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. 2012 May;3(5):568-575.
doi: 10.18632/oncotarget.526.

Novel therapeutic targets in the brain tumor microenvironment

Joanna J Phillips  1   2
Affiliations

Novel therapeutic targets in the brain tumor microenvironment

Joanna J Phillips. Oncotarget. 2012 May.

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.

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Figures

Figure 1
Figure 1. Heparan sulfate proteoglycan (HSPG) glycosaminoglycan side chains bind and sequester ligands in the extracellular environment
(A) Dependent on the HSPG core protein, HSPGs are found at the cell surface, in the extracellular matrix, or in secretory vesicles. HSPG function is critical for normal growth and development and includes regulation of ligand-mediated signaling, cell adhesion, and formation of the extracellular matrix for cell migration. (B) Model for SULF2 regulated RTK signaling in glioblastoma. SULF2 acts on HSPGs, present in the tumor microenvironment, to decrease 6O-sulfation, release sequestered ligands such as PDGF and increase activation of the RTK PDGFR-alpha and downstream signaling pathways in tumor cells. RTK, receptor tyrosine kinase.
Figure 2
Figure 2. Altered HSPG-related gene expression in human GBM
The mean expression of a number of HSPG-related genes, including HSPG core proteins (GPCs, SDCs, AGRN, SRGN, and HSPG2) and modifying enzymes (HPSE and SULFs) are altered in GBM relative to normal controls. Bars represent the mean ratio of log2(Tumor/Normal) +/− SEM gene expression. Upregulated (red) and down regulated, log2 (Tumor/Normal) greater than or equal to 0.5 or less than or equal to -0.5, respectively. TCGA Data Portal [71]; http://cancergenome.nih.gov. (n=170 human tumors). GPC, glypican; SDC, syndecan; SULF, extracellular sulfatase; AGRN, agrin; SRGN, serglycin; HSPG2, perlecan; HSPE, heparanase.
Figure 3
Figure 3. Expression of SULF2 protein in human GBM
Representative images of immunohistochemical staining for SULF2 in adult (A) and pediatric (B) GBM. Immunohistochemistry was performed as described previously [40]. Magnification 400x.
Figure 4
Figure 4. Subtype-specific alterations in the expression of HSPGs and HSPG modifying enzymes in GBM
The mean expression of HSPG-related genes are compared between the Mesenchymal (Mes) and Proneural (Pro) subtype of adult GBM. Bars represent the mean ratio of log2(Tumor/Normal) +/− SEM gene expression in each subgroup and a two-sided t-test was used to compare expression between the two groups. p<0.05, Mes n=56 and Pro n=53. Expression data from TCGA Data Portal [71]; http://cancergenome.nih.gov.
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