Sulfated Chondroitin Sulfate Glycosaminoglycans in Glioblastoma Progression

Glioblastoma (GBM) is the most commonly occurring and most malignant astrocytoma in adults. The lethality of GBM lies in its ability to resist standard-of-care treatments while rapidly invading functional brain regions. No significant breakthroughs have been made in GBM treatment over the last 30 years, and prognosis of GBM patients continues to be poor. The lack of extracranial metastasis of this highly invasive tumor suggests that the tumor microenvironment (TME) plays an important role in mediating GBM progression. In this work, we examined the functional significance of chondroitin sulfate (CS) proteoglycans (CSPGs) and their associated glycosaminoglycan (GAG) side chains in the TME, and their role in facilitating GBM progression. I have characterized the pro-infiltrative effects of differently sulfated CS-GAGs on both human and rat GBM cells and discovered that extracellular sulfated CS-GAG microenvironments enhanced GBM cell migration, and regulated the expression and binding to cell surface receptors. I also discovered that increasing sulfation and altering the sulfation profile in extracellular CS-GAG matrices potently increased migration as well as haptotaxis in response to the cell homing chemokine CXCL12. To understand how targeted inhibition of TME-associated sulfated GAG activity might be translated into a therapeutic strategy against GBM, I used a sulfated GAG antagonist (Surfen) in a rodent model of GBM. In addition to reducing growth of the tumors, Surfen treatment of tumor cells disrupted the composition of the TME and glioma stem cell (GSC) niche around GBM. These studies demonstrated the cytostatic effects of Surfen on GBM, and revealed the potential of Surfen treatment to safely limit tumor spread, angiogenesis, and necrosis in conjunction with cytotoxic approaches. Future research into the role of CS-GAG sulfation in promoting GBM invasion would greatly advance our understanding of TME and contribute to the development of innovative therapeutic interventions for this intractable disease.