Antagonistic Effect of NK4, a Novel Hepatocyte Growth Factor Variant, on in Vitro Angiogenesis of Human Vascular Endothelial Cells

Antagonistic Effect of NK4, a Novel Hepatocyte Growth Factor Variant, on in Vitro Angiogenesis of Human Vascular Endothelial Cells1

Metastasis Research Group, University Department of Surgery, University of Wales College of Medicine, Cardiff CF14 4XN, United Kingdom [W. G. J., S. E. H., C. P., T. A. M., R. E. M.], and Biomedical Research Centre, Osaka University Medical School, Suita, Osaka 565, Japan [K. M., T. N.]

Abstract

Hepatocyte growth factor (HGF), also known as scatter factor (SF), is known to act on cancer cells as well as endothelial cells and stimulate angiogenesis, thus playing an unwanted role in the development and progression of cancer. The current study examined the effects of a newly discovered HGF variant, NK4, on angiogenesis in vitro. Chemically generated NK4 (from recombinant 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 formation from human umbilical vein endothelial cells that was induced by both HGF/SF and a HGF/SF-producing fibroblast (MRC5). Under the same settings, NK4 failed to increase tubular formation. NK4 had no effects on interleukin 8- and vascular endothelial growth factor-induced tubule formation. Using computer-assisted motion analysis, it was further shown that NK4 inhibited HGF-induced migration of human umbilical vein endothelial cells in a migration 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 control of cancer progression through its role in angiogenesis. Additional in vivo studies are warranted.

Footnotes

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↵1 Supported by the World Cancer Research Fund.
↵2 To whom requests for reprints should be addressed, at Metastasis Research Group, University Department of Surgery, University of Wales College of Medicine, Cardiff CF14 4XN, United Kingdom. Phone: 44-29-2074-2895; Fax: 44-29-2076-1623; E-mail: jiangw{at}cf.ac.uk
↵3 The abbreviations used are: HGF, hepatocyte growth factor; SF, scatter factor; rhHGF/SF, recombinant human HGF/SF; HUVEC, human umbilical vein endothelial cell; IL, interleukin; VEGF, vascular endothelial growth factor; MDCK, Madin-Darby canine kidney; RT-PCR, reverse transcription-PCR.
- Accepted August 27, 1999.
- Received May 28, 1999.
- Revision received August 24, 1999.