TGF-β Signaling in Onset and Progression of Hepatocellular Carcinoma

Transforming growth factor (TGF)-beta is a central regulator in chronic liver disease, contributing to all stages of disease progression from initial liver injury through inflammation and fibrosis to cirrhosis and hepatocellular carcinoma. Liver damage-induced levels of active TGF-beta enhance hepatocyte destruction and mediate hepatic stellate cell and fibroblast activation resulting in a wound-healing response, including myofibroblast generation and extracellular matrix deposition. Further evidence points to a decisive role of cytostatic and apoptotic functions mediated on hepatocytes, which is critical for the control of liver mass, with loss of TGF-beta activities resulting in hyperproliferative disorders and cancer. This concept is based on studies that describe a bipartite role of TGF-beta with tumor suppressor functions at early stages of liver damage and regeneration, whereas during cancer progression TGF-beta may turn from a tumor suppressor into a tumor promoter that exacerbates invasive and metastatic behavior. We have delineated this molecular switch of the pathway from cytostatic to tumor promoting in further detail and identify activation of survival signaling pathways in