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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. 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, αM β2 (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. 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. © 2020 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.


Jindao Wu, Wen Gao, Qiyun Tang, Yue Yu, Wei You, Zhengshan Wu, Ye Fan, Long Zhang, Chen Wu, Guoyong Han, Xueliang Zuo, Yao Zhang, Zhiqiang Chen, Wenzhou Ding, Xiangcheng Li, Fengming Lin, Hongbing Shen, Jinhai Tang, Yaqin Zhang, Xuehao Wang. M2 Macrophage-Derived Exosomes Facilitate HCC Metastasis by Transferring αM β2 Integrin to Tumor Cells. Hepatology (Baltimore, Md.). 2021 Apr;73(4):1365-1380

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PMID: 32594528

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