Exosomal Complement Factor H Promotes Liver Cancer Metastasis by Inhibiting Complement-dependent Cytotoxicity of Tumor Cells

Hepatocellular carcinoma (HCC), the seventh most common malignancy in the world, can cause deaths of approximately 780,000 patients each year. Although a large number of studies have been conducted for a long time, the current treatment level of HCC is very limited, and many treatments are only effective for early HCC. However, most HCC are diagnosed in the advanced stage. Usually, patients with advanced stage have extrahepatic metastasis. This metastasis is not a random process. Therefore, studying the mechanism of HCC metastasis is beneficial to the early diagnosis of patients and the development of novel therapeutic strategy.<br> <br>Many recent studies have found that exosomes play an important role in intercellular communication. Exosomes transfer their contents, causing localized effects of cancer cells on surrounding cells and systemic effects on distant cells. Our results indicate that exosomes derived from metastatic HCC cells increased the migratory and invasive potentials of liver cancer cells and metastasis in animal models. Further analysis of exosomal proteins by proteomic analysis revealed that complement factor H (CFH) is highly expressed in exosomes of metastatic HCC cells.<br> <br>CFH is a major inhibitor of the immune defense complement system. We generated stable CFH knockdown clones in metastatic HCC cells. It was confirmed that reduced CFH expression was observed in the total cell lysates and exosomes of the stable clones, resulting in the decreased oncogenic properties of cells and exosomes. We also showed that HCC cells treated with exosomes of non-target control cells had a decrease in complement-mediated cytotoxicity when compared to the cells treated with exosomes derived from CFH knockdown cells suggesting that CFH protects HCC cells by evading complement attack.<br> <br>Based on the above, we hypothesize that exosomal CFH inhibits complement activation in the tumor microenvironment to promote HCC tumorigenesis and metastasis. Although we do not fully understand the role of CFH in tumor development, our study provides new insights into the functional role of CFH in HCC and provides a basis for further study of other potential roles of CFH in carcinogenesis.<br><br>