Title: Contributions of Activated Hepatic Stellate Cells to Hepatocarcinogenesis
Description: Hepatocellular carcinoma (HCC), the second leading cause of worldwide cancer mortality, develops almost exclusively in patients with chronic liver disease. Approximately 90% of HCCs arise in fibrotic livers suggesting that wound healing contributes to HCC development. Despite this strong association, it is not known whether fibrosis actively contributes to HCC development. Here, we investigate the hypothesis that activated hepatic stellate cells (HSCs), the primary source of hepatic myofibroblasts, contribute to hepatocarcinogenesis. In a first study, we demonstrate that the intestinal microbiota and Toll-like receptor 4 (TLR4) promote hepatocarcinogenesis. Activation of TLR4 on activated HSCs triggered the secretion of the hepatomitogen epiregulin and epiregulin-dependent promotion of hepatocarcinogenesis. Non-absorbable antibiotics reduced HCC development, even when given at late stages of hepatocarcinogenesis, suggesting that targeting the intestinal microbiota-TLR4 pathway represents a novel therapeutic approach for HCC prevention.

In a second study, we tested the hypothesis that extracellular matrix production by activated HSCs contributes to a tumor-prone hepatic microenvironment. We generated a novel genetic model of selective HSC activation that allows investigating functional links between fibrosis and HCC development without confounding injury, inflammation and regeneration common to most fibrosis models. We provide functional evidence that HSC activation and liver fibrosis actively promote hepatocarcinogenesis, as evidenced by a five-fold increase in tumor burden in mice with genetically-induced HSC activation. Taken together, our studies implicate activated HSCs in the promotion of HCC through inflammatory and non-inflammatory signaling pathways, and suggest that HSCs should be considered a possible target for HCC prevention strategies.