Inhibition of HGF/SF-induced breast cancer cell motility and invasion by the HGF/SF variant, NK4

NK4 is a variant form of HGF/SF, comprising the N-terminal and subsequent f our kringle domains of mature HGF/SF. HGF/SF is a multifunctional cytokine that enhances the metastatic behaviour of tumour cells in vitro by stimulat ion of the c-met receptor tyrosine kinase and has been implicated in the de velopment of tumour metastasis in vivo. The aims of this study were to furt her investigate the potential antagonistic effects of the recently describe d variant form of HGF/SF, NK4, on HGF/SF activity in breast cancer cells. A ll cell lines used expressed both the HGF/SF receptor gene and protein as s hown by RT-PCR and Western blotting. NK4 inhibited HGF/SF-induced tumour ce ll invasion through an artificial basement membrane. Tumour cell motility a nd scattering induced by HGF/SF were also dramatically reduced by the inclu sion of NK4. Immunoprecipitation studies revealed that NK4 inhibited the ph osphorylation of the c-met receptor in response to HGF/SF. Treatment of the se cells with NK4 alone did not have any significant effects on their metas tatic behaviour. From this data we conclude that NK4 demonstrates significa nt antagonistic properties towards HGF/SF, inhibiting HGF/SF-stimulated bre ast tumour cell invasion, motility and migration. NK4 may therefore be of p otential benefit in the development of anti-metastasis therapies.