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Authors Wei C, Yang C, Wang S, Shi D, Zhang C, Lin X, Xiong B
Received 13 December 2018
Accepted for publication 12 March 2019
Published 18 April 2019 Volume 2019:12 Pages 3051—3063
DOI https://doi.org/10.2147/OTT.S198126
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Colin Mak
Peer reviewer comments 2
Editor who approved publication: Dr William Cho
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.
Keywords: M2
macrophages, colorectal cancer, 5-fluorouracil, chemotherapy resistance, CCL22