Jindao Wu1,2,3,4, Wen Gao5, Qiyun Tang6, Yue Yu1,2,3, Wei You1,2,3,6, Zhengshan Wu1,2,3,6, Ye Fan1,2,3,6, Long Zhang1,2,3, Chen Wu1,2,3, Guoyong Han1,2,3, Xueliang Zuo1,2,3, Yao Zhang1,2,3, Zhiqiang Chen1,2,3, Wenzhou Ding1,2,3, Xiangcheng Li1,2,3, Fengming Lin7, Hongbing Shen4,8, Jinhai Tang6, Yaqin Zhang9,10, Xuehao Wang1,2,3,4. 1. Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. 2. Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China. 3. NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China. 4. State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China. 5. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. 6. Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. 7. The State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China. 8. Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China. 9. Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China. 10. The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
Abstract
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, 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. 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.
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, 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. 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.
Authors: Agathe Quesnel; Amy Broughton; George S Karagiannis; Panagiota S Filippou Journal: Cancer Metastasis Rev Date: 2022-04-08 Impact factor: 9.264