**5.2 Inhibition of tumor angiogenesis by NK4 treatment**

In a culture of EC, NK4 produces anti-angiogenetic effects via a MET-independent pathway (Kuba *et al*., 2000; Nakabayashi *et al*., 2003). These effects are also observed in animal models of malignant tumors: administration of recombinant NK4 suppressed primary tumor growth, metastasis of Lewis lung carcinoma, and Jyg-MC(A) mammary carcinoma implanted into mice (Kuba *et al*., 2000), although neither HGF nor NK4 affected proliferation and survival of these tumor cells *in vitro*. NK4 treatment resulted in a remarkable decrease in microvessel density and an increase in apoptotic tumor cells in primary tumors, suggesting that the inhibition of tumor growth by NK4 may be achieved by the suppression of tumor angiogenesis (Kuba *et al*., 2000). The anti-angiogenic effects of NK4 are widely demonstrated in various types of cancers [see our review articles (Matsumoto & Nakamura, 2005; Matsumoto *et al*., 2008a,b)]. Because the inhibition of angiogenesis by NK4 leads to tumor hypoxia, hypoxia-primed apoptosis may contribute to a reduction in tumor size during NK4 supplemental therapy.
