Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor

Oncogene. 1998 Dec 10;17(23):3045-54. doi: 10.1038/sj.onc.1202231.


Invasion of various carcinoma cells follows their interaction with stromal cells. Hepatocyte growth factor (HGF), four-kringle-containing growth factor, is a mesenchymal or stromal-derived mediator which affects the growth and the invasiveness of carcinoma cells. We now have evidence that a four-kringle-containing antagonist for HGF, HGF/NK4 inhibits invasion of tumors in vivo, as well as in vitro. HGF/NK4 competitively inhibited the binding of HGF to Met/ HGF receptors on GB-d1 human gallbladder carcinoma cells. HGF induced invasion of the cells through Matrigel basement membrane components and into collagen gels, but HGF-induced invasion was inhibited by HGF/NK4. Invasion of GB-d1 cells was induced by co-cultivation with stromal fibroblasts, which mimics tumor-stromal interaction, but it was almost completely suppressed by HGF/NK4. Likewise, invasive growth induced by HGF in collagen gels in GB-dl cells, HuCC-T1 human cholangiocarcinoma cells, and ME-180 human uterus cervical carcinoma cells was also strongly inhibited by HGF/NK4. When GB-d1 cells were implanted subcutaneously into nude mouse, tumor cells invaded muscular tissue, but the infusion of HGF/NK4 inhibited this invasion. Furthermore, HGF/NK4 increased apoptotic cell death of GB-d1 cells and inhibited tumor growth in vivo. These results indicate that HGF/ NK4 may inhibit growth and invasion of carcinoma cells, as mediated by HGF during tumor-stromal interactions. We propose that there is a unique therapeutic potential for HGF/NK4 to prevent tumor invasion and perhaps even metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Female
  • Gallbladder Neoplasms / physiopathology*
  • Hepatocyte Growth Factor / antagonists & inhibitors*
  • Humans
  • Kringles*
  • Male
  • Matrix Metalloproteinase 9
  • Matrix Metalloproteinase Inhibitors
  • Mice
  • Mice, Nude
  • Middle Aged
  • Neoplasm Invasiveness*
  • Neoplasm Transplantation
  • Phosphorylation
  • Proto-Oncogene Proteins c-met / metabolism
  • Tumor Cells, Cultured
  • Tyrosine
  • Urokinase-Type Plasminogen Activator / antagonists & inhibitors


  • Matrix Metalloproteinase Inhibitors
  • Tyrosine
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met
  • Urokinase-Type Plasminogen Activator
  • Matrix Metalloproteinase 9