Novel Therapeutic Targets in the Brain Tumor Microenvironment

Abstract

ABSTRACT:Glioblastoma (GBM), a highly malignant brain tumor of adults and children, diffusely invades within the non-neoplastic brain. Despite aggressive current therapeutic interventions, improved therapeutic strategies are greatly needed. Interactions between the tumor and constituents of its microenvironment are known to regulate malignancy, and heparan sulfate proteoglycans (HSPGs) are important as they bind diverse extracellular proteins, including growth factors and cell adhesion molecules, regulating the activity of several ligand-mediated signaling pathways. Recent work from our group described a mechanism by which GBM regulates PDGFR-alpha signaling via enzymatic alteration of heparan sulfate proteoglycans (HSPGs) in the extracellular microenvironment. Blocking tumor-induced alterations of HSPGs, which can be achieved by pharmacological strategies, would potentially inhibit multiple oncogenic signaling pathways in tumor cells and disrupt critical tumormicroenvironment interactions. Here we examine HSPGs and the enzymes that modify them in GBM. We compare their expression across tumor subtypes, their potential roles in oncogenesis, and their potential as novel therapeutic targets in GBM.

Syndecan-1 alters heparan sulfate composition and signaling pathways in malignant mesothelioma

“…HS biosynthesis and turnover are strictly regulated processes involving many enzymes interrelated to each other [49,50]. In the course of their synthesis in Golgi, HS chains are elongated by exostosins (EXT1-2).…”

Proteoglycans and their roles in brain cancer

“…Proteoglycans, including heparan sulfate and chondroitin sulfate proteoglycans (HSPG and CSPG, respectively), regulate the activity of many signalling pathways, as well as cell–microenvironment interactions. As a result of these diverse functions, proteoglycans and their modifying enzymes have been implicated in tumourigenesis in a number of cancers . In brain cancer, data from our laboratory and other studies suggest that proteoglycans regulate multiple oncogenic pathways in tumour cells and promote critical tumour–microenvironment interactions .…”

“…As noted above, the levels of 6O‐sulfation are critical for HSPG function, and altered SULF levels have been associated with a large number of human cancers, including brain, breast, nonsmall cell lung carcinoma, multiple myeloma, gastric, pancreatic cancer and hepatocellular carcinoma . In brain cancer, SULF2 has been directly implicated in driving tumourigenesis in murine and human malignant glioma .…”

“…Moreover, the SULFs, which act to decrease HS 6O‐sulfation levels in the extracellular environment, are up‐regulated in GBM (Fig. B) .…”

Novel insights into Notum and glypicans regulation in colorectal cancer

“…Conversely, the expression of this glypican is up-regulated in hepatocellular carcinomas, although Glypican-3 is not expressed in the liver, suggesting that in this case it behaves as an oncofoetal protein [50]. Recent studies have also showed a downmodulation of Glypican-3 and an up-regulation of Glypican-1 gene expression in glioblastoma [51]. The molecular and immunohistochemical analysis performed in our human CRC set revealed very similar results, indicating the significant association of GPC1 overexpression and GPC3 under-expression in tumor lesions with respect to the normal colon mucosa (Figure 6).…”