Liver Cancer

> Liver cancer is one of the major lethal malignancies worldwide. The main histological subtype is hepatocellular carcinoma, which is derived from hepatocytes, the predominant epithelial cell type in the liver, and often retains biochemical and morphological markers of hepatocyte differentiation.

^ Hepatocellular carcinoma develops as a rule in the context of chronic inflammation and liver cirrhosis caused by the hepatitis viruses HBV or HCV, by chronic alcohol abuse, or more rarely by hereditary diseases such as hemochromatosis. Chemical carcinogens such as aflatoxin B1 from the mold Aspergillus flavus act synergistically with the causes of inflammation, in particular with chronic HBV infection. Aflatoxins cause a diagnostic G^T mutation at codon 249 of TP53.

^ In addition to disrupting the TP53 network, genetic and epigenetic alterations in hepatocellular carcinoma inactivate cell cycle regulation by RB1 and cause constitutive activity of the WNT signaling pathway, most often by mutations of P-Catenin and more rarely by inactivation of Axin1 and APC. WNT pathway activation may be exacerbated by loss of E-cadherin.

^ Several growth factors and their receptors controlling normal hepatocyte proliferation and regeneration are also implicated in the growth and survival of hepatocellular carcinoma, by autocrine and paracrine mechanisms. In addition to activation of HGF/MET and TGFa/ERBB1 circuits, a particular important change may consist in increased stimulation by the insulin-like factor IGF2 through the IGFIR receptor tyrosine kinase, while the scavenger receptor IGFRII may become inactivated.

^ The pivotal role of HBV in liver carcinogenesis appears mainly to be due to a continuous hepatocyte destruction by T-cells which attempt to eliminate the infection and their repletion from differentiated cells and eventually liver stem cells. This process may select for genetically altered cells with diminished response to the virus and to apoptotic signals. Increased oxidative stress in the inflammated tissue may contribute to mutagenesis and at the same time increase the selective pressure. Inhibition of TP53 function by the viral HBX protein may aid in down-regulation of apoptosis during early stages carcinogenesis and permit the accumulation of cells with aberrant genomes. Furthermore, integration of viral genomes may promote genomic instability.

^ Importantly, while therapeutic options are limited once HCC is established, vaccination against HBV and anti-viral treatment against HCV appear to be efficacious in preventing this cancer.

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