CertainEBVgeneproductscontributetooncogenesisbystimulatingnormalB-cellproliferationpathways.ConcomitantcompromiseofimmunecompetenceallowssustainedB-cellproliferation,leadingeventuallytodevelopmentoflymphoma.
The epidemiologic evidence linking chronic HBV and hepatitis C virus (HCV) infection with hepatocellular carcinoma is strong (Chapter 16). It is estimated that 70% to 85% of hepatocellular carcinomas worldwide are caused by HBV or HCV. However, the mode of action of these viruses in tumorigenesis is not fully elucidated. The HBV and HCV genomes do not encode any viral oncoproteins, and although the HBV DNA is integrated within the human genome, there is no consistent pattern of integration in liver cells. Indeed, the oncogenic effects of HBV and HCV are multifactorial, but the dominant effect seems to be immunologically mediated chronic inflammation with hepatocyte death, leading to regeneration and genomic damage. Although the immune system generally is thought to be protective, recent work has demonstrated that in the setting of unresolved chronic inflammation, as occurs in viral hepatitis or chronic gastritis caused by H. pylori (see later), the immune response may become maladaptive, promoting tumorigenesis.
As with any cause of hepatocellular injury, chronic viral infection leads to the compensatory proliferation of hepatocytes. This regenerative process is aided and abetted by a plethora of growth factors, cytokines, chemokines, and other bioactive substances produced by activated immune cells that promote cell survival, tissue remodeling, and angiogenesis. The activated immune cells also produce other mediators, such as reactive oxygen species, that are genotoxic and mutagenic. A key molecular step seems to be activation of the nuclear factor-κB (NF-κB) pathway in hepatocytes caused by mediators derived from the activated immune cells. Activation of the NF-κB pathway blocks apoptosis, allowing the dividing hepatocytes to incur genotoxic stress and to accumulate mutations. Although this seems to be the dominant mechanism in the pathogenesis of virus-induced hepatocellular carcinoma, both HBV and HCV also contain proteins within their genomes that may more directly promote the development of cancer. The HBV genome contains a gene known as HBx, and hepatocellular cancers develop in mice engineered to have HBx transgenes. HBx can directly or indirectly activate a variety of transcription factors and several signal transduction pathways, and may interfere with p53 function. In addition, viral integration can cause secondary rearrangements of chromosomes, including multiple deletions that may harbor unknown tumor suppressor genes.
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HCV, an RNA virus, also is strongly linked to the pathogenesis of liver cancer. The molecular mechanisms used by HCV are even less well defined than those for HBV. In addition to chronic liver cell injury and compensatory regeneration, components of the HCV genome, such as the HCV core protein, may have a direct effect on tumorigenesis, possibly by activating a variety of growth-promoting signal transduction pathways.
Between70%and85%ofhepatocellularcarcinomasworldwideareduetoinfectionwithHBVorHCV.
TheoncogeniceffectsofHBVandHCVaremultifactorial,butthedominanteffectseemstobeimmunologicallymediatedchronicinflammation,withhepatocellularinjury,stimulationofhepatocyteproliferation,andproductionofreactiveoxygenspeciesthatcandamageDNA.
TheHBxproteinofHBVandtheHCVcoreproteincanactivateavarietyofsignaltransductionpathwaysthatalsomaycontributetocarcinogenesis.