Pathogenesis and prevention of hepatitis C virus-induced hepatocellular carcinoma

Abstract

Hepatitis C virus (HCV) is one of the major aetiologic agents that causes hepatocellular carcinoma (HCC) by generating an inflammatory, fibrogenic, and carcinogenic tissue microenvironment in the liver. HCV-induced HCC is a rational target for cancer preventive intervention because of the clear-cut high-risk condition, cirrhosis, associated with high cancer incidence (1% to 7% per year). Studies have elucidated direct and indirect carcinogenic effects of HCV, which have in turn led to the identification of candidate HCC chemoprevention targets. Selective molecular targeted agents may enable personalized strategies for HCC chemoprevention. In addition, multiple experimental and epidemiological studies suggest the potential value of generic drugs or dietary supplements targeting inflammation, oxidant stress, or metabolic derangements as possible HCC chemopreventive agents. While the successful use of highly effective direct-acting antiviral agents will make important inroads into reducing long-term HCC risk, there will remain an important role for HCC chemoprevention even after viral cure, given the persistence of HCC risk in persons with advanced HCV fibrosis, as shown in recent studies. The successful development of cancer preventive therapies will be more challenging compared to cancer therapeutics because of the requirement for larger and longer clinical trials and the need for a safer toxicity profile given its use as a preventive agent. Molecular biomarkers to selectively identify high-risk population could help mitigate these challenges. Genome-wide, unbiased molecular characterization, high-throughput drug/gene screening, experimental model-based functional analysis, and systems-level in silico modelling are expected to complement each other to facilitate discovery of new HCC chemoprevention targets and therapies.

Keywords: Carcinogenesis; Hepatitis C virus; Hepatocellular carcinoma; Prevention.

Figure 1. Natural history and biological processes in HCV-induced HCC development

HCV: hepatitis C virus, HCC: hepatocellular carcinoma, LPS: lipopolysaccharide, SNP: single nucleotide polymorphism.

Figure 2. Interactions of HCV with cellular components in cirrhotic tissue microenvironment that promote hepatocarcinogenesis

Potential HCC chemoprevention targets are extracted from the broader pathogenic involvement of HCV in the development of hepatitis, fibrosis, and cirrhosis. HCV proteins directly or indirectly promote cellular proliferation and survival, induce inflammation, metabolic pathway deregulation leading to steatosis, oxidative stress, endoplasmic reticulum (ER) stress, DNA damage and genetic instability, expansion of tumor-initiating cell (TIC)/cancer stem cell (CSC), fibrogenesis by activating hepatic stellate cells, and attenuate immune cell response leading to immune evasion. Genes/proteins and pathways for which pharmacological interventions have been clinically evaluated (not limited to liver diseases) are highlighted in bold. HCV: hepatitis C virus, HCC: hepatocellular carcinoma, ECM: extracellular matrix.