M2 Macrophage-Derived Exosomes Facilitate HCC Metastasis by Transferring αMβ2 Integrin to Tumor Cells

Background and Aims The development and progression of hepatocellular carcinoma (HCC) is dependent on its local microenvironment. Tumor-associated macrophages (TAMs) are deemed a key factor for the tumor microenvironment and attribute to contribute to tumor aggressiveness. However, the detailed mechanism underlying the pro-metastatic effect of TAMs on HCC remains undefined. Approach and Results The present study proved that TAMs were enriched in HCC. TAMs were characterized by an M2-polarized phenotype and accelerated the migratory potential of HCC cells in vitro and in vivo. Furthermore, we found that M2-derived exosomes induced TAM-mediated pro-migratory activity. With the use of mass spectrometry, we identified that integrin, alpha(M)beta(2) (CD11b/CD18), was notably specific and efficient in M2 macrophage-derived exosomes (M2 exos). Blocking either CD11b and/or CD18 elicited a significant decrease in M2 exos-mediated HCC cell metastasis. Mechanistically, M2 exos mediated an intercellular transfer of the CD11b/CD18, activating the matrix metalloproteinase-9 signaling pathway in recipient HCC cells to support tumor migration. Conclusions Collectively, the exosome-mediated transfer of functional CD11b/CD18 protein from TAMs to tumor cells may have the potency to boost the migratory potential of HCC cells, thus providing insights into the mechanism of tumor metastasis.

Automated summary

This study showed that TAMs are enriched in HCC and promote the migratory potential of HCC cells through M2-derived exosomes. The specific and efficient presence of CD11b/CD18 in M2 exos was identified using mass spectrometry. Blocking CD11b and/or CD18 significantly decreased M2 exos-mediated HCC cell metastasis, highlighting the potential role of TAM-derived exosomes in promoting tumor migration.