Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China.
Hepatology. 2021 Apr;73(4):1365-1380. doi: 10.1002/hep.31432.
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, α β (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.
肝细胞癌（HCC）的发生发展依赖于其局部微环境。肿瘤相关巨噬细胞（TAMs）被认为是肿瘤微环境的关键因素，并有助于促进肿瘤侵袭性。然而，TAMs 对 HCC 促转移作用的详细机制尚不清楚。
本研究证明 TAMs 在 HCC 中富集。TAMs 表现出 M2 极化表型，并在体外和体内加速 HCC 细胞的迁移潜能。此外，我们发现 M2 衍生的外泌体诱导了 TAM 介导的促迁移活性。通过使用质谱，我们鉴定出整合素，αβ（CD11b/CD18）在 M2 巨噬细胞衍生的外泌体（M2 外泌体）中具有显著的特异性和效率。阻断 CD11b 和/或 CD18 可显著减少 M2 外泌体介导的 HCC 细胞转移。在机制上，M2 外泌体介导了 CD11b/CD18 细胞间的转移，激活了受体 HCC 细胞中的基质金属蛋白酶-9 信号通路，从而支持肿瘤迁移。
总之，TAMs 到肿瘤细胞的外泌体介导的功能性 CD11b/CD18 蛋白转移可能具有增强 HCC 细胞迁移潜能的潜力，从而深入了解肿瘤转移的机制。
