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Inhibition of Fibroblast Growth Factor/Fibroblast Growth Factor Receptor Activity in Glioma Cells Impedes Tumor Growth by Both Angiogenesis-dependent and -independent Mechanisms¹

Growth Factor and Cell Differentiation Laboratory, University Bordeaux I, 33 405 Talence, France [P. A., D. B. G., S. L., A. B.]; Department of Histology, Hopital Ramon Y Cajal, 28006 Madrid, Spain [D. R., P. C., F. C.]; and Unité des Cytokines et Développement Lymphoide, Departement d’Immunologie, Institut Pasteur, 75 724 Paris, France [J. P. D. S.]

We undertook a series of systematic studies to address the role of fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) activity in tumor growth and angiogenesis. We expressed dominant-negative FGFR2 (FGFR2-DN) or FGFR1 (FGFR1-DN) in glioma C6 cells by using constitutive or tetracycline-regulated expression systems. Anchorage-dependent or independent growth was inhibited in FGFR-DN-expressing cells. Tumor development after xenografting FGFR-DN-expressing cells in immunodeficient mice or after transplantation in rat brain was strongly inhibited. Quantification of microvessels demonstrated a significant decrease in vessel density in tumors derived from FGFR-DN-expressing cells. Furthermore, in a rabbit corneal assay, the angiogenic response after implantation of FGFR-DN-expressing cells was decreased. In tumors expressing FGFR-DN, vascular endothelial growth factor expression was strongly inhibited as compared with control tumor. These results indicate that inhibition of FGF activity may constitute a dominant therapeutic strategy in the treatment of FGF-producing cerebral malignancies and may disrupt both angiogenesis-dependent and -independent signals required for glioma growth and invasion.

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