DIFFERENTIAL DISTRIBUTION OF MET AND EPIDERMAL GROWTH-FACTOR RECEPTORIN NORMAL AND CARCINOGEN-TREATED RAT-LIVER

Transforming growth factor-alpha (TGF-alpha) and hepatocyte growth fac tor (HGF) are strong hepatocyte mitogens and important regulators of L iver regeneration, The TGF-alpha receptor EGFr appears primarily to me diate a proliferative signal, whereas mitogenic, motogenic, and morpho genic effects have been attributed to activation of the HGF receptor M et, We have studied the localization of Met and EGFr in normal and car cinogen-treated rat livers. Oval cells and preneoplastic lesions were induced by diethylnitrosamine initiation, followed by promotion with 2 -acetylaminofluorene combined with a partial hepatectomy. Different li ver cell populations and their receptor expression were characterized by two-color immunofluorescence and confocal laser scanning microscopy , Hepatocytes were detected by keratin K8 staining, and oval cells and bile ducts were recognized by keratin K19 expression, Enzyme-altered preneoplastic lesions were identified by expression of placental gluta thione S-transferase (GST-pi). Staining for these cellular markers was combined with immunodetection of EGFr and Met, Normal liver exhibited strong staining for EGFr in hepatocytes, whereas blood vessels, bile ducts, and some sinusoidal cells were Met-positive, In carcinogen-trea ted livers, oval cells showed Met but not EGFr immunostaining, GST-pi- positive foci displayed EGFr immunostaining at a similar intensity as surrounding hepatocytes, whereas Met was not detected, Our data indica te that putative liver cells (oval cells) have a growth receptor pheno type similar to that of bile ducts, whereas preneoplastic liver lesion s appear hepatocyte-like, These results indicate that the preferential proliferation of preneoplastic liver lesions compared to surrounding hepatocytes is not associated with an altered EGFr or Met phenotype.