Glypican-1 Is Frequently Overexpressed in Human Gliomas and Enhances FGF-2 Signaling in Glioma Cells

Abstract

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.

Novel Therapeutic Targets in the Brain Tumor Microenvironment

“…In multiple myeloma high levels of shed syndecan-1 correlate with poor prognosis and have been associated with increased tumor growth in animal models [56,57]. In GBM, both total and specific HSPGs core proteins are altered (Figure 2), including increased levels of syndecan-1 and glypican-1 as previously demonstrated [23,58].…”

Diagnostic and prognostic significance of glypican 5 and glypican 6 gene expression levels in gastric adenocarcinoma

“…For example, increased GPC1 expression in human gliomas and glioma-derived cell lines have been reported and it has been suggested that GPC1 acts by enhancing FGF basic signaling and mitogenesis (21). Similarly, GPC1 overexpression has been demonstrated in pancreatic cancer cells and it has been suggested that GPC1 plays an essential role in the response of pancreatic cancer cells to certain mitogenic stimuli, such as FGF and heparin-binding epidermal growth factor (EGF)-like growth factor (22).…”

Autoregulation of glypican-1 by intronic microRNA-149 fine-tunes the angiogenic response to fibroblast growth factor in human endothelial cells

“…There are six members of the GPC family. GPC1 is involved in tumorigenesis and angiogenesis, and is frequently overexpressed in different human malignancies including pancreatic carcinoma, breast cancer and glioma (Aikawa et al, 2008;Kleeff et al, 1998;Kleeff et al, 1999;Matsuda et al, 2001;Su et al, 2006). GPC1 has been proposed to act as a co-receptor for FGF that enhances the binding of FGF to its receptor, subsequently promoting FGF-FGFR activation and signaling (Zhang et al, 2001).…”