Anti-cancer approach with NK4: Bivalent action and mechanisms.

We identified NK4, the N-terminal and four kringle domains of hepatocyte growth factor (HGF), as a specific inhibitor of HGF. NK4 binds to the Met/HGF receptor, but does not activate the Met receptor, thereby competitively inhibiting the HGF-Met pathway. Independent of its inhibition of HGF-Met, NK4 acts as an angiogenesis inhibitor. The angioinhibitory action of NK4 is mediated by perlecan, a multidomain proteoglycan involved in vascular basement membrane assembly. The extracellular binding of NK4 to perlecan inhibits cell-associated assembly of fibronectin, and the impaired fibronectin assembly suppresses integrin-dependent angiogenic responses, i.e., endothelial cell proliferation, migration and tube formation. NK4 or an NK4-like fragment is generated by proteases expressed in inflammatory cells, suggesting regulation of physiological or pathological processes by NK4 or NK4-like fragments. In a variety of cancer models, NK4 exhibited anti-cancer effects due to its bifunctional characteristics, including inhibition of invasion and metastasis, inhibition of angiogenesis-dependent tumor growth, and promotion of survival. Several lines of strategies and different molecules that inhibit the HGF-Met pathway have been developed, including small molecular inhibiters of Met tyrosine kinase. The biological action of NK4 as an angiogenesis inhibitor has definite advantages over other molecules. In addition to the well-acknowledged role of HGF-Met in cancer invasion and metastasis, recent studies indicate that activation of the HGF-Met pathway makes tumor-initiating cells invasive and resistant to chemical and radiation therapy. Treatment with NK4 could offer a new therapeutic option for the inhibition of cancer metastasis and growth, and better outcomes for cancer patients.