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Review Article
- Multistep Carcinogenesis of Hepatocellular Carcinoma
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Ja-June Jang
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Journal of the Korean Liver Cancer Study Group. 2008;8(1):39-46. Published online June 30, 2008
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Abstract
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- Epidemiological and experimental data have demonstrated that the process of carcinogenesis is progressive and
multistage in nature. Model systems in animals exhibit this property of cancer development for several organ
systems. The rat liver is one of the most extensively studied models of carcinogenesis. Multiple formats have
been described for the analysis of cancer development in this organ, including the resistant hepatocyte selection
regimens, the neonatal rat model and the partial hepatectomy model. The evolution of hepatic neoplasia is a slow
process leading from the normal state via preneoplasia to benign and malignant neoplasia. On the histological
level, hepatic preneoplasia usually emerges as foci of altered hepatocytes (FAH) which are perfectly integrated in
the normal liver parenchyma and have no obvious neoplastic nature. The early emergence of FAH seems to be
a general phenomenon of hepatocarcinogenesis in all species, no matter how this process has been elicited. The
hallmark for the definition and detection of hepatic preneoplasia are biochemical and morphological changes in the
hepatocellular phenotypes, which are neither uniform nor stable. In rodent liver treated with various chemical
carcinogens, most of phenotypes have been shown to represent successive stages in an ordered sequence of
cellular changes, progressing from glycogenic, clear and eosinophilic cell foci, through intermediate, mixed and
basophilic cell populations, to hepatocellular adenomas and carcinomas, the fast growing variants of which consist
of glycogen-poor, basophilic (ribosome-rich) cells. The identification of the placental isozyme of glutathione
S-transferase (GST-P) as a highly expressed cytoplasmic protein during early carcinogenesis has led to its use
as a marker of hepatic tumor development in early focal lesions, nodules and carcinomas. Different lesions have
been suggested to represent preneoplastic conditions in human liver. They include large-cell change, small-cell
change, foci of altered hepatocytes and dysplastic nodules. Experimental results suggest that multiple progressive
factors are also involved in human hepatocarcinogenesis.
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