Abundant TGF alpha precursor and EGF receptor expression as a possible mechanism for the preferential growth of carcinogen-induced preneoplastic and neoplastic hepatocytes in rats.

Expression of transforming growth factor alpha (TGF alpha) was investigated immunohistochemically in preneoplastic and neoplastic hepatocytes induced by the Solt-Farber regimen. Although TGF alpha was almost negative in early lesions comparing carcinogen-altered hepatocytes, it was expressed in approximately 65% of the late lesions. Growth factor localization was predominantly in the cytoplasm or at the bile canalicular membrane within individual lesions, both types being observed at various ratios. Hyperplastic nodules (HPN) predominantly consisting of cells with cytoplasmic type staining showed expansive growth with more abundant expression of EGF receptors (EGFR) and proliferating cell nuclear antigen (PCNA) than those with the membranous localization. The staining patterns of TGF alpha, EGFR and PCNA in hepatocellular carcinomas (HCC) were similar to those of cytoplasmic type growth factor-positive HPN. Western blotting analysis for TGF alpha demonstrated a single 30 kDa protein in lysates of HPN and HCC. Since this protein was broken down to the 6 kDa mature TGF alpha via 20, 16 and 14 kDa forms by treatment with bovine pancreatic elastase, it may represent a physiological precursor. No mature TGF alpha was detected in the conditioned medium of cultured HPN cells, although a small amount of the 30 kDa form was identified. These results suggest that this form of TGF alpha may have an important role in the growth of preneoplastic and neoplastic hepatocytes during rat hepatocarcinogenesis.