HEPATOCYTE GROWTH-FACTOR SCATTER FACTOR AND ITS RECEPTOR C-MET ARE OVEREXPRESSED AND ASSOCIATED WITH AN INCREASED MICROVESSEL DENSITY IN MALIGNANT PLEURAL MESOTHELIOMA

Hepatocyte growth factor/scatter factor (HGF/SF) stimulates cell proli feration, motility and invasiveness via its receptor c-Met during embr yogenesis and repair processes. It induces angiogenesis, promoting end othelial cell migration and capillary-tube formation in vivo. Go-expre ssion of HGF/SF and c-Met receptor results in enhanced tumour growth, invasiveness and a mesenchymal-epithelial transition in some experimen tal tumours. Since mesothelioma cells have been reported to express c- Met receptor and to migrate in response to HGF/SF, we investigated hum an malignant pleural mesotheliomas for the demonstration of possible c oexpression of the growth factor and its receptor. The microvessel den sity of the tumours was also analysed in order to assess the influence of HGF/SF expression on tumour angiogenesis. Thirty-nine paraffin-emb edded specimens of malignant pleural mesotheliomas were immunostained by anti-HGF/SF and anti-c-Met antibodies and semiquantitatively evalua ted. c-Met mRNA expression was visualised in ten tumour samples by a f luorescent in situ hybridisation method. Microvessel density was calcu lated by counting microvessels with a high-power field. (200x) on von- Willebrand-factor-stained slides. We found an increased production of HGF/SF in 33/39 tumours and a corresponding overexpression of c-Met re ceptor in 29/39 specimens. The FISH method detected increased transcri ption of c-Met mRNA in malignant cells and in neighbouring vascular en dothelial cells. HGF/SF-positive mesotheliomas had significantly highe r microvessel densities compared to their HGF/SF-negative counterparts . The observed coexpression of HGF/SF and c-Met in malignant pleural m esotheliomas suggests a possible self-stimulation (autocrine loop) of tumour cells. On the basis of the significantly higher microvessel den sity values of malignant mesotheliomas overexpressing HGF/SF, we postu late, that HGF/SF may be an additional relevant factor in tumour angio genesis in malignant pleural mesotheliomas.