lower overall survival (OS) rate compared with lower ones. Conclusion: Our findings indicate that M2 macrophage regulated 5-FU-mediated CRC chemoresistance via the EMT program, PI3K/AKT pathway, and caspase-mediated apoptosis by releasing CCL22.
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