Exosome-encapsulated miRNAs contribute to CXCL12/CXCR4-induced liver metastasis of colorectal cancer by enhancing M2 polarization of macrophages

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.