Hepatocyte growth factor (HGF) exhibits mitogenic, motogenic, morphogenic, and anti-apoptotic activities, through Met/HGF receptor. In a variety of tumor tissues, HGF is involved in malignant behavior of cancers as a mediator in tumor-stromal interaction, enhancing tumor invasion and metastasis. To establish a new strategy to inhibit tumor invasion and metastasis, we prepared an antagonistic molecule for HGF. The antagonist, NK4, is an internal fragment of HGF that encompasses the N-terminal hairpin and four kringle domains. Notably, NK4 inhibits tumor angiogenesis, growth and metastasis, as an angiogenesis inhibitor, as well as HGF-antagonist.
In vitro, NK4 specifically inhibited tumor invasion induced by HGF. In contrast, NK4 inhibited growth and migration of microvascular endothelial cells induced by basic fibroblast growth factor (bFGF), vascular endothelial cell growth factor (VEGF), and HGF. NK4 inhibited bFGF-induced angiogenesis in rabbit cornea. We concluded that NK4 is bifunctional: it is HGF-antagonist and angiogenesis inhibitor. When the anti-tumor activity of NK4 was examined in murine metastatic tumors, Lewis lung carcinoma, administration of NK4 suppressed the growth of primary tumors subcutaneously implanted in mice, and decreased the number of metastatic nodules in the lung. NK4 suppressed neovascularization of tumor cells. Likewise, NK4 inhibited invasion, tumor angiogenesis, peritoneal dissemination, and liver metastasis of pancreatic cancer. The bifunctional properties of NK4 to act as an angiogenesis inhibitor and as a HGF antagonist raises possibility that NK4 may prove a therapeutic for cancer patients.
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