Overexpression of the hepatocyte growth factor (HGF) receptor (Met) and presence of a truncated and activated intracellular HGF receptor fragment in locally aggressive/malignant human musculoskeletal tumors

Enhanced hepatocyte growth factor (HGF) receptor (Met) signaling has been s uggested to play an important role in the development and progression of va rious epithelial and nonepithelial tumors. N-terminally truncated forms of the HGF receptor have been shown to be constitutively activated and tumorig enic in animal experiments. In the present study, 102 benign and malignant human musculoskeletal tumors were examined for expression of the HGF recept or by Western blotting and/or immunohistochemistry. A clear predominance of HGF receptor expression was seen in malignant as compared to benign tumors (Western blotting, P < 0.001; immunohistochemistry, P < 0.02). For the fir st time we show HGF receptor expression in the following four tumor types: dermatofibrosarcoma protuberans, clear cell sarcoma of tendons, malignant p rimitive neuroectodermal tumor, and benign fibrous histiocytoma, In three c ases of sarcoma with high HGF receptor expression by Western blotting, we f ound indications of a short 85-kd N-terminally truncated HGF receptor that was tyrosine phosphorylated and located in the cytoplasm, Although fragment s of this length were seen in 18 of 65 tumors, most were not tyrosine-phosp horylated. Northern blotting revealed only the 7.5-kb full-length HGF recep tor transcript, suggesting that the 85-kd fragment is generated by an alter native initiation of translation or by proteolytic cleavage. Southern blott ing detected no amplification of the Hgfr/Met gene in the 35 tumors examine d, in contrast to our recent report of Hgfr/Met gene amplification in 7,12- dimethylbenz(a)anthracene (DMBA)-induced rat sarcomas, The present data sug gest that the locally aggressive and malignant properties of human mesenchy mal tumors maybe related, in part, to high levels of full-length HGF recept ors, and in some cases to the occurrence of N-terminally truncated HGF rece ptors, activated independently of HGF.