Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality and has an increasing incidence worldwide. HCC can be induced by multiple etiologies, is influenced by many risk factors, and has a complex pathogenesis. Furthermore, HCCs exhibit substantial heterogeneity, which compounds the difficulties in developing effective therapies against this highly lethal cancer. With advances in cancer biology and molecular and genetic profiling, a number of different mechanisms involved in the development and progression of HCC have been identified. Despite the advances in this area, the molecular pathogenesis of hepatocellular carcinoma is still not completely understood. This review aims to elaborate our current understanding of the most relevant genetic alterations and molecular pathways involved in the development and progression of HCC, and anticipate the potential impact of future advances on therapeutic drug development.

Keywords: HCC; hepatocellular carcinoma; liver cancer.

Figure 1.. Natural history of precancerous lesions.

Dysplastic foci (<1 mm) or dysplastic nodules (DNs) (≥1 mm) are considered precancerous lesions and are classified into low and high grade. Both low- and high-grade nodules have the potential to evolve into HCC, but high-grade DN have a much greater risk. Early HCCs are characterized by the presence of stromal invasion. HCC is further subclassified into early HCC and progressed HCC based on features noted in the figure. Abbreviations: HCC, hepatocellular carcinoma; HG-DN, high-grade dysplastic nodule; LG-DN, low-grade dysplastic nodule.

Figure 2.. Pathogenesis of Hepatocellular Carcinoma.

Chronic exposure of the liver to injury from viral hepatitis, alcohol abuse or NASH causes repeated hepatocyte damage and sets up a vicious cycle of cell death and regeneration which eventually results in cirrhosis. The resultant genomic instability leads to initiation of HCC. Step wise accumulation of multiple genetic events including gene rearrangements, somatic mutations, copy number alterations, epigenetic changes and growth factor pathway alterations eventually lead to tumor progression and metastases. Abbreviations: Hep B, hepatitis B; Hep C, hepatitis C; HCC, hepatocellular carcinoma; NASH, non-alcoholic steatohepatitis.