Chemically-induced rat hepatocarcinogenesis will be probed using alloantigens specified by the rat RT1 major histocompatibility gene complex. Alloantigens will be used as heritable genetic markers for liver cells throughout carcinoma development in genotypic mosaic livers constructed by intravenous transplantation of carcinogen-altered parental donor livers cells into F1 hybrid host rats. Strain-specific alloantisera will be prepared and used as reagents for identification of liver cells of a particular genotype by indirect immunofluorescence. Quantitation of populations of donor-origin liver cells progressing to carcinomas in the genotypic mosaic livers will be done using these alloantisera. The capacity of donor-origin premalignant liver cells to form and repair covalent DNA adducts with 2-acetylaminofluorene will be quantitated to identify subpopulations of these cells with altered metabolism of carcinogens. The cell surface localization of the alloantigens will be exploited in the development of immunological. techniques for purifying donor-origin liver cells at defined time points during carcinoma development. Purified donor-origin liver cells will be tested for their capacity to colonize livers of secondary host rats to define the point at which growth control autonomy is manifested. The purified donor-origin liver cells will be radio-labeled with 125I, 35S-methionine or 3H-fucose, and surface-localized alloantigens immunoprecipitated with S.aureus before and after treatment of the cells with chemical crosslinking reagents to detect altered alloantigen expression. Established hepatoma cell lines will be similarly analyzed in parallel studies, so that comparison of alloantigens on premalignant and malignant cells can be made. Thus, a set of novel marker antigens may be discovered indicative of commitment of certain subpopulations of carcinogen-altered liver cells to cellular lineages leading to carcinomas. Purified donor-origin liver cells will also be used as immunogens in rats to detect cell-mediated immunity effector cells responding to neoantigens present on premalignant donor-origin liver cells. Immune effector cell activity will be quantitated in vivo by Winn Assays and in vitro by 51Cr release assays. the ultimate goal of these studies will be the development of cancer treatment regimens to eradicate premalignant liver cells.
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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 |
