© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 18, 1548-1556,
September 15, 1999
© 1999 Oxford University Press
Reversion of Human Glioblastoma Malignancy by U1 Small Nuclear RNA/Ribozyme Targeting of Scatter Factor/Hepatocyte Growth Factor and c-met Expression
Affiliations of authors: R. Abounader, A. Book (Department of Neuroscience and Kennedy Krieger Research Institute), S. Ranganathan, K. Fielding (Kennedy Krieger Research Institute), B. Lal (Department of Neurology and Kennedy Krieger Research Institute), H. Dietz (Institute of Medical Genetics and Howard Hughes Medical Institute), P. Burger (Department of Pathology), J. Laterra (Departments of Neuroscience, Oncology, and Neurology and Kennedy Krieger Research Institute), The Johns Hopkins University School of Medicine, Baltimore, MD.
Correspondence to: John Laterra, M.D., Ph.D., Kennedy Krieger Research Institute, 707 N. Broadway, Baltimore, MD 21205 (e-mail: laterra{at}kennedykrieger.org).
BACKGROUND: Expression of scatter factor (SF), also known as hepatocyte growth factor (HGF), and its receptor, c-met, is often associated with malignant progression of human tumors, including gliomas. Overexpression of SF/HGF in experimental gliomas enhances tumorigenicity and tumor-associated angiogenesis (i.e., growth of new blood vessels). However, the role of endogenous SF/HGF or c-met expression in the malignant progression of gliomas has not been examined directly. In this study, we tested the hypothesis that human glioblastomas can be SF/HGF–c-met dependent and that a reduction in endogenous SF/HGF or c-met expression can lead to inhibition of tumor growth and tumorigenicity. METHODS: Expression of the SF/HGF and c-met genes was inhibited by transfecting glioblastoma cells with chimeric transgenes consisting of U1 small nuclear RNA, a hammerhead ribozyme, and antisense sequences. The effects of reduced SF/HGF and c-met expression on 1) SF/HGF-dependent induction of immediate early genes (c-fos and c-jun), indicative of signal transduction; 2) anchorage-independent colony formation (clonogenicity), an in vitro correlate of solid tumor malignancy; and 3) intracranial tumor formation in immunodeficient mice were quantified. Statistical tests were two-sided. RESULTS: Introduction of the transgenes into glioblastoma cells reduced expression of the SF/HGF and c-met genes to as little as 2% of control cell levels. Reduction in c-met expression specifically inhibited SF/HGF-dependent signal transduction (P<.01). Inhibition of SF/HGF or c-met expression in glioblastoma cells possessing an SF/HGF–c-met autocrine loop 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 expression in a tumor model directly demonstrating a role for endogenous SF/HGF and c-met in human glioblastoma. Our results suggest that targeting the SF/HGF–c-met signaling pathway may be an important approach in controlling tumor progression.
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