Heparan Sulfate Glycosaminoglycans in Glioblastoma Promote Tumor Invasion

Abstract

Glioblastoma (GBM) is the most common primary malignant brain tumor of adults and confers a poor prognosis due, in part, to diffuse invasion of tumor cells. Heparan sulfate (HS) glycosaminoglycans, present on the cell surface and in the extracellular matrix, regulate cell signaling pathways and cell-microenvironment interactions. In GBM, the expression of HS glycosaminoglycans and the enzymes that regulate their function are altered but the actual HS content and structure are unknown. However, inhibition of HS glycosaminoglycan function is emerging as a promising therapeutic strategy for some cancers. In this study, we use liquid chromatography-mass spectrometry (LC/MS) analysis to demonstrate differences in HS disaccharide content and structure across four patient-derived tumorsphere lines (GBM1, 5, 6, 43) and between two murine tumorsphere lines derived from murine GBM with enrichment of mesenchymal and proneural gene expression (mMES and mPN, respectively) markers. In GBM, the heterogeneous HS content and structure across patient-derived tumorsphere lines suggested diverse functions in the GBM tumor microenvironment (TME). In GBM5 and mPN, elevated expression of sulfatase 2 (SULF2), an extracellular enzyme that alters ligand binding to HS, was associated with low trisulfated HS disaccharides, a substrate of SULF2. In contrast, other primary tumorsphere lines had elevated expression of the HS-modifying enzyme heparanase (HPSE). Using gene editing strategies to inhibit HPSE a role for HPSE in promoting tumor cell adhesion and invasion was identified. These studies characterize the heterogeneity in HS glycosaminoglycan content and structure across GBM and reveal their role in tumor cell invasion.

RETRACTED ARTICLE: MicroRNA-422a functions as a tumor suppressor in non-small cell lung cancer through SULF2-mediated TGF-β/SMAD signaling pathway

“…Moreover, our researchers observed the involvement of SULF2 in the regulation of tumor-related biological processes including angiogenesis and Wnt signaling pathways. Some researchers also reported that SULF2 was involved in various nuclear events in the cell cycle [17] as well as in the regulation of cancer development [18][19][20]. Conjointly, the above analysis suggested that miR-422a was of great potential to function as a regulator in NSCLC via regulation of SULF2.…”

Heparan Sulfate Biosynthetic System Is Inhibited in Human Glioma Due to EXT1/2 and HS6ST1/2 Down-Regulation

“…In the nervous system, HS interacts with a variety of physiologically important macromolecules, and plays a significant role in brain development and normal functioning, while undergoing changes during malignant transformation [ 12 , 13 , 14 ]. Different glioblastoma primary cell cultures have been shown to possess a high heterogeneity of the HS structure and composition, which has been associated with the adhesive properties and invasive activity of these cells [ 15 ]. However, molecular mechanisms of deregulation of HS in gliomas remain poorly understood, and appear to be determined by the balance of the processes of biosynthesis of HS and its extracellular degradation [ 16 ].…”

“…In a model of experimental animals, the correlation of SULF2 expression with PDGFRα phosphorylation and decreased MAPK signaling has been shown, whereas the knockout of Sulf2 (−/−) resulted in an inhibition of tumour growth in experimental animals in vivo [ 23 ]. Increased expression of sulfatase in the neurospheres of primary cultures of human and mouse gliomas was associated with a low content of trisulfated disaccharides of HS in the system in vitro [ 15 ], while increased expression of SULF1 and SULF2 in brain cancer was associated with progression and prognosis of the disease in vivo [ 24 ]. At the same time, expression of SULF1 and SULF2 demonstrates subtype-specific differences, and can be both significantly reduced in classical GBM and significantly elevated in proneural GBM, suggesting different functions in GBM subgroups [ 22 ].…”

Chemoradiotherapy Increases Intratumor Heterogeneity of HPSE Expression in the Relapsed Glioblastoma Tumors

“…The interrelation of HPSE expression with the presence of its substrate HS was not studied yet, although some data on HS presence in gliomas are available. It was shown that glioblastoma Grade IV possesses higher HS than astrocytoma Grade II [31]; HS content is present in patient-derived glioma tumor sphere cell lines and within the same tumor in a highly heterogeneous manner [32]. Increased HS content is demonstrated in GBM tumors and associated with low relapse-free survival of the GBM patients [4].…”