INCREASED SUSCEPTIBILITY TO N-NITROSOMETHYLUREA GASTRIC CARCINOGENESIS IN TRANSFORMING GROWTH-FACTOR-ALPHA TRANSGENIC MICE WITH GASTRIC HYPERPLASIA

Glandular stomach carcinogenesis after N-nitrosomethylurea (NMU) treat ment was examined in transgenic mice bearing a human transforming grow th factor alpha (TGF-alpha) cDNA driven by the mouse metallothionein-I promoter (mouse line MT100) in the inbred mouse line FVB/N. Untreated MT100 mice exhibit a severe age-related gastric fundic hyperplasia. B oth sexes of MT100 mice were given 10 weekly intragastric intubations of 0.5 mg NMU per mouse from 6 weeks of age and/or zinc chloride in dr inking water to stimulate transgene expression from 5.5 weeks of age t o the experiment termination. Animals were killed sequentially at 10, 19 and 29 experimental weeks. Several histochemical markers (AB-PAS, T GF-alpha, pepsinogen isozyme 1, proliferating cell nuclear antigen) we re used. Abnormal histochemical patterns were found in untreated MT100 and NMU-treated MT100 mice for all 4 markers of differentiation and c arcinogenesis. Precancerous lesions including atypical and/or adenomat ous hyperplasia were found in the fundic region of 16/22 male and 8/22 female MT100 mice but not in 27 male and 24 female FVB/N mice treated with NMU. One of 22 MT100 males had fundic carcinoma. FVB/N mice trea ted with NMU had neither precancerous lesions nor carcinomas in the fu ndus. Well differentiated adenocarcinomas in the pyloric region were i nduced at incidences of 2/22 male and 1/22 female MT100 mice treated w ith NMU and 4/27 male and 4/24 female FVB/N mice treated with NMU. Bot h strains also had a high incidence (55 to 92%) of squamous cell carci nomas of the forestomach, In conclusion, TGF-alpha induced a hyperplas tic lesion in the gastric fundus that appeared to predispose the MT100 mice to carcinogenesis by NMU.