Abstract
We have investigated growth and vascularization of malignant glioma in mice upon conditional inhibition of fibroblast growth factor (FGF) receptor activity. C6 rat glioma cells were transfected with a dominant-negative fibroblast growth factor receptor-2 (FGFR2-DN) cDNA under the control of a tetracycline-regulated expression promoter (tet off) and implanted in the brain of immunodeficient mice. Magnetic resonance imaging analysis showed a significant decrease in tumor growth 14 days after implantation when FGFR2-DN was expressed compared to control. This size difference disappeared after 20 days. However, after 20 days, tumor and endothelial cells apoptosis were higher in the FGFR2-DN group and consequently angiogenesis was decreased whereas tumor cells were similarly associated with blood vessels at the tumor periphery. Pericyte coverage was not different between the two groups but a higher amount of pericytes not associated with vessels was found in the FGFR2-DN expressing group. This demonstrates, that conditional expression of inhibitor of FGF receptor activity in gliomas implanted in the brain of immunodeficient mice can be achieved efficiently, and that FGFs are major players in glioma development and in glioma angiogenesis.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bikfalvi A, Klein S, Pintucci G, Rifkin DB. Biological roles of fibroblast growth factor-2. Endocr Rev 1997; 18: 26–45.
Ornitz DM, Itoh N. Fibroblast growth factors. Genome Biol 2001; 2: 7–11.
Florkiewicz RZ, Anchin J, Baird A. The inhibition of fibroblast growth factor-2 export by cardenolides implies a novel function for the catalytic subunit of Na+, K+-ATPase. J Biol Chem 1998; 273: 544–51.
Javerzat S, Auguste P, Bikfalvi A. The role of fibroblast growth factors in vascular development. Trends Mol Med 2002; 8: 483–9.
Auguste P, Javerzat S, Bikfalvi A. Regulation of vascular development by fibroblast growth factors. Cell Tissue Res 2003; 314: 157–66.
Florkiewicz RZ, Sommer A. Human basic fibroblast growth factor gene encodes four polypeptides: Three initiate translation from non-AUG codons. Proc Natl Acad Sci USA 1989; 86: 3978–81.
Prats H, Kaghad M, Prats A C et al. High molecular mass forms of basic fibroblast growth factor are initiated by alternative CUG codons. Proc Natl Acad Sci USA 1989; 86: 1836–40.
Arnaud E, Touriol C, Boutonnet C et al. A new 34-k isoform of human fibroblast growth factor 2 is capdependently synthesized by using a non-AUG start codon and behaves as a survival factor. Mol Cell Biol 1999; 19: 505–14.
Ornitz DM, Xu J, Colvin JS et al. Receptor specificity of the fibroblast growth factor family. J Biol Chem 1996; 271: 15292–7.
Goldbrunner RH, Bendszus M, Sasaki M. et al. Vascular endothelial growth factor-driven glioma growth and vascularization in an orthotopic rat model monitored by magnetic resonance imaging. Neurosurgery 2000; 47: 921–29; discussion 929–30.
Plate KH, Breier G, Weich HA, Risau W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 1992; 359: 845–8.
Morrison RS, Yamaguchi F, Saya H et al. Basic fibroblast growth factor and fibroblast growth factor receptor I are implicated in the growth of human astrocytomas. J Neurooncol 1994; 18: 207–16.
Auguste P, Gursel DB, Lemiere, S et al. Inhibition of fibroblast growth factor/fibroblast growth factor receptor activity in glioma cells impedes tumor growth by both angiogenesis-dependent and-independent mechanisms. Cancer Res 2001; 61: 1717–26.
Blouw B, Song H, Tihan T et al. The hypoxic response of tumors is dependent on their microenvronment. Cancer Cell 2003; 4: 133–46.
Holash J, Maisonpierre PC, Compton D et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 1999; 284: 1994–18.
Zagzag D, Amirnovin R, Greco MA et al. Vascular apoptosis and involution in gliomas precede neovascularization: a novel concept for glioma growth and angiogenesis. Lab Invest 2000; 80: 837–49.
Vajkoczy P, Farhadi M, Gaumann A et al. Microtumor growth initiates angiogenic sprouting with simultaneous expression of VEGF, VEGF receptor-2, and angiopoietin-2. J Clin Invest 2002; 109: 777–85.
Folberg R, Hendrix MJ, Maniotis AJ. Vasculogenic mimicry and tumor angiogenesis. Am J Pathol 2000; 156: 361–81.
Quesson B, Bouzier AK, Thiaudiere E et al. Magnetization transfer fast imaging of implanted glioma in the rat brain at 4.7 T: interpretation using a binary spin-bath model. J Magn Reson Imaging 1997; 7: 1076–83.
Quesson B, Thiaudiere E, Delalande C et al. Magnetization transfer imaging in vivo of the rat brain at 4.7 T: interpretation using a binary spin-bath model with a superLorentzian lineshape. Magn Res 1997; Med 38: 974–80.
Hennig J, Nauerth A, Friedburg H. RARE imaging: A fast imaging method for clinical MR. Magn Res Med 1986; 3: 823–33.
Colucci F, Soudais C, Rosmaraki E et al. Dissecting NK cell development using a novel alymphoid mouse model: Investigating the role of the c-abl proto-oncogene in murine NK cell differentiation. J Immunol 1999; 162: 2761–65.
Bello L, Lucini V, Carrabba G et al. Simultaneous inhibition of glioma angiogenesis, cell proliferation, and invasion by a naturally occurring fragment of human metalloproteinase-2. Cancer Res 2001; 61: 8730–36.
O'Reilly MS, Holmgren L, Chen C, Folkman J. Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med 1996; 2: 689–92.
Cassiman D, Libbrecht L, Desmet V et al. Hepatic stellate cell/ myofibroblast subpopulations in fibrotic human and rat livers. J Hepatol 2002; 36: 200–09.
Morikawa S, Baluk P, Kaidoh T et al. Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol 2002; 160: 985–1000.
Ramadori G, Saile B. Mesenchymal cells in the liver–one cell type or two? Liver 2002; 22: 283–94.
Seghezzi G, Patel S, Ren CJ et al. Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries: an autocrine mechanism contributing to angiogenesis. J Cell Biol 1998; 141: 1659–73.
Bergers G, Song S, Meyer-Morse N et al. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 2003; 111: 1287–95.
Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000; 407: 249–57.
Carmeliet P, Lampugnani MG, Moons L et al. Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGFmediated endothelial survival and angiogenesis. Cell 1999; 98: 147–57.
Ferrara N, Carver-Moore K, Chen H et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996; 380: 439–42.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Miraux, S., Lemière, S., Pineau, R. et al. Inhibition of FGF receptor activity in glioma implanted into the mouse brain using the tetracyclin-regulated expression system. Angiogenesis 7, 105–113 (2004). https://doi.org/10.1007/s10456-004-1037-0
Issue Date:
DOI: https://doi.org/10.1007/s10456-004-1037-0