Links between injury, fibrosis and cancer in the liver

80-90% of HCCs arise in fibrotic livers, typically following decades of chronic injury and fibrogenesis. Accordingly, carcinogenesis in the liver has been compared to a “wound that does not heal”, with stepwise progression... [ view full abstract ]

80-90% of HCCs arise in fibrotic livers, typically following decades of chronic injury and fibrogenesis. Accordingly, carcinogenesis in the liver has been compared to a “wound that does not heal”, with stepwise progression from fibrosis to cirrhosis and HCC. Here, we will present data on the role of liver injury (part I) and fibrosis (part II) in the development of HCC. Hepatocellular death is a key driver of inflammation and maladaptive wound healing in the injured liver, thereby fostering the development of a tumor-prone environment. It is well established that cell death increases the risk for the development of hepatocellular carcinoma (HCC) in patients and mouse models. However, the mechanisms by which cell death promotes HCC remain largely elusive. We investigated the hypothesis that damage-associated molecular patterns (DAMPs) may link hepatocellular death to fibrosis and carcinogenesis in the liver, focusing on the contribution of high mobility group box 1 (HMGB1), a DAMP with key roles in hepatic wound healing responses. Albumin-Cre induced ablation of HMGB1 inhibited HCC formation in three mouse models of HCC with chronic cell death. In contrast, HMGB1 ablation did not alter HCC development in a model without chronic cell death. We did not observe any significant differences in proliferation, fibrosis or inflammation between HMGB1-deleted mice and their floxed counterpart, but found a significant reduction of progenitors markers expression in chronic liver injury and within HCC. Mechanistic studies suggested a role for HMGB1 and its receptor RAGE in determining HCC phenotype and aggressiveness. In part II of this presentation, we will present data on the role of myfibroblasts in HCC development. Using lineage tracing, we found that the majority of cancer-associated fibroblasts (CAF) were derived from hepatic stellate cells (HSC). Next, we genetically activated HSC, which resulted in a significant increase in tumor formation in a model of DEN-induced hepatocarcinogenesis, supporting the hypothesis that CAF provide a supportive niche that promotes liver cancer growth. Increased HCC formation was accompanied by reduced apoptosis in tumors. Together, our data suggest that HSC-derived CAF may represent a potential therapeutic target in liver cancer.