EXTRACELLULAR REGULATORS OF GLIOBLASTOMA SIGNALING

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Abstract

BACKGROUND: Extracellular proteoglycans, including heparan sulfate proteoglycan (HSPG), play critical roles in the regulation of neural stem cell signaling and progenitor cell migration via their interactions with extracellular ligands, matrix, and cell receptors and may serve similar purposes in oncogenic states. In glioblastoma (GBM), our studies suggest that proteoglycans regulate critical oncogenic signaling pathways. Here we assess the function of proteoglycans and their alterations that drive GBM, and test the hypothesis that these may represent novel therapeutic targets and biomarkers of disease. METHODS: To investigate the role for proteoglycans in tumorigenesis we used a combination of primary human GBM, primary human GBM cultures, and a murine model for malignant glioma based on the genetic manipulation of neural progenitor cells. GAG structure was elucidated and quantified using liquid chromatography-mass spectrometry (LCMS), an ultra-sensitive and high-resolution technique that can overcome problems associated with low availability of biological samples. RESULTS: In GBM we identified patterns of altered expression of HSPG protein cores and their modifying enzymes relative to non-tumor brain, including the extracellular enzyme SULF2. Indeed, SULF2 is overexpressed in many human GBM and ablation of SULF2 function results in decreased activation of PDGFRα signaling and in decreased tumor growth in vivo. Consistent with a role for SULF2 in PDGFRA signaling in human GBM, SULF2 is upregulated in PDGFRA-amplified compared to non-amplified tumors (p < 0.05, n = 40 amplified, 332 non-amplified). SULF2 reduced HS sulfation, specifically the HS6S component of heparin, as determined by liquid chromatography-mass spectrometry (LCMS) and immunohistochemistry. As HS6S sulfation is an important determinant of HS-ligand binding, we investigated whether SULF2 could alter PDGF binding to HS. While ligand binding was similar, SULF2 was associated with altered expression and cell surface localization of PDGFRA. Thus, SULF2, and possibly HS6S, may regulate PDGFRA signaling via two distinct mechanisms. As HS structure is critical for normal neural stem cell proliferation and differentiation, we analyzed HS structure over tumor progression using LCMS. We demonstrate that tumor progression is associated with changes in GAG structure, and we are now using HS mimetics to try to inhibit the oncogenic role for proteoglycans in GBM. CONCLUSIONS: Our data demonstrate the functional importance of proteoglycans in GBM and suggest GAG structure may be particularly important for oncogenic signaling. While therapeutic targeting of single RTKs has been difficult in GBM, a drug targeting HS has the potential to simultaneously inhibit multiple oncogenic pathways in tumor cells and disrupt critical tumor-microenvironment interactions. SECONDARY CATEGORY: n/a.

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