Based on the background that hepatocyte growth factor (HGF) and Met/HGF receptor tyrosine kinase play a definite role in tumor invasion and metastasis, NK4 was isolated as a competitive antagonist against functional association between HGF and Met. NK4 is an internal fragment of HGF and composed of the N-terminal and four kringle domains. Independently on its HGF-antagonist action, NK4 inhibited angiogenesis induced by vascular endothelial cell growth factor and basic fibroblast growth factor, as well as HGF, indicating that NK4 is a bifunctional molecule that acts as an HGF-antagonist and angiogenesis inhibitor. In experimental models of distinct types of cancers, NK4 gene therapy inhibited Met receptor activation and this was associated with inhibition of tumor invasion and metastasis. Likewise, NK4 gene therapy inhibited tumor angiogenesis, thereby suppressing angiogenesis-dependent tumor growth. Cancer treatment with NK4 suppresses malignant tumors to be 'static' in both tumor growth and spreading. NK4 warrants further investigation and attention as potential cancer therapy for humans.
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