Malignant glioma continues to be fatal, despite improved insight into its underlying molecular mechanisms. The most malignant form, glioblastoma (GBM), is characterized by aberrant activation of receptor tyrosine kinases (RTK) and infiltrative growth. Heparan sulfate proteoglycans (HSPGs), integral components of the extracellular matrix of brain tumors (HPSE), which cleaves HSPGs, for its role in glioma. This hypothesis was evaluated using tissue microarrays, GBM cells derived from patients, murine in vitro and in vivo can regulate activation of many RTK pathways. This prompted us to investigate heparanase models of glioma, and public databases. Down-regulation of HPSE attenuated glioma cell proliferation, while addition of HPSE stimulated growth, and activated ERK and AKT signaling. Using HPSE transgenic and knockout mice it was demonstrated that tumor development in vivo was positively correlated to HPSE levels in the brain. HPSE also modified the tumor microenvironment, influencing reactive astrocytes, microglia/monocytes and tumor angiogenesis. Furthermore, inhibition of HPSE reduces tumor cell numbers, both in vitro and in vivo. HPSE was highly expressed in human glioma and GBM cell lines, compared to normal brain tissue. Indeed, a correlation was observed between high levels of HPSE and shorter survival of patients with high-grade glioma. In conclusion, these data provide proof-of-concept for anti-HPSE treatment of malignant glioma, as well as novel insights for the development of HPSE as a therapeutic target.
IMPLICATIONS: This study aims to target both the malignant brain tumor cells per se, and their microenvironment by changing the level of an enzyme, heparanase, that breaks down modified sugar chains on cell surfaces and in the extracellular space.