**4. Structure and activity of NK4 as HGF antagonist**

HGF is a stromal-derived paracrine factor that has stimulated cancer invasion at least *in vitro* (Matsumoto *et al*., 1994; Matsumoto *et al*., 1996a; Nakamura *et al*., 1997). Clinical studies suggest that the degree of serum HGF and Met expressions in cancer tissues appears to correlate with a given prognosis (Yoshinaga *et al*., 1993; Osada *et al*., 2008). Thus, it is hypothesized that *in vivo* inhibition of HGF-MET signaling may be a reasonable strategy to prohibit cancer metastasis. To test this hypothesis, we prepared NK4 as an intra-molecular fragment of HGF via a chemical digestive process (Date *et al*., 1997; Matsumoto *et al*., 1998). As expected, NK4 bounded to MET and inhibited HGF-MET coupling as a competitive inhibitor. An additional "unexpected" value was that NK4 inhibited tumor angiogenesis via a MET-independent pathway. This section focuses on the biological value of NK4 as an HGF-antagonist and as an angiogenesis inhibitor.
