Exosome-encapsulated miRNAs contribute to CXCL12/CXCR4-induced liver metastasis of colorectal cancer by enhancing M2 polarization of macrophages
Exosome-encapsulated miRNAs contribute to CXCL12/CXCR4-induced liver metastasis of colorectal cancer by enhancing M2 polarization of macrophages
复制标题
外泌体封装的 miRNA 通过增强巨噬细胞的 M2 极化促进 CXCL12/CXCR4 诱导的结直肠癌肝转移
DOI：
10.1016/j.canlet.2020.01.005
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发表时间：
2020-01-01
期刊：
影响因子：
9.7
通讯作者：
Yu, Xinfeng
中科院分区：
文献类型：
--
作者：
Wang, Dong;Wang, Xiaohui;Yu, Xinfeng
肿瘤相关巨噬细胞（Tumor-associated macrophages，TAM）是与肿瘤转移相关的重要免疫细胞。然而，TAMs是否在介导CXCL 12/CXCR 4诱导的结直肠癌（CRC）肝转移中起主导作用仍有待研究。在此，我们发现在临床标本中，浸润在浸润前沿的CD 206（+）TAMs与CXCR 4表达和结直肠癌肝转移相关。在CRC细胞中通过激活CXCL 12/CXCR 4轴而上调的几种miRNA（miR-25- 3 p、miR-130 b-3 p、miR-425- 5 p）可以通过外泌体转移到巨噬细胞。这些外泌体miRNAs通过激活PI 3 K/Akt信号通路调节PTEN，诱导巨噬细胞M2极化。反过来，M2极化巨噬细胞通过增强上皮-间充质转化（EMT）和分泌血管内皮生长因子（VEGF）促进癌症转移。CRC细胞与用这些miRNA转染或用外来体处理的巨噬细胞的共培养增强了它们在体外和体内的转移能力。临床上，外泌体miR-25- 3 p、miR-130 b-3 p和miR-425- 5 p的血清水平与结直肠癌的进展和转移相关。总之，这些结果揭示了外泌体miRNA在介导CXCR 4过表达癌细胞和TAM之间的串扰中的关键作用，为规避CRC的肝转移提供了潜在的治疗靶点。
Tumor-associated macrophages (TAMs) are important immunocytes associated with cancer metastasis. However, whether TAMs play a dominant role in mediating CXCL12/CXCR4-induced liver metastasis of colorectal cancer (CRC) remains unexplored. Herein, we found that CD206(+) TAMs, which infiltrated at the invasive front, were correlated with CXCR4 expression and liver metastasis of CRC in clinical specimens. Several miRNAs (miR-25-3p, miR-130b-3p, miR-425-5p), upregulated in CRC cells by activation of the CXCL12/CXCR4 axis, could be transferred to macrophages via exosomes. These exosomal miRNAs induced M2 polarization of macrophages by regulating PTEN through activation of PI3K/Akt signaling pathway. In turn, M2 polarized macrophages promoted cancer metastasis by enhancing epithelial-mesenchymal transition (EMT) and secreting vascular endothelial growth factor (VEGF). Co-culture of CRC cells with macrophages transfected with these miRNAs or treated with exosomes enhanced their metastatic capacity both in vitro and in vivo. Clinically, the serum levels of exosomal miR-25-3p, miR-130b-3p and miR-425-5p were correlated with progression and metastasis of CRC. In conclusion, these results reveal a crucial role of exosomal miRNAs in mediating the crosstalk between CXCR4 overexpressing cancer cells and TAMs, providing potential therapeutic targets for circumventing liver metastasis of CRC.