Glypican-1 is frequently overexpressed in human gliomas and enhances FGF-2 signaling in glioma cells.
Signaling by fibroblast growth factor 2 (FGF-2), an autocrine stimulator of glioma growth, is regulated by heparan sulfate proteoglycans (HSPGs) via a ternary complex with FGF-2 and the FGF receptor (FGFR). To characterize glioma growth signaling, we examined whether altered HSPGs contribute to loss of growth control in gliomas. In a screen of five human glioma cell lines, U118 and U251 cell HSPGs activated FGF-2 signaling via FGFR1c. The direct comparison of U251 glioma cells with normal astrocyte HSPGs demonstrated that the glioma HSPGs had a significantly elevated ability to promote FGF-2-dependent mitogenic signaling via FGFR1c. This enhanced activity correlated with a higher level of overall sulfation, specifically the abundance of 2S- and 6S-containing disaccharides. Glioma cell expression of the cell-surface HSPG glypican-1 closely mirrored the FGF-2 coactivator activity. Furthermore, forced expression of glypican-1 in (glypican-1-deficient) U87 glioma cells enhanced their FGF-2 response. Immunohistochemical analysis revealed a highly significant overexpression of glypican-1 in human astrocytoma and oligodendroglioma samples compared with nonneoplastic gliosis. In summary, these observations suggest that altered HSPGs contribute to enhanced signaling of FGF-2 via FGFR1c in gliomas with glypican-1 playing a significant role in this mitogenic pathway.
Su
Gui
G
University of Wisconsin-Madison, Department of Pathology and Laboratory Medicine, Clinical Sciences Center K4/850, 600 Highland Ave., Madison, WI 53792-8550, USA.
Meyer
Kristy
K
Nandini
Chilkunda D
CD
Qiao
Dianhua
D
Salamat
Shahriar
S
Friedl
Andreas
A
D000818:Animals; D001253:Astrocytes / Q000166:cytology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016543:Central Nervous System Neoplasms / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000378:metabolism*; D006025:Glycosaminoglycans; D019812:Heparan Sulfate Proteoglycans / Q000096:biosynthesis*; D006801:Humans; D051381:Rats; D015398:Signal Transduction; D014162:Transfection
D006025:Glycosaminoglycans; D019812:Heparan Sulfate Proteoglycans; D016222:Fibroblast Growth Factor 2