Inducible factors for cancer-associated fibroblasts in liver cancer versus myofibroblasts in inflammatory liver disease.

The importance of cancer-associated fibroblasts (CAFs) in liver cancer, cholangiocarcinoma (CC) and hepatocellular carcinoma (HCC), has been appreciated in the past 5 years. We focused on how they get activated in the tumor microenvironment in this review. Not only hepatic stellate cells (HSCs) but also portal fibroblasts (PFs) have been appreciated to be key players in liver fibrogenesis, and their different roles have just started to be recognized. Since the role of cholangiocyte in biliary fibrogenic disease might have some similarities to that of CC, we focused on the role of cholangiocytes activating stromal fibroblasts, which would presumably be helpful for better understanding the mechanism of tumor-CAFs interaction. In addition, the activation of CAFs should be different from that of CAFs in HCC, which we consider to be potentially similar to MFs in hepatocyte injury-dependent liver fibrogesis. Herein, we describe the activation of CAFs in CC in comparison to MFs seen in other liver diseases such as 1) MFs in liver fibrosis caused by hepatocyte injury such as alcoholic hepatitis, viral hepatitis, and nonalcoholic steatosis, 2) MFs in liver fibrosis caused by cholestatic disease, and 3) CAFs in hepatocellular carcinoma (HCC). This review on the activation of fibroblasts either in liver cancer or in chronic liver disease would contribute to CAF-targeted therapy in liver cancer.