Review Article

Cellular and molecular mechanisms of hepatic fibrogenesis leading to liver cancer

Samuele De Minicis, Marco Marzioni, Stefania Saccomanno, Chiara Rychlicki, Laura Agostinelli, Luciano Trozzi, Antonio Benedetti, Gianluca Svegliati-Baroni


Currently, hepatic fibrosis is considered a model of the wound-healing response to chronic liver injury (1). The excessive extracellular matrix (ECM) deposition that distorts the hepatic architecture by forming fibrotic scars, and the subsequent development of nodules of regenerating hepatocytes defines liver cirrhosis (2-5). The clinical importance of liver cirrhosis is related to the associated hepatocellular dysfunction and increased intrahepatic resistance to blood flow, which result in hepatic insufficiency and portal hypertension, respectively, and to the occurrence of hepatocellular carcinoma (6). The incidence of hepatocellular carcinoma (HCC) is rising in North America, Europe, and Eastern countries such as China and Japan (7). This increase is largely due to the emergence of hepatitis C virus (HCV), the continued problem of hepatitis B virus (HBV) infection control, and the liver pathologies associated with obesity and chronic alcohol abuse. The increasing levels of obesity in these countries is a particularly significant epidemiological factor that will ensure further worldwide rises in HCC incidence over the next decade (8). There is therefore an urgent need to understand how HCC develops in the diseased liver. In this respect, it is often overlooked that 90% of HCC cases have a natural history of unresolved inflammation and severe fibrosis (or cirrhosis). Approaches to HCC prevention should therefore focus on the molecular regulators of a disease process that we could define as the inflammation-fibrosis-cancer (IFC) axis.