부산대학교 도서관

BACKGROUND: Expression of scatter factor (SF), also knownas hepatocyte growth factor (HGF), and its receptor, c-met, is oftenassociated with malignant progression of human tumors, includinggliomas. Overexpression of SF/HGF in experimental gliomas enhancestumorigenicity and tumor-associated angiogenesis (i.e., growth of newblood vessels). However, the role of endogenous SF/HGF or c-metexpression in the malignant progression of gliomas has not beenexamined directly. In this study, we tested the hypothesis that humanglioblastomas can be SF/HGF–c-met dependent and that a reduction inendogenous SF/HGF or c-met expression can lead to inhibition of tumorgrowth and tumorigenicity.W METHODS: Expression of the SF/HGFand c-met genes was inhibited by transfecting glioblastoma cells withchimeric transgenes consisting of U1 small nuclear RNA, a hammerheadribozyme, and antisense sequences. The effects of reduced SF/HGF andc-met expression on 1) SF/HGF-dependent induction of immediateearly genes (c-fos and c-jun), indicative of signal transduction; 2)anchorage-independent colony formation (clonogenicity), an invitro correlate of solid tumor malignancy; and 3) intracranialtumor formation in immunodeficient mice were quantified. Statisticaltests were two-sided. RESULTS: Introduction of the transgenesinto glioblastoma cells reduced expression of the SF/HGF and c-metgenes to as little as 2% of control cell levels.Reduction in c-met expression specifically inhibited SF/HGF-dependentsignal transduction (P<.01). Inhibition of SF/HGF or c-metexpression in glioblastoma cells possessing an SF/HGF–c-met autocrineloop reduced tumor cell clonogenicity (P=.005 for SF/HGF and P=.009 for c-met) and substantially inhibited tumorigenicity(P<.0001) and tumor growth in vivo(P<.0001). CONCLUSIONS: To our knowledge,this is the first successful inhibition of SF/HGF and c-met expressionin a tumor model directly demonstrating a role for endogenous SF/HGFand c-met in human glioblastoma. Our results suggest that targeting theSF/HGF–c-met signaling pathway may be an important approach incontrolling tumor progression.