Antagonistic effect of NK4, a novel hepatocyte growth factor variant, on in vitro angiogenesis of human vascular endothelial cells

Hepatocyte growth factor (HGF), also known as scatter factor (SF), is known to act on cancer cells as well as endothelial cells and stimulate angiogen esis, thus playing an unwanted role in the development and progression of c ancer. The current study examined the effects of a newly discovered HGF var iant, NK4, on angiogenesis in vitro. Chemically generated NK4 (from recombi nant human HGF/SF) was found to be able to inhibit HGF-induced activation ( tyrosine phosphorylation) of the HGF/SF receptor cMET but was itself unable to activate cMET, Furthermore, NK4 was demonstrated to inhibit tubule form ation from human umbilical vein endothelial cells that was induced by both HGF/SF and a HGF/SF-producing fibroblast (MRCS), Under the same settings, N K4 failed to increase tubular formation. NK4 had no effects on interleukin 8- and vascular endothelial growth factor-induced tubule formation. Using c omputer-assisted motion analysis, it was further shown that NK4 inhibited H GF-induced migration of human umbilical vein endothelial cells in a migrati on assay and in an endothelial wounding assay, These data show that NK4 is a complete antagonist to HGF, It inhibits HGF-induced endothelial movement and tubule formation. Thus, NK4 may have an important bearing on the contro l of cancer progression through its role in angiogenesis, Additional in viv o studies are warranted.