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.

中文翻译：

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外泌体包裹的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。

肿瘤相关巨噬细胞 (TAM) 是与癌症转移相关的重要免疫细胞。然而，TAM 是否在介导 CXCL12/CXCR4 诱导的结直肠癌 (CRC) 肝转移中起主导作用仍有待探索。在此，我们发现在侵袭前沿浸润的 CD206+ TAM 与临床标本中 CXCR4 的表达和 CRC 的肝转移相关。通过激活 CXCL12/CXCR4 轴在 CRC 细胞中上调的几种 miRNA（miR-25-3p、miR-130b-3p、miR-425-5p）可以通过外泌体转移到巨噬细胞中。这些外泌体 miRNA 通过激活 PI3K/Akt 信号通路来调节 PTEN，从而诱导巨噬细胞的 M2 极化。反过来，M2极化巨噬细胞通过增强上皮间质转化（EMT）和分泌血管内皮生长因子（VEGF）来促进癌症转移。CRC 细胞与转染这些 miRNA 或用外泌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-25-3p、miR-130b-3p 和 miR-425-5p 的血清水平与 CRC 的进展和转移相关。总之，这些结果揭示了外泌体 miRNA 在介导 CXCR4 过表达癌细胞和 TAM 之间的串扰中的关键作用，为规避 CRC 肝转移提供了潜在的治疗靶点。临床上，外泌体 miR-25-3p、miR-130b-3p 和 miR-425-5p 的血清水平与 CRC 的进展和转移相关。总之，这些结果揭示了外泌体 miRNA 在介导 CXCR4 过表达癌细胞和 TAM 之间的串扰中的关键作用，为规避 CRC 肝转移提供了潜在的治疗靶点。临床上，外泌体 miR-25-3p、miR-130b-3p 和 miR-425-5p 的血清水平与 CRC 的进展和转移相关。总之，这些结果揭示了外泌体 miRNA 在介导 CXCR4 过表达癌细胞和 TAM 之间的串扰中的关键作用，为规避 CRC 肝转移提供了潜在的治疗靶点。