Open Access<p>M2 macrophages confer resistance to 5-fluorouracil in colorectal cancer through the activation of CCL22/PI3K/AKT signaling</p>
Author(s) -
Wei Chen,
Chaogang Yang,
Shuyi Wang,
Dongdong Shi,
Chunxiao Zhang,
Xiaobin Lin,
Bin Xiong
Publication year - 2019
Publication title -
oncotargets and therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.054
H-Index - 60
ISSN - 1178-6930
DOI - 10.2147/ott.s198126
Subject(s) - ccl22 , tumor associated macrophage , cancer research , protein kinase b , apoptosis , cd163 , pi3k/akt/mtor pathway , colorectal cancer , macrophage , m2 macrophage , tumor microenvironment , cd68 , medicine , cancer , chemistry , immunology , chemokine , inflammation , immunohistochemistry , chemokine receptor , in vitro , tumor cells , biochemistry
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.