Abstract
The controversy surrounding the interpretation of observed increases in the high spontaneous liver tumor incidence of the B6C3F1 mouse after administration of certain chemical agents necessitates a mechanistic understanding into the nature of tumor development in this particular strain of mouse.
Recently, cancer genes (oncogenes) have been detected in the DNA from a variety of human tumors and tumor cell lines. These genes have been implicated to play a role in the transformation of normal cells into cancerous ones.
To investigate the role that cellular oncogenes might play in the development of spontaneous liver tumors in the B6C3F1 mouse, DNA was isolated from spontaneously occurring liver tumors and transfected into NIH 3T3 fibroblasts. DNA from this tumor tissue was capable of transforming NIH 3T3 cells from 82% of the animals examined strongly suggesting the presence of an active cellular oncogene. In contrast, DNA isolated from surrounding non-tumorous liver tissue and liver tissue from non-tumor bearing mice did not cause any transformation in the NIH 3T3 assay. These data demonstrate that the active cellular oncogene is not present in the hepatic tissue via a germ-line transmission but is activated only in those cells of the tumor tissue.
Experiments using Southern blot hybridization analysis have identified this active cellular oncogene to be a member of the ras oncogene family.
Identification of this cellular oncogene will now allow the evaluation of factors which might modify its expression. These future studies will lead to an increased understanding of potential mechanisms by which hepatic tumors are enhanced and should provide more informed estimates of risk for man based on bioassay data generated in this strain of mouse.
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References
Becker FF (1982) Morphological classification of mouse liver tumors based on biological characteristics. Cancer Res 42: 3918
Chan C (1984) NTP technical report on the toxicology and characterization studies of dimethyl mor- pholenophosphoramidate in F344/N rats and B6C3F1 mice. Cas No 597-25-1
Compisi J, Gray AB, Pardee AB, Dean M, Sonensheim GE (1984) Cell-cycle control of c-cyc but not c-ras expression is lost following chemical transformation. Cell 36: 241
Eva A, Tronick SR, Gal RA, Pierce JH, Aaronson SA (1983) Transforming genes of human hematopoietic tumors: frequent detection of ras-related oncogenes whose activation appears to be independent of tumor phenotype. Proc Natl Acad Sci USA 80: 4926
Fox TR, Watanabe PG (1985) Detection of a Cellular Oncogene in Spontaneous Liver Tumors of B6C3F1 Mice. Science 228: 596
Goyette M, Petropoulos CJ, Shank PR, Fausto N (1983) Expression of a cellular oncogene during liver regeneration. Science 219: 510
Interdisciplinary Panel on Carcinogenicity (1984) Criteria for evidence of chemical carcinogenicity. Science 225: 682
Land H, Parada L, Weinberg R (1983) Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature 304: 596–601
National Cancer Institute (1976) Carcinogenesis bioassay of chloroform. Natl Tech Inform, Service No PB264018/AS
National Cancer Institute (1977) Bioassay of tetrachloroethylene for possible carcinogenicity. DHEW Publication No 77–813
Newbold R, Overell R (1983) Fibroblast immortality is a prerequisite for transformation by EJ c-Ha-ras oncogene. Nature 304 (5927): 648–651
Nutrition Foundation (1983) The relevance of mouse liver hepatoma to human carcinogenic risk: Report of the International Expert Advisory Committee to the Nutrition Foundation. The Nutrition Foundation, Inc, Washington, DC
Pulciani S, Santos E, Lauver AV, Long LK, Robbins KC, Barbacid M (1982a) Oncogenes in human tumor cell lines: molecular cloning of a transforming gene from human bladder carcinoma cells. Proc Natl Acad Sci USA 79: 2845
Pulciani S, Santos E, Lauver AV, Long LK, Aaronson SA, Barbacid M (1982b) Oncogenes in solid human tumors. Nature 300: 539
Reddy EP, Reynolds RK, Santos E, Barbacid M (1982) A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene. Nature 300: 149
Reitz RH, Fox TR, Quast JF (1982) Mechanistic considerations for carcinogenic risk estimation: chloroform. Environ Health Perspectives 46: 163
Reynolds SH, Stowers SJ, Maronpot RR, Anderson MW, Aaronson SA (1986) Detection and identification of activated oncogenes in spontaneously occuring benign and malignant hepatocellular tumors of the B6C3F1 mouse. Proc Natl Acad Sci USA (in press)
Rigby PWJ, Dieckmann M, Rhodes C, Bery P (1977) Labeling deoxyribonucleic acid to high specific activity in vitro by neck translation with DNA polymerose. J Mol Biol 113: 237
Ruley H (1983) Adenovirus early region 1A enables viral and cellular transforming genes to transform primary cells in culture. Nature 304: 602
Schumann AM, Quast JF, Watanabe PG (1980) The pharmacokinetics and macromolecular iterations of perchloroethylene in mice and rats as related to oncogenicity. Tox and Appl Pharmacol 55: 207
Schwab M, Alitalo K, Varmus HE, Bishop D, George A (1983) A cellular oncogene (c-ki-ras) is amplified, overexpressed and located within karyotypic abnormalities in mouse adrenocortical tumor cells. Nature 303: 497
Shilo BZ, Weinberg RA (1981) Unique transforming gene in carcinogen-transformed mouse cells. Nature 300: 607
Southern EM (1975) Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol 98: 503
Spandidos DA, Kerr IB (1984a) Elevated expression of the human ras oncogene family in premalignant and malignant tumors of the colorectum. Br J Cancer 49:681–688
Spandidos DA, Wilkie NM (1984b) Malignant transformation of early passage rodent cells by a single mutated human oncogene. Nature 310: 469
Task Force of Past Presidents - Society of Toxicology (1982) Fundamental and Appl Tox 2: 101
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Fox, T.R., Schumann, A.M., Watanabe, P.G. (1987). Activation of a Cellular Proto-Oncogene in Spontaneous Liver Tumor Tissue of the B6C3F1 Mouse. In: Chambers, P.L., Henschler, D., Oesch, F. (eds) Mouse Liver Tumors. Archives of Toxicology, vol 10. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-71617-1_20
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DOI: https://doi.org/10.1007/978-3-642-71617-1_20
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