Transforming growth factor betas and their signaling receptors in human hepatocellular carcinoma

BACKGROUND: Transforming growth factor betas (TGF-beta s) are multifunction al polypeptides that have been suggested to influence tumor growth. They me diate their functions via specific cell surface receptors (type I ALK5 and type II TGF-beta receptors). The aim of this study was to analyze the roles of the three TGF-beta s and their signaling receptors in human hepatocellu lar carcinoma (HCC). METHODS: HCC tissue samples were obtained from 18 patients undergoing parti al liver resection. Normal liver tissues from 7 females and 3 males served as controls. The tissues for histological analysis were fixed in Bouin's so lution and paraffin embedded. For RNA analysis, freshly obtained tissue sam ples were snap frozen in liquid nitrogen and stored at -80 degrees C until used. Northern blot analysis was used in normal liver and HCC to examine th e expression of TGF-beta 1, -beta 2, -beta 3 and their receptors: type I AL K5 (T beta R-I ALK5), type II (T beta R-II), and type III (T beta R-III). I mmunohistochemistry was performed to localize the corresponding proteins. RESULTS: All three TGF-beta s demonstrated a marked mRNA overexpression in HCC in comparison with normal controls, whereas the levels of all three TGF -beta receptors showed no significant changes. Intense TGF-beta 1, TGF-beta 2, and TGF-beta 3 immunostaining was found in hepatocellular carcinoma cel ls and in the perineoplastic stroma with immunohistochemistry, whereas no o r mild immunostaining was present in the normal liver. For T beta R-I ALK5 and T beta R-II, the immunostaining in both HCC and normal liver was mild t o moderate, with a slightly higher intensity in the normal tissues. CONCLUSION: The upregulation of TGF-beta s in HCC suggests an important rol e for these isoforms in hepatic carcinogenesis and tumor progression. Moreo ver, the localization of the immunoreactivity in both malignant hepatocytes and stromal cells suggests that TGF-beta s act via autocrine and paracrine pathways in this neoplasm. (C) 1999 by Excerpta Medica, Inc.