title: Heparan sulfate proteoglycans as regulators of fibroblast growth factor-2 signaling in brain endothelial cells. Specific role for glypican-1 in glioma angiogenesis.
abstract: Fibroblast growth factor-2 (FGF2) is a potent angiogenic factor in gliomas. Heparan sulfate promotes ligand binding to receptor tyrosine kinase and regulates signaling. The goal of this study was to examine the contribution of heparan sulfate proteoglycans (HSPGs) to glioma angiogenesis. Here we show that all brain endothelial cell HSPGs carry heparan sulfate chains similarly capable of forming a ternary complex with FGF2 and fibroblast growth factor receptor-1c and of promoting a mitogenic signal. Immunohistochemical analysis revealed that glypican-1 was overexpressed in glioma vessel endothelial cells, whereas this cell-surface HSPG was consistently undetectable in normal brain vessels. To determine the effect of increased glypican-1 expression on FGF2 signaling, we transfected normal brain endothelial cells, which express low base-line levels of glypican-1, with this proteoglycan. Glypican-1 expression enhanced growth of brain endothelial cells and sensitized them to FGF2-induced mitogenesis despite the fact that glypican-1 remained a minor proteoglycan. In contrast, overexpression of syndecan-1 had no effect on growth or FGF2 sensitivity. We conclude that the glypican-1 core protein has a specific role in FGF2 signaling. Glypican-1 overexpression may contribute to angiogenesis and the radiation resistance characteristic of this malignancy.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin, Clinical Sciences Center K4/850, Madison, WI 53562-8550, USA.
authors.forename: Dianhua
authors.initials: D
authors.lastname: Qiao
authors.forename: Kristy
authors.initials: K
authors.lastname: Meyer
authors.forename: Christoph
authors.initials: C
authors.lastname: Mundhenke
authors.forename: Sally A
authors.initials: SA
authors.lastname: Drew
authors.forename: Andreas
authors.initials: A
authors.lastname: Friedl
mesh_terms: D000818:Animals; D002455:Cell Division; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000494:pharmacology; D005910:Glioma / Q000098:blood supply*; D019812:Heparan Sulfate Proteoglycans / Q000502:physiology*; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000209:etiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology
chemical_list: D019812:Heparan Sulfate Proteoglycans; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; C496348:FGFR1 protein, human; C496349:Fgfr1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1