Abundant TGFα a precursor and EGF receptor expression as a possible mechanism for the preferential growth of carcinogeninduced preneoplastic and neoplastic hepatocytes in rats

Abstract

Expression of transforming growth factor a (TGFα) was investigated immunohistochemically in preneoplastic and neoplastic hepatocytes induced by the SoK-Farber regimen. Although TGFa was almost negative in early lesions comprising carcinogen-altered hepatocytes, it was expressed in ∼65% of the late lesions. Growth factor localization was predominantly in the cytoplasm or at the bile canalicular membrane within individual lesions, both types beingobserved 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 TGFα, EGFR and PCNA in hepatocellular carcinomas (HCC) were similar to those of cytoplasmic type growth factor-positive HPN. Western blotting analysis for TGFα demonstrated a single 30 kDa protein in lysates of HPN and HCC. Since this protein was broken down to the 6 kDa mature TGFa via 20, 16 and14 kDa forms by treatment with bovine pancreatic elastase, it may represent a physiological precursor. No mature TGFa 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 TGFa mayhave an important role in the growth of preneoplastic and neoplastic hepatocytes during rat hepatocarcinogenesis.