NK4, a new HGF/SF variant, is an antagonist to the influence of HGF/SF on the motility and invasion of colon cancer cells

Hepatocyte Growth Factor/Scatter Factor (HGF/SF) is a heterodimeric molecul e that plays a key role in the regulation of migration, invasion and angiog enesis in cancer, via activation of its receptor, c-met, HGF/SF is composed of an alpha-chain, containing the N-terminal hairpin domain and 4 kringle domains, plus the serine protease-like beta-chain, We have examined here th e properties of NK4, an HGF variant containing the hi-terminal hairpin plus the 4 kringle domains, on tumour cell proliferation, dissociation and inva sion using human colorectal cancer cells (HT115), The expression of HGF/SF and its receptor was also examined by RT-PCR and Western blotting. Analysis revealed NK4 to be an HGF/SF antagonist that, at a wide range of concentra tions, did not exert any biological effects of its own. HT115 cells were sh own to express the HGF/SF receptor mRNA and protein. HGF/SF-induced recepto r tyrosine phosphorylation was suppressed, in a dose-dependent manner, upon addition of NK4, whereas the addition of NK4 alone caused no phosphorylati on. Tumour cell motility was induced by HGF and inhibited by NK4, Furthermo re, HGF/SF induced the invasion of cells through Matrigel basement membrane components, and again this induced invasion was suppressed by NK4. Our res ults show that the ability of HGF/SF to stimulate tumour cell motility and invasion, properties required for metastatic spread, can be inhibited by NK 4, Thus, NK4 may have an important role in the control of cancer metastasis . Int. J. Cancer 85:563-570, 2000, (C) 2000 Wiley-Liss, Inc.