Heparan sulfate in the regulation of neural differentiation and glioma development

Abstract

Heparan sulfate proteoglycans (HSPGs) are the main components of the extracellular matrix, where they interact with a large number of physiologically important macromolecules. The sulfation pattern of heparan sulfate (HS) chains determines the interaction potential of the proteoglycans. Enzymes of the biosynthetic and degradation pathways for HS chains are thus important regulators in processes ranging from embryonic development to tissue homeostasis, but also for tumor development. Formation of the nervous system is also critically dependent on intact HSPGs, and several studies have outlined the role of HS in neural induction from embryonic stem cells. High-grade glioma is the most common malignant primary brain tumor among adults, and the outcome is poor. Neural stem cells and glioma stem cells have several common traits, such as sustained proliferation and a highly efficient migratory capacity in the brain. There are also similarities between the neurogenic niche where adult neural stem cells reside, and the tumorigenic niche. These include interactions with the extracellular matrix, and many of the matrix components are deregulated in glioma, e.g. HSPGs and enzymes implementing the biosynthesis and modification of HS. In this article, we will present how HS-regulated pathways are involved in neural differentiation, and discuss their impact on brain development. We will also review and critically discuss the important role of structural modifications of HS in glioma growth and invasion. We propose that targeting invasive mechanisms of glioma cells through modulation of HS structure and HS-mediated pathways may be an attractive alternative to other therapeutic attempts, which so far have only marginally increased survival for glioma patients.

Integrative Analysis of DNA Methylation and Gene Expression Identify a Three-Gene Signature for Predicting Prognosis in Lower-Grade Gliomas

“…In this study, we found that higher EMILIN3 expression was associated with worse OS and RFS in LGG patients and that promoter methylation in EMLIN3 was negatively correlated with gene expression. According to previous studies, the mechanism via which EMILIN3 affects glioma development may be explained by its interaction with heparin and heparin sulfate proteoglycans (HSPG) on the extracellular matrix [38-40]. Further studies are needed to explore the exact mechanisms of EMILIN3 in the tumor microenvironment and its pro-tumorigenic function in gliomas.…”

Human sulfatase 1 exerts anti-tumor activity by inhibiting the AKT/ CDK4 signaling pathway in melanoma

“…The biological function of hSulf-1 is to desulfate cell surface HSPG via the hydrolysis of 6-O-bond glucosamine sulfate in the highly sulfated sugar chains of HSPG [12]. Sulfation of HSPG is critical for interactions between extracellular growth factors and their receptor tyrosine kinases [13, 14]. Accordingly, desulfation of HSPG caused by hSulf-1 is capable of inhibiting the signaling pathways of various growth factors, including those of epidermal growth factor (EGF), fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF).…”

Heparan sulfate disaccharide measurement from biological samples using pre-column derivatization, UPLC-MS and single ion monitoring

“…Many studies have demonstrated regulatory effects of glycosaminoglycans on cell function including proliferation, differentiation and invasion [3,37,38]. In addition, several studies have examined the effects of specific HS and CS disaccharides on cell function.…”