Collaboration between growth factors and diverse chemical carcinogens in hepatocarcinogenesis of transforming growth factor α transgenic mice

• Published in: Cancer research (Chicago, Ill.) Vol. 53; no. 18; pp. 4329 - 4336
• Main Authors: TAKAGI, H, SHARP, R, TAKAYAMA, H, ANVER, M. R, WARD, J. M, MERLINO, G
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.09.1993
• Subjects: Animal tumors. Experimental tumors; Animals; Biological and medical sciences; Diethylnitrosamine - toxicity; Dimethylnitrosamine - toxicity; Experimental digestive system and abdominal tumors; Female; Liver Neoplasms, Experimental - chemically induced; Male; Medical sciences; Mice; Mice, Transgenic; Receptor, Epidermal Growth Factor - analysis; Transforming Growth Factor alpha - analysis; Transforming Growth Factor alpha - genetics; Transforming Growth Factor alpha - physiology; Tumors; Transforming growth factor; Liver; Nitrosamine; Rodentia; Transgenic animal; Hepatic disease; Tumor initiation; Malignant tumor; Carcinogenesis; Mechanism; Carcinogen; Vertebrata; Mammalia; Mouse; Digestive diseases; Tumor promotion
• ISSN: 0008-5472; 1538-7445

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.