Liver hepatocyte growth factor does not always correlate with hepatocellular proliferation in human liver lesions: Its specific receptor c-met does (original) (raw)

Differences have been found in the expression of c-met pro-Increased levels of expression of hepatocyte growth tooncogene product (c-met pp) and HGF in liver tissue. In factor (HGF) and its specific receptor c-met have been normal human liver, HGF has been detected in bile duct shown in the liver of several benign and malignant paepithelia and in endothelial cells of both the central-lobular thologies, both in experimental models and humans. We vein and portal tracts vessels, 8-10,12 whereas c-met pp has been investigated by immunohistochemistry the presence of identified only in normal mature hepatocytes. 6 In rat liver, both HGF and c-met protooncogene product (c-met pp) HGF has also been found to be expressed in Kupffer cells in 20 hepatocellular carcinomas (HCCs), 5 focal nodular and Ito cells, 9-13 and c-met pp in the ''facultative stem cells'' hyperplasias (FNHs), 4 cases of fulminant hepatitis (FH), often referred to as oval cells (OCs). 13 The latter are considand 1 case of regenerated liver. The c-met protooncogene ered to be bipotential progenitor cells, because they can difproduct was expressed in all cases with marked overexferentiate either toward bile duct epithelial cells or hepatopression in the HCCs and in ductular metaplasia. HGF cytes. 14 Small single cells with an oval nucleus, scanty was detected in the Ito cells of all cases and in neoplastic cytoplasm, and ultrastructural and phenotypic features simihepatocytes of 9 of 20 HCCs (45%). The proliferative inlar to rat OCs have recently been identified in human regendex of each lesion was evaluated by means of the polyerating liver. 15 These cells react with the rat OC-specific clonal antibody anti-cyclin A. When the level of expresmonoclonal antibody (MoAb), OV-6. 16 sion of HGF and c-met protooncogene product with the Increases in c-met pp expression have been reported in percentage of cyclin A / nuclei were compared, the closhepatocytes of many benign and malignant human liver tisest relationship was between c-met protooncogene prodsues. 17-19 Furthermore, in experimental hepatic regeneration, uct and cyclin A. In 11 of 20 HCCs (55%), there was no the overexpression of c-met pp in OCs matches that of HGF correlation between HGF positivity and cyclin A. This in Ito cells. 13 To the best of our knowledge, however, the seems to suggest that, independently of the levels of naexpression of HGF and its specific c-met pp receptor has not tive liver HGF, c-met protooncogene product is the most yet been studied extensively in different pathological human active modulator of liver cell proliferation. (HEPATOLOGY liver conditions, although conflicting results have been re-1996;24:60-64.) ported in a small series of hepatomas. 20 Identification of the mechanism that modulates the proliferation of OCs could Hepatocyte growth factor (HGF) is believed to be the most benefit our understanding of liver regeneration and the early important mitogen for hepatocytes in vitro, and the humoral steps of liver carcinogenesis. mediator of liver regeneration. 1 Originally identified in the It has been shown that HCCs overexpress c-met pp in comserum of partially hepatectomized rats, 2 HGF has also been parison with normal liver. 17-19 We therefore decided to invesisolated from humans and its gene cloned. 3-5 HGF's receptor tigate the expression of HGF and c-met pp in a series of has been characterized as the product of the protooncogene benign and malignant liver lesions that involve mature pac-met, 6 which is overexpressed in solid tumors, such as colonic renchymal cells, malignant hepatocytes, and OCs. The postuand gastric cancers. 7 This suggests an involvement of HGF, lated mitogenic effect of HGF was evaluated by comparing which is present in many organs 8-12 in some developmental the expressions of HGF, c-met pp, and the cell-cycle-related steps of human carcinogenesis. 6 antigen, cyclin A.