THE MET HGF RECEPTOR IS OVER-EXPRESSED IN HUMAN OSTEOSARCOMAS AND IS ACTIVATED BY EITHER A PARACRINE OR AN AUTOCRINE CIRCUIT/

The c-MET oncogene encodes the receptor for the Hepatocyte Growth Fact or/Scatter Factor (HGF), a cytokine that stimulates the invasive growt h of normal and neoplastic cells. The Met/HGF receptor is expressed by epithelial cells and its ligand by cells of mesenchymal origin. Recep tor-ligand interaction occurs via a paracrine circuit. We studied the expression of the Met/HGF receptor and of its ligand in mesenchymal hu man tumours by examining 39 clinical samples of bone tumours. The Met/ HGF receptor was not detectable in the majority of bone tumours, as ex pected from their mesenchymal origin. Notably, the receptor was overex pressed in 60% of the osteosarcomas examined. In 12 osteosarcoma cell lines the Met/HGF receptor was overexpressed, phosphorylated by HGF st imulation and fully functional, HGF was detected in two out of seven c linical specimens of osteosarcoma. The ligand and the receptor are co- expressed in two clonal osteosarcoma cell lines. In these lines the Me t/HGF receptor was constitutively phosphorylated; phosphorylation was suppressed by suramin treatment, a known blocker of autocrine loops. T hese data suggest that activation of the Met/HGF receptor by a paracri ne or an autocrine mechanism might play a role in the particularly agg ressive behaviour of osteosarcomas.