Chemically induced hepatocarcinogenesis in rats will be studied from the standpoint of the RT1 major histocompatibility complex Class I alloantigens expressed on the surface of liver cells. The working hypothesis is that during carcinogen-induced evolution of certain normal liver cells into carcinomas, detectable changes in RT1 Class I alloantigens on premalignant liver cells occur, indicative of functional alterations in cellular growth control mechanisms in these carcinoma precursor cell subpopulations. The genotypic mosaic liver model of hepatocarcinogenesis will be used to generate donor origin premalignant liver lesions in hybrid host rat livers. Donor origin lesions identified in histologic sections by indirect immunofluorescence using rat strain-specific alloantisera will be histochemically characterized, then puch- dissected for analysis in situ of alloantigen expression by the lesion cells. The punch-dissected lesion tissue microsamples will be detergent-extracted, and the cell proteins radioiodinated, immunoprecipitated, and analyzed by 2-D IEF/SDS-PAGE. Altered alloantigen expression will be scored from gel autoradiograms as a potentially new marker of authentic carcinoma precursor cells. Donor origin premalignant liver cells will be purified from cell suspensions prepared using strain-specific alloantisera for complement mediated cytolysis. The purified cells will be placed in short-term (less than 24hr) culture for radiolabeling alloantigens using 35S-methionine. Altered alloantigen expression by these cells will be compared with in situ expression, and may represent a new marker for premalignant liver cells in culture. Finally, the genotypic mosaic model will be used to trace the fate of subpopulations of donor liver cells in host rat livers. Donor liver cells will be reacted prior to transplantation with a panel of monoclonal antibodies (mAb) specific for epitopes of premalignant and malignant liver cells. Donor liver cells """"""""targeted"""""""" by reaction with particular mAb will be selectively removed or killed. Immunohistochemical characterization of the development of donor origin lesions over a 17-month period will identify lesions arising from non-targeted donor liver cells. These transplantation experiments are expected to identify precursor cells of phenotypically distinct donor origin liver lesions, inlcuding hepatocellular carcinomas. The ultimate goal of these studies is to identify, as early as possible, the authentic cellular precursors of hepatocellular carcinomas. The elimination of these premalignant cells could eventually serve as a novel preventive therapy for primary human liver cancer.
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| Sell, S; Hunt, J M; Knoll, B J et al. (1987) Cellular events during hepatocarcinogenesis in rats and the question of premalignancy. Adv Cancer Res 48:37-111 |
