Heparan Sulfate Proteoglycans in Brain Tumor Development

Malignant brain tumors are aggressive neoplasms that remain challenging to treat in spite of their detailed molecular characterization. Both adults and children may suffer from brain tumors, which, if not lethal, can cause severe long-term and devastating side effects. The exceptionally invasive behavior of tumor cells, causing infiltrative disease, is among the reasons why these brain tumors often remain fatal. This thesis focuses on a group of molecules of the brain tumor microenvironment, heparan sulfate proteoglycans (HSPGs), and their roles in development of malignant brain tumors. The extracellular matrix in the brain has a unique composition with abundant HSPGs, and the hypothesis was, therefore, that heparan sulfate (HS)-degrading and HS-biosynthetic enzymes may have an important role in glioma and pediatric brain tumors. In our first study, we describe the role of the HS degrading enzyme, heparanase (HPSE), in glioblastoma (GBM) development, as well as its clinical relevance. A series of mechanistic studies revealed the effect of HPSE on signaling pathway activation and its protumorigenic activity in vitro and in vivo. Next, we expanded our work to encompass HPSE in pediatric brain tumors by presenting evidence of high HPSE expression in human tumors, and in cells derived from patients. We showed that tumor cell growth and invasion were increased by HPSE, an effect that could be inhibited by pharmacological treatment against the enzyme, suggesting that HPSE could be a targetable molecule in these tumors. We further explored the molecular mechanisms underlying the pro-tumorigenic properties of HPSE and in study III we describe a novel HPSE-CD24-L1CAM axis which was found to influence glioma tumorigenesis. Clinical data revealed a significantly shorter patient survival in HPSE-high/CD24-high tumors compared to CD24-low tumors, and experiments in mice showed that anti-CD24 and anti-L1CAM treatment inhibited tumor growth. In the fourth study, we investigated the dysregulation of the HS biosynthetic machinery and focused on N-deacetylase/N-sulfotransferase 1 (NDST1) in GBM development. We show overall low NDST1 expression levels across GBM patient samples, and patient-derived cell lines, and that low NDST1 levels correlate to poorer patient survival. Furthermore, altering the NDST1 expression had profound effects on GBM cell invasion, migration and stemness