QUANTITATIVE RELATIONSHIP BETWEEN TRANSFORMING GROWTH-FACTOR-ALPHA AND HEPATIC FOCAL PHENOTYPE AND PROGRESSION IN FEMALE MOUSE-LIVER

Modulations in the positive hepatocyte growth factor, transforming gro wth factor-alpha (TGF-alpha) and its receptor epidermal growth factor receptor (EGFR), occur in rat and human liver tumors. The purpose of t his study was to determine if TGF-alpha and EGFR are altered in basoph ilic and acidophilic preneoplastic and neoplastic liver lesions genera ted in DEN-initiated mice exposed to a variety of hepatocarcinogens. F emale B6C3F1 mice were initiated with N-nitrosodiethylamine (DEN) and treated with hepatocarcinogenic concentrations of unleaded gasoline va por (2,000 ppm), methyl tertiary butyl ether vapor (7,814 ppm), phenob arbital (500 ppm, diet), or chlordane (25 ppm, diet). Hepatic foci and tumors were identified and evaluated immunohistochemically with antib odies for TGF-alpha and EGFR. In all treatment groups, basophilic hepa tic foci were negative for TGF-alpha immunoreactivity (554/564, 98%). In contrast, regardless of treatment, acidophilic hepatic foci were im munoreactive for TGF-alpha (107/108, 99%). There was no significant di fference in mean hepatic labeling index as measured by the incorporati on of 5-bromo-2'-deoxyuridine between foci immunoreactive and nonimmun oreactive for TGF-alpha. The incidence of immunoreactivity for TGF-alp ha increased in hepatocellular tumors that were predominantly of the b asophilic phenotype. Of basophilic hepatocellular adenomas, 16/81 (20% ) were immunoreactive for TGF-alpha, while 17/29 (59%) of hepatocellul ar carcinomas stained positive for TGF-alpha. A similar increased inci dence of EGFR immunoreactivity was found in basophilic hepatocellular adenomas (17/67, 25%) and carcinomas (19/28, 68%) relative to basophil ic foci (11/367, 3%), suggesting an autocrine mechanism for the develo pment of mouse liver tumors. The increased incidence of TGF-alpha immu noreactivity in basophilic liver tumors suggests that TGF-alpha is a m arker of tumor progression in mouse liver. Furthermore, TGF-alpha modu lations were dependent on phenotype rather than treatment, indicating inherent differences in the expression of TGF-alpha in basophilic and acidophilic hepatic lesions.