Hepatocyte growth-factor-scatter factor can stimulate post-operative tumor-cell proliferation in childhood hepatoblastoma

Rapid growth of residual tumor after partial hepatectomy has been observed during the period of liver regeneration in children with malignant embryona l hepatoblastoma. The aim of this study was to elucidate the role of hepato cyte growth-factor-scatter factor (HGF-SF) in this phenomenon. Markedly inc reased serum levels of HGF-SF up to 15 ng/ml were found in 13/18 patients a fter liver resection and in 6/16 patients with regressive tumors after chem otherapy, in comparison with 15 patients with non-pre-treated hepatoblastom a and 20 healthy children of the same age group. In the tumors, epithelial tumor cells highly expressed the HGF-SF receptor c-met, as shown by immunoh istochemistry and m-RNA RT-PCR. The hepatoblastoma cell lines HepTI, HepT3 and HUH6 reacted with significantly increased proliferation to rhHGF-SF in these concentrations (1-15 ng/ml). In the tumors, HGF-SF was found to be ex pressed in the stromal fibroblasts, In culture, hepatoblastoma cells (HepT3 , HUH6) stimulated secretion of the factor by human fibroblasts, indicating the paracrine fashion of intratumoral HGF-SF production. Cultured hepatobl astoma cells ceased to proliferate at 20-50 ng/ml HGF-SF, and they underwen t cell death at greater than or equal to 100 ng/ml. In contrast, the hepato cellular-carcinoma cell line HepG2 decreased growth under HGF-SF in a dose- dependent manner. We conclude that post-operatively secreted and intratumor ally produced HGF-SF can function as a growth factor for hepatoblastoma, wh ile the same agent has a cytostatic effect in unphysiologically high concen trations. (C) 2000 Wiley-Liss, Inc.