TRANSFORMING GROWTH-FACTOR-ALPHA EXPRESSION IS ALTERED DURING EXPERIMENTAL HEPATOCARCINOGENESIS

In order to characterize the role of transforming growth factor-alpha (TGF alpha) during hepatocarcinogenesis, liver tissue was examined at 10, 16, and 19 weeks following initial 10-week diethylnitrosamine (50 mg l(-1) drinking water) exposure in female Wistar rats, Liver tissue protein extracts were electrophoresed and transferred to nitrocellulos e filters, Levels of tissue-derived TGF alpha and epidermal growth fac tor receptor (EGFr) mere assessed using an anti-TGF alpha monoclonal a ntibody (Ab-l) and an anti-EGFr polyclonal antibody (AB-4), coupled wi th scanning densitometric quantification. Immunolocalization of TGF al pha was performed in Bouin's-fixed, paraffin-embedded liver tissue sec tions, The distribution and intensity of TGF alpha immunoreactivity va ried according to the degree of dysplasia, severely dysplastic cells b eing strongly immunoreactive. At week 10, mild hepatocyte dysplasia an d perivenular inflammation were evident, together with a corresponding increase in perivenular TGF alpha immunoreactivity, By week 16, foci of moderate to severe dysplasia mere observed; at this stage, there ma s a decrease in perivenular immunoreactivity but a further increase in overall liver tissue TGF alpha levels, Some 'altered foci' and dyspla stic nodules showed intense immunoreactivity for TGF alpha, At these t ime points, immunodetectable Liver EGFr was found to decrease signific antly in comparison with normal control tissue, TGF alpha immunoreacti vity was observed in fully developed carcinomas at week 19, although s ome tumours were negative by immunohistochemistry. The up-regulation o f immunodetectable TGF alpha and the concomitant down-regulation of EG Fr demonstrated positive (P<0.01) and negative (P<0.001) correlations, respectively, with hepatocyte proliferation indices. These findings s uggest that the TGF alpha/EGFr ligand receptor system may be important during tumour promotion and in the stimulation of continued prolifera tion in hepatocellular carcinomas.