Prevention of hepatocellular carcinoma: potential targets, experimental models, and clinical challenges

Abstract

Chronic fibrotic liver diseases such as viral hepatitis eventually develop liver cirrhosis, which causes occurrence of hepatocellular carcinoma (HCC). Given the limited therapeutic efficacy in advanced HCC, prevention of HCC development could be an effective strategy for improving patient prognosis. However, there is still no established therapy to meet the goal. Studies have elucidated a wide variety of molecular mechanisms and signaling pathways involved in HCC development. Genetically-engineered or chemically-treated experimental models of cirrhosis and HCC have been developed and shown their potential value in investigating molecular therapeutic targets and diagnostic biomarkers for HCC prevention. In this review, we overview potential targets of prevention and currently available experimental models, and discuss strategies to translate the findings into clinical practice.

Fig. (1)

Mechanisms of hepatocarcinogenesis. Molecular pathways involved in HCC tumor development are summarized in upper panel. HCC tumor often develops as subnodule within high-grade dysplastic nodule accompanied with various molecular aberrations. Lower panel summarizes molecular alterations observed during the course of progressive liver fibrosis that leads to establishment of cirrhosis. Cirrhotic microenvironment in the liver is assumed to support initiation and promotion of hepatocarcinogenesis (so called “field effect” or “field cancerization”). HCC: hepatocellular carcinoma, HBV: hepatitis B virus, HCV: hepatitis C virus, NAFLD: non-alcoholic fatty liver disease, HSC: hepatic stellate cell

Fig. (2)

Molecular pathways in hepatic myofibroblast. Hepatic myofibroblasts, mainly derived from transdifferentiated hepatic stellate cells and periportal/perivascular fibroblasts, play major role in liver fibrogenesis. Various paracrine stimuli trigger the activation characterized by several phenotypic changes that involve specific genes and pathways (see text for details).