Molecular pathogenesis of human hepatocellular carcinoma.
Hepatocarcinogenesis is a slow process during which genomic changes progressively alter the hepatocellular phenotype to produce cellular intermediates that evolve into hepatocellular carcinoma. During the long preneoplastic stage, in which the liver is often the site of chronic hepatitis, cirrhosis, or both, hepatocyte cycling is accelerated by upregulation of mitogenic pathways, in part through epigenetic mechanisms. This leads to the production of monoclonal populations of aberrant and dysplastic hepatocytes that have telomere erosion and telomerase re-expression, sometimes microsatellite instability, and occasionally structural aberrations in genes and chromosomes. Development of dysplastic hepatocytes in foci and nodules and emergence of hepatocellular carcinoma are associated with the accumulation of irreversible structural alterations in genes and chromosomes, but the genomic basis of the malignant phenotype is heterogeneous. The malignant hepatocyte phenotype may be produced by the disruption of a number of genes that function in different regulatory pathways, producing several molecular variants of hepatocellular carcinoma. New strategies should enable these variants to be characterized.
Thorgeirsson
Snorri S
SS
Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. snorri_thorgeirsson@nih.gov
Grisham
Joe W
JW
D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology*; D002869:Chromosome Aberrations; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D011230:Precancerous Conditions / Q000209:etiology / Q000235:genetics / Q000473:pathology; D016211:Transforming Growth Factor alpha / Q000235:genetics
D016211:Transforming Growth Factor alpha; D007335:Insulin-Like Growth Factor II