Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma

Department of Biology and Sbarro Health Research Organization, College of Science and Technology, Temple University, 1900 N. 12th Street, Philadelphia, Pennsylvania 19122, USA.
Nature Reviews Cancer (Impact Factor: 29.54). 12/2012; 13(2):123-35. DOI: 10.1038/nrc3449
Source: PubMed

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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Available from: Mark A Feitelson, Jul 26, 2015
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    • "The putative mechanisms of how antiviral therapy reduces HCC risk may include downregulation of hepatic inflammation and related nuclear signaling pathways that lead to neoplastic transformation at the cellular level, as well as reversal of fibrosis and reduction of regenerative stimuli at the tissue level. Antiviral therapy may also reduce expression of HBx protein to levels insufficient to promote HCC development, or act at a genomic level by preventing HBV DNA integration into host chromosomes or affecting its malignant potential [3] [4] [5]. "
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    ABSTRACT: In the treatment of chronic hepatitis B (CHB), the ultimate goal is preventing hepatitis B virus (HBV)-associated liver disease, including hepatocellular carcinoma (HCC). Recently published studies show that in CHB patients treated with the currently recommended first-line nucleos(t)ide analogs (NAs) entecavir or tenofovir, annual HCC incidences range from 0.01-1.4% in non-cirrhotic patients, and from 0.9-5.4% in those with cirrhosis. In Asian studies including matched untreated controls, current NA therapy consistently resulted in a significantly lower HCC incidence in patients with cirrhosis, amounting to an overall HCC risk reduction of ∼30%; in non-cirrhotic patients, HCC risk reduction was overall ∼80%, but was observed in some studies only. For patients of Caucasian origin, no appropriate comparative studies are available to date to evaluate the impact of NA treatment on HCC. Achievement of a virologic response under current NA therapy was associated with a lower HCC risk in Asian, but not Caucasian studies. Studies comparing entecavir or tenofovir with older NAs generally found no difference in HCC risk reduction between agents, except for one study which used no rescue therapy in patients developing lamivudine resistance. Overall, these data indicate that with the current, potent NAs, HCC risk can be reduced but not eliminated, probably due to risk factors that are not amenable to change by antiviral therapy, or events that may have taken place before treatment initiation. Validated pre- and on-therapy HCC risk calculators that inform the best practice for HCC surveillance and facilitate patient counseling would be of great practical value. Copyright © 2015. Published by Elsevier B.V.
    Journal of Hepatology 01/2015; 62(4). DOI:10.1016/j.jhep.2015.01.002 · 10.40 Impact Factor
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    • "Furthermore , one of the HBV-derived proteins, HBxAg, also has direct tumorigenic effects [155]. Hepatocyte regeneration, either influenced by KC or not, allows HBxAg integration in DNA of hepatocytes , which is one of the processes involved in the development of HCC (reviewed in [153]). Whether HBxAg directly interacts with KC is not described. "
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    ABSTRACT: Globally, over 500 million people are chronically infected with the hepatitis B virus (HBV) or hepatitis C virus (HCV). These chronic infections cause liver inflammation, and may result in fibrosis/cirrhosis or hepatocellular carcinoma. Albeit that HBV and HCV differ in various aspects, clearance, persistence and immunopathology of either infection depends on the interplay between the innate and adaptive responses in the liver. Kupffer cells, the liver-resident macrophages, are abundantly present in the sinusoids of the liver. These cells have been shown to be crucial players to maintain homeostasis, but also contribute to pathology. However, it is important to note that especially during pathology, Kupffer cells are difficult to distinguish from infiltrating monocytes/macrophages and other myeloid cells. In this review we discuss our current understanding of Kupffer cells, and assess their role in the regulation of anti-viral immunity and disease pathogenesis during HBV and HCV infection.
    Journal of Hepatology 05/2014; DOI:10.1016/j.jhep.2014.04.026 · 10.40 Impact Factor
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    • "hepatitis, fibrosis, cirrhosis, and eventually hepatocellular carcinoma (Arzumanyan et al., 2013). "
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    ABSTRACT: Approximately 12% of all human cancers are caused by oncoviruses. Human viral oncogenesis is complex, and only a small percentage of the infected individuals develop cancer, often many years to decades after the initial infection. This reflects the multistep nature of viral oncogenesis, host genetic variability, and the fact that viruses contribute to only a portion of the oncogenic events. In this review, the Hallmarks of Cancer framework of Hanahan and Weinberg (2000 and 2011) is used to dissect the viral, host, and environmental cofactors that contribute to the biology of multistep oncogenesis mediated by established human oncoviruses. The viruses discussed include Epstein-Barr virus (EBV), high-risk human papillomaviruses (HPVs), hepatitis B and C viruses (HBV and HCV, respectively), human T cell lymphotropic virus-1 (HTLV-1), and Kaposi's sarcoma herpesvirus (KSHV).
    Cell host & microbe 03/2014; 15(3):266-282. DOI:10.1016/j.chom.2014.02.011 · 12.19 Impact Factor
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