摘要：

Heparan sulfate (HS) / Heparan sulfate proteoglycans (HSPGs) are implicated in tumor malignancy based on their ability to promote cell signaling and tumor invasion. The mechanisms by which they do this in an individual tumor type, however, are often poorly defined. Using both patient-derived glioblastoma (GBM) tumorsphere lines and a murine model for GBM, we investigate how cell surface HSPGs modulate cell signaling in infiltrating astrocytoma. In human tumorsphere lines, chemical ablation of cell surface HS reduced the phosphorylation of several receptor-tyrosine kinases (RTKs) including platelet-derived growth factor receptor α (PDGFRα). The reduction in PDGFRA activation was associated with decreased binding of tagged PDGF-BB ligand to the cell surface suggesting HS can promote ligand retention and activity at the cell surface. To ablate all HS production we established HS-deficient murine tumor-prone cells by knockout of Ext1, a glycosyltransferase required for HS chain elongation. HS-deficient cells had decreased growth in vitro, decreased invasion in a 3D spheroid invasion assays, and reduced activation of RTKs as detected by Western blotting compared to control cells. Preliminary in vivo experiments suggest HS-deficient cells also exhibit reduced growth in vivo and the structural role for HS in RTK signaling in glioma can now be addressed.

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