Inhibition of Intracerebral Glioblastoma Growth by Local Treatment with the Scatter Factor/Hepatocyte Growth Factor-Antagonist NK4

Purpose: Scatter factor/hepatocyte growth factor (SF/ HGF) and its tyrosine kinase receptor MET are strongly up-regulated in malignant gliomas. The SF/HGF-MET system contributes to glioma invasion and angiogenesis via autocrine and paracrine mechanisms. We analyzed whether local treatment with NK4, an antagonistic fragment of SF/ HGF, could inhibit glioma growth in vivo. Experimental Design: A guide-screw system was used to implant tumor cells intracerebrally and to perform therapeutic injections. Mice received daily intratumoral injections of NK4 or buffer as of day 1 or 7 after tumor cell injection until day 20. Functional effects of NK4 on glioma and endothelial cells were analyzed in vitro. Results: Tumor volume was reduced by 61.1% in mice treated with NK4 compared with controls when treatment was initiated on day 1 (P 30% regardless of when NK4-treatment was initiated. The apoptotic fraction of tumor cells was increased 2-fold and 1.5-fold when animals were treated with NK4 as of day 1 or day 7, respectively. In vitro, NK4 inhibited SF/HGF-induced glioblastoma, and endothelial cell migration and proliferation in a dose-dependent fashion. Conclusion: NK4 inhibits glioblastoma growth in vivo, most likely via antimitogenic, antimotogenic, proapoptotic, and antiangiogenic mechanisms. Given the strong up-regulation of SF/HGF and MET in human malignant gliomas, NK4 holds promise as a direct interstitial therapeutic agent for these fatal tumors.