Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain Neoplasms / blood supply*
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Brain Neoplasms / genetics
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Brain Neoplasms / metabolism
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Brain Neoplasms / pathology*
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Cell Division / physiology
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Endothelial Growth Factors / biosynthesis
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Endothelial Growth Factors / genetics
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Fibroblast Growth Factor 2 / biosynthesis
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Fibroblast Growth Factor 2 / genetics
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Fibroblast Growth Factor 4
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Fibroblast Growth Factors / antagonists & inhibitors*
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Fibroblast Growth Factors / biosynthesis
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Fibroblast Growth Factors / genetics
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Fibroblast Growth Factors / physiology
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Gene Expression Regulation, Neoplastic / drug effects
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Glioma / blood supply*
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Glioma / genetics
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Glioma / metabolism
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Glioma / pathology*
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Lymphokines / biosynthesis
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Lymphokines / genetics
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Male
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Mice
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Neovascularization, Pathologic / metabolism
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Neovascularization, Pathologic / pathology*
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Phenotype
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Rabbits
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Rats
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Rats, Sprague-Dawley
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Receptor Protein-Tyrosine Kinases / biosynthesis
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / physiology
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Receptor, Fibroblast Growth Factor, Type 1
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Receptor, Fibroblast Growth Factor, Type 2
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Receptors, Fibroblast Growth Factor / antagonists & inhibitors*
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Receptors, Fibroblast Growth Factor / biosynthesis
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Receptors, Fibroblast Growth Factor / genetics
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Receptors, Fibroblast Growth Factor / physiology
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Tetracycline / pharmacology
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Transfection
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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Endothelial Growth Factors
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Fgf4 protein, mouse
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Fgf4 protein, rat
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Fibroblast Growth Factor 4
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Lymphokines
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Proto-Oncogene Proteins
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Receptors, Fibroblast Growth Factor
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Fibroblast Growth Factor 2
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Fibroblast Growth Factors
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Fgfr1 protein, mouse
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Fgfr1 protein, rat
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Fgfr2 protein, mouse
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Fgfr2 protein, rat
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Receptor Protein-Tyrosine Kinases
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Receptor, Fibroblast Growth Factor, Type 1
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Receptor, Fibroblast Growth Factor, Type 2
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Tetracycline