Enhanced
hepatocyte growth factor (
HGF) receptor (Met) signaling has been suggested to play an important role in the development and progression of various epithelial and nonepithelial
tumors. N-terminally truncated forms of the
HGF receptor have been shown to be constitutively activated and tumorigenic in animal experiments. In the present study, 102 benign and malignant human musculoskeletal
tumors were examined for expression of the
HGF receptor 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 first time we show
HGF receptor expression in the following four
tumor types:
dermatofibrosarcoma protuberans,
clear cell sarcoma of tendons, malignant
primitive neuroectodermal tumor, and
benign fibrous histiocytoma. In three cases of
sarcoma with high
HGF receptor expression by Western blotting, we found indications of a short 85-kd N-terminally truncated
HGF receptor that was
tyrosine phosphorylated and located in the cytoplasm. Although fragments of this length were seen in 18 of 65
tumors, most were not
tyrosine-phosphorylated. Northern blotting revealed only the 7.5-kb full-length
HGF receptor transcript, suggesting that the 85-kd fragment is generated by an alternative initiation of translation or by proteolytic cleavage. Southern blotting detected no amplification of the Hgfr/Met gene in the 35
tumors examined, in contrast to our recent report of Hgfr/Met gene amplification in 7, 12-dimethylbenz(a)anthracene (DMBA)-induced rat
sarcomas. The present data suggest that the locally aggressive and malignant properties of human mesenchymal
tumors maybe related, in part, to high levels of full-length HGF receptors, and in some cases to the occurrence of N-terminally truncated HGF receptors, activated independently of HGF.