| Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Genetic alterations suspected of playing a role in HCC onset and progression have been the subject of intense investigation. Transgenic mouse models allow specific targeting of selected oncogenes using cell- or tissue-specific promoters. I used the tetracycline inducible system to systematically introduce oncogenic manipulations at defined stages of growth into liver. Specifically, the inducible system allowed me to examine the effects of turning on oncogene expression in the adult liver rather than targeting expression throughout development, and to determine how focal rather than diffuse hepatocyte targeting influences cancer progression. Several new transgenic lines of mice expressing inducible oncogenes were characterized. c-Myc or c-Myc plus TGF-alpha caused hyperplasia and progression to neoplasia as early as 4 and 3 months of age, respectively. c-Myc-induced liver disease in our model progressed more rapidly than previous in constitutively-expressed models, even though the level of c-Myc expression was lower in the inducible than in the constitutively expressed model. I examined gene expression patterns using microarray and found that constitutively expressed c-Myc and inducible c-Myc caused different patterns of gene expression with little in common.;I next evaluated the effect of neighboring normal cells on the ability of genetically altered cells to initiate growth in a quiescent liver environment, testing whether genetically altered hepatocytes over-expressing c-Myc or TGF-alpha or expressing mutant H-ras or beta-catenin, alone or in combination, can initiate growth when turned on as clusters or as single cells in a quiescent liver. No oncogene combination could transform all transplant foci into altered hepatocyte foci, indicating that progression required donor cells to accumulate additional changes. When oncogene expression was restricted to single cells in non-transgenic recipients, only oncogene combinations initiated neoplastic progression.;I examined the liver's capacity for lesion reversal late in the progression stage of carcinogenesis, and explored changes in gene expression patterns and molecular mechanisms that accompany phenotypic reversion of HCC when transgene expression was silenced. Silencing oncogene expression near end stage liver disease almost completely reversed liver lesions, indicating that continued oncogene expression is necessary for oncogene-induced growth disruption. |
