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Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma

Nature Reviews Cancer volume 13, pages 123–135 (2013)Cite this article

Subjects

Key Points

  • Hepatitis B virus (HBV) and hepatitis C virus (HCV) are major aetiological agents of chronic liver disease and hepatocellular carcinoma (HCC). HCC is the fifth most prevalent tumour type and the third leading cause of cancer-related deaths worldwide, which is why it is so important to find early diagnostic markers and therapeutic targets, particularly when these markers and targets are common to both chronic infections.

  • Alterations in multiple signalling pathways and patterns of host gene expression have been documented following HBV and HCV infections, but their relative importance to the pathogenesis of HCC has not been clearly defined. This has limited the ability to design appropriate therapeutic intervention strategies, and to determine the best time during chronic infection for their application.

  • The pathogenesis of HBV and HCV infections is generally immune mediated, although these viruses have evolved multiple mechanisms to escape immune elimination and to continue replicating in an infected host for many years.

  • Chronic infection with either virus can result in inflammation and oxidative stress. A prolonged fibrotic response, resulting in cirrhosis, is also common in both infections, which is accompanied by the appearance of localized hypoxia, rearrangement of tissue architecture (epithelial–mesenchymal transition) and angiogenesis.

  • Altered host gene expression in chronic liver disease may be mediated by epigenetic changes, by inhibition of DNA repair and/or by differential expression of microRNAs. These alterations include constitutive upregulated expression of factors involved in 'stemness', suggesting that both viruses may contribute to HCC by promoting stemness.

  • Early biomarkers and tumour-specific treatments for HCC are mostly lacking, although several signalling cascades that are activated in the liver before tumour appearance suggest that oncogene addiction may be important to the pathogenesis of HCC.

  • Understanding common mechanisms of HBV and HCV pathogenesis will help to focus efforts on therapeutic targets that may be most useful in the development of new treatment approaches.

Abstract

Hepatocellular carcinoma (HCC) is a highly lethal cancer, with increasing worldwide incidence, that is mainly associated with chronic hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections. There are few effective treatments partly because the cell- and molecular-based mechanisms that contribute to the pathogenesis of this tumour type are poorly understood. This Review outlines pathogenic mechanisms that seem to be common to both viruses and which suggest innovative approaches to the prevention and treatment of HCC.

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Figure 1: The HBV genome and encoded genes.
Figure 2: The HCV genome and encoded proteins.
Figure 3: Immunity in the natural history of HBV and HCV infections.
Figure 4: Signalling pathways targeted by HBV and HCV in CLD pathogenesis.
Figure 5: Examples of epigenetic alterations in host gene expression that are relevant to the pathogenesis of HBV- and HCV-associated HCC.

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Acknowledgements

This work was supported by US National Institutes of Health (NIH) grants AI076535 and CA104025 to M.A.F.

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Authors and Affiliations

  1. Department of Biology and Sbarro Health Research Organization, College of Science and Technology, Temple University, 1900 N. 12th Street, Philadelphia, 19122, Pennsylvania, USA

    Alla Arzumanyan & Mark A. Feitelson

  2. MIT Portugal Program, Av. Rovisco Pais, Lisboa, 1049–001, Portugal

    Helena M. G. P. V. Reis

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  1. Alla Arzumanyan
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Glossary

Hepatitis

The accumulation of inflammatory cells in the liver.

Fibrosis

The accumulation of extracellular matrix material in the liver that eventually forms septa.

Cirrhosis

Occurs when fibrotic septa completely surround islands of hepatocytes.

Nucleoside analogues

Derivatives of standard nucleosides that are incorporated into DNA or RNA during virus replication and that bring about chain termination, thereby effectively inhibiting virus replication.

HBV-transgenic mice

Mice generated by introducing a larger than full-length molecular clone of hepatitis B virus (HBV) DNA into fertilized ova, which are then transferred into the uterus of pseudopregnant female mice. The offspring stably replicate HBV from virus RNA made by one or more virus DNA templates that are integrated into the host DNA. These mice resemble human chronic carriers in that they persistently replicate virus, but do not develop liver disease or hepatocellular carcinoma.

Episome

A virus nucleoprotein complex that replicates independently of host chromatin.

Cis-acting mechanisms

Occur when viral DNA integration results in the altered expression of a gene adjacent to or close to the site of integration.

Trans-acting mechanisms

Occur when a virus encodes one or more proteins that influence the expression of host genes at many chromosomal sites.

Oxidative stress

An increase in the intracellular levels of reactive oxygen species (ROS), which are associated with most pathological states, particularly those involving inflammation.

Virus inoculum

The amount of virus that an individual is exposed to during acute infection.

Innate immunity

Comprises responses that develop rapidly, but that are antigen nonspecific. Often mediated by molecules binding to toll-like receptors.

Adaptive immunity

Comprises responses that are primed by innate immunity and that are strong and antigen specific.

Tolerogenic environment

An environment in which immune responses are not readily triggered against antigens.

HIF1

A transcription factor comprised of an α-subunit and a β-subunit that triggers changes in gene expression that promote cell survival under hypoxic conditions.

Autophagy

An adaptive response that promotes cell survival under conditions of stress.

Senescence

Occurs when a particular cell type has undergone a predetermined number of cell divisions. These cells remain metabolically active but no longer divide.

Epithelial–mesenchymal transition

(EMT). A transient and reversible switch from a polarized, epithelial phenotype to a fibroblastoid or mesenchymal phenotype. EMT is divided into three categories: type 1 occurs in development (associated with embryo implantation, formation and organ development); type 2 occurs in fibrosis (associated with tissue damage and inflammation, and generates repair-associated mesenchymal cells and fibroblasts); and type 3 occurs in cancer and metastasis.

Fibrogenesis

Involves the synthesis and deposition of extracellular matrix proteins, and is a form of tissue repair that follows a bout of hepatitis, in which hepatocytes are injured and destroyed.

Cancer stem cells

(CSCs). A subset of tumour cells that share properties with normal tissue stem cells, including self-renewal (by symmetric and asymmetric division) and the capacity to differentiate.

Epithelial cell adhesion molecule

(EpCAM). A cell adhesion molecule found on hepatic stem cells and cancer stem cells; when activated by proteolysis, an intracellular domain reaches the nucleus, where it triggers cell cycle progression and mitosis by upregulating cyclin E and MYC expression.

Telomerase reverse transcriptase

(TERT). Helps to prevent the erosion of chromosomal ends (telomeres) after each cycle of cell division. Constitutive overexpression of telomerase (of which TERT is a component) is characteristic of many tumour types.

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Arzumanyan, A., Reis, H. & Feitelson, M. Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer 13, 123–135 (2013). https://doi.org/10.1038/nrc3449

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