M2 macrophages confer resistance to 5-fluorouracil in colorectal cancer through the activation of CCL22/PI3K/AKT signaling
M2 macrophages confer resistance to 5-fluorouracil in colorectal cancer through the activation of CCL22/PI3K/AKT signaling
复制标题
M2 巨噬细胞通过激活 CCL22/PI3K/AKT 信号传导赋予结直肠癌对 5-氟尿嘧啶的耐药性
DOI：
10.2147/ott.s198126
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发表时间：
2019-01-01
影响因子：
4
通讯作者：
Xiong, Bin
中科院分区：
文献类型：
--
作者：
Wei, Chen;Yang, Chaogang;Xiong, Bin
背景资料：M2巨噬细胞是肿瘤微环境的重要组成部分，经常与人类癌症的治疗性治疗有关，但其在结直肠癌（CRC）对5-氟尿嘧啶（5-FU）的化疗敏感性中的作用仍然不清楚。方法：本研究旨在阐明M2巨噬细胞的生物学功能及其对结直肠癌细胞对5-FU化疗敏感性的影响。然后，我们分析了CCL 22与CD 68+和CD 163+肿瘤相关巨噬细胞（TAM）之间的相关性，并进一步阐明了CCL 22和CD 163 + M2巨噬细胞在临床CRC样本中的预后价值。结果如下：M2巨噬细胞通过分泌CCL 22降低5-FU对结直肠癌细胞迁移和侵袭的抑制作用，并抑制5-FU诱导的细胞凋亡。用中和性抗CCL 22抗体治疗破坏了这些作用。我们进一步阐明M2巨噬细胞通过上皮-间质转化（EMT）程序、PI 3 K/AKT通路和caspase介导的凋亡来调节CRC细胞的5-FU抗性。临床上，发现CCL 22在CRC组织样品中具有升高的表达，并且与CD 163 + TAM正相关。此外，大肠癌组织中CD 163 + M2巨噬细胞和CCL 22表达较高的患者的总生存率（OS）较低。结论：我们的研究结果表明，M2巨噬细胞通过EMT程序，PI 3 K/AKT通路和通过释放CCL 22的半胱天冬酶介导的凋亡来调节5-FU介导的CRC化疗耐药性。
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.