RAPID DEVELOPMENT OF HEPATIC-TUMORS IN TRANSFORMING GROWTH-FACTOR A TRANSGENIC MICE ASSOCIATED WITH INCREASED CELL-PROLIFERATION IN PRECANCEROUS HEPATOCELLULAR LESIONS INITIATED BY N-NITROSODIETHYLAMINE AND PROMOTED BY PHENOBARBITAL

The carcinogenic and tumor-promoting effects of human transforming gro wth factor alpha (TGF-alpha) overexpression were examined in a two-sta ge chemical carcinogenesis protocol using TGF-alpha transgenic mouse l ine MT42. Male MT42 and CD-1 mice received a single i.p. injection of 5 mg N-nitrosodiethylamine (DEN)/kg body wt at 15 days of age, and wer e placed on a diet containing 0.05% of phenobarbital (PB) from 4 weeks of age for 35 weeks. DEN-, PB-treated and saline-injected animals in each strain were used as controls. A total of three sequential sacrifi ces (at 10, 23 and 37 experimental weeks) was performed. Hepatocellula r carcinomas (HCCs) developed earlier at high incidence (100%) after 2 3 experimental weeks in MT42 mice receiving DEN/PB, while CD-1 mice ha d a 40% incidence of HCCs only after week 37. HCCs also developed in t he DEN-initiated MT42 mice at 80% incidence after week 23, but no HCCs were observed in the DEN-initiated CD-1 mice. PB induced preneoplasti c foci (67%), adenomas (33%) and HCCs (33%) after 37 weeks in MT42 mic e, but no lesions were found in CD-1 mice. Thus, the carcinogenic resp onse to DEN and/or PB was accelerated in the MT42 transgenic mice. Fur thermore, PB promotion was observed from week 10 in MT42 mice and week 23 in CD-1 mice. Thus, the promoting effect of PB was also accelerate d in the MT42 transgenic mice. proliferating cell nuclear antigen (PCN A) labeling indices of hepatocellular foci and adenomas in DEN- or DEN /PB-treated MT42 mice were significantly higher than those of CD-1 mic e. TGF-alpha expression determined by immunohistochemistry revealed hi gher levels in these lesions than in hepatocytes of surrounding parenc hyma of MT42 transgenic mice. In conclusion, TGF-alpha transgenic mice clearly demonstrated enhanced sensitivity to the development of hepat ocellular carcinoma in the DEN initiation and PB promotion regime, pos sibly through a mechanism of increased hepatocyte proliferation in pre cancerous lesions (foci and adenomas), driven by high expression of th e mitogen TGF-alpha in these lesions.