title: Collaboration between growth factors and diverse chemical carcinogens in hepatocarcinogenesis of transforming growth factor alpha transgenic mice.
abstract: Transforming growth factor alpha (TGF-alpha) has been shown to induce liver tumors within 1 year in transgenic male mice in which this potent mitogen is overexpressed. To determine more precisely how TGF-alpha participates in multistep tumorigenesis of the liver, genotoxic (diethylnitrosamine or dimethylnitrosamine) and nongenotoxic (phenobarbital) chemical carcinogens were administered independently to TGF-alpha transgenic mice [line MT42 on a Crl:CD-1(ICR)BR background]. TGF-alpha overexpression dramatically accelerated carcinogen-induced hepatocarcinogenesis in MT42 males but not females. Interestingly, all three chemical agents were found to enhance strongly both hepatic tumor formation and progression in TGF-alpha transgenic male mice. In this study 100%, 90%, and 78% of transgenic males exposed to diethylnitrosamine, dimethylnitrosamine or phenobarbital, respectively, developed tumors between 24 and 32 weeks of age. Moreover, approximately 70% of tumor-bearing transgenic mice from each treatment group had hepatocellular carcinomas; no malignant lesions were found in any carcinogen-treated or untreated nontransgenic mice or in untreated MT42 mice at this age. These results demonstrate that chemical agents as diverse as nitrosamines and phenobarbital act as cocarcinogens with TGF-alpha in the livers of these transgenic mice, indicating that TGF-alpha possesses the unique ability to complement both initiation and promotion in hepatocarcinogenesis. Furthermore, because carcinogen-induced malignant conversion was restricted to transgenic mice, constitutive TGF-alpha overexpression may promote liver tumor progression as well.
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892.
authors.forename: H
authors.initials: H
authors.lastname: Takagi
authors.forename: R
authors.initials: R
authors.lastname: Sharp
authors.forename: H
authors.initials: H
authors.lastname: Takayama
authors.forename: M R
authors.initials: MR
authors.lastname: Anver
authors.forename: J M
authors.initials: JM
authors.lastname: Ward
authors.forename: G
authors.initials: G
authors.lastname: Merlino
mesh_terms: D000818:Animals; D004052:Diethylnitrosamine / Q000633:toxicity; D004128:Dimethylnitrosamine / Q000633:toxicity; D066246:ErbB Receptors / Q000032:analysis; D005260:Female; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016211:Transforming Growth Factor alpha / Q000032:analysis / Q000235:genetics / Q000502:physiology*
chemical_list: D016211:Transforming Growth Factor alpha; D004052:Diethylnitrosamine; D066246:ErbB Receptors; D004128:Dimethylnitrosamine