Inhibition of fibroblast growth factor/fibroblast growth factor receptor activity in glioma cells impedes tumor growth by both angiogenesis-dependent and -independent mechanisms.
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.
Growth Factor and Cell Differentiation Laboratory, University Bordeaux I, Talence, France.
P
P
Auguste
D B
DB
Gürsel
S
S
Lemière
D
D
Reimers
P
P
Cuevas
F
F
Carceller
J P
JP
Di Santo
A
A
Bikfalvi
D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000502:physiology; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000235:genetics; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D013752:Tetracycline / Q000494:pharmacology; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; C496446:Fgf4 protein, mouse; C496447:Fgf4 protein, rat; D051519:Fibroblast Growth Factor 4; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D017468:Receptors, Fibroblast Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D005346:Fibroblast Growth Factors; C496349:Fgfr1 protein, mouse; C496350:Fgfr1 protein, rat; C496354:Fgfr2 protein, mouse; C496356:Fgfr2 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D013752:Tetracycline