Heparan sulfate accumulation and perlecan/HSPG2 up-regulation in tumour tissue predict low relapse-free survival for patients with glioblastoma

Abstract

Glycosaminoglycans are major components of brain extracellular matrix (ECM), although heparan sulfate (HS) contribution in brain physiology and carcinogenesis remains underinvestigated. This study examined HS content and distribution in glioblastoma multiforme (GBM) tissues in the context of potential molecular mechanisms underlying its deregulation in brain tumours. Totally, 42 tissue samples and paraffin-embedded tissues for 31 patients with different prognosis were investigated. HS expression was demonstrated in 50-55% of the GBM tumours by immunohistochemistry (IHC), while almost no HS content was detected in the surrounding paratumourous brain tissues. Heterogeneous HS distribution in the HS-positive tumours was more related to the necrosis or glandular-like brain zones rather than glioma cells with high or low Ki-67 index. According the Kaplan-Meier curves, HS accumulation in glioma cells was associated with low relapse-free survival (RS) of the GBM patients (p < 0.05) and was likely to be due to the increased transcriptional activity of HSPG core proteins (syndecan-1, 2-3 fold; glypican-1, 2,5 fold; perlecan/HSPG2, 13-14 fold). Activation of perlecan/HSPG2 expression correlated with the patients' survival according Kaplan-Meier (p = 0.0243) and Cox proportional-hazards regression (HR = 3.1; P(Y) = 0.03) analyses, while up-regulation of syndecan-1 and glypican-1 was not associated with the patients survival. Taken together, the results indicate that increase of HS content and up-regulation of perlecan/HSPG2 expression in glioblastoma tissues contribute to tumour development through the transformation of brain extracellular matrix into tumour microenvironment, and represent negative prognostic factors for glioblastoma progression.

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

“…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]. The obtained data on the decreased expression of HPSE in GBM tumors and the tendency of its negative correlation with HS content might suggest a possible molecular mechanism for HS upregulation in GBM tumors, along with other mechanisms involved in maintaining HS content in brain tissue.…”

“…These molecules are tightly involved in cell-cell and cell-matrix interactions as well as cell signaling, and their distortion by intensive chemoradiotherapy might be of importance for the residual GBM cells and their interaction with the surrounding brain tissue and relapse development. It was shown that HS is involved in glioma development, and its accumulation in GBM tumors is associated with low relapse-free survival for GBM patients [4].…”

“…Previously, we have shown that mRNA level of HPSE is significantly decreased in Grade II-IV gliomas [19] and distribution of its substrate HS is associated with low relapse-free survival of the glioma patients [4]. To study a possible effect of adjuvant anti-glioblastoma chemoradiotherapy on HPSE expression and its interrelation with HS content, we performed their comparative analysis in primary tumors and the relapsed tumors developed after the treatment.…”

Proteoglycans in normal physiology and carcinogenesis

“…В следу-ющих разделах мы приведем данные об участии ПГ в развитии тех типов опухолей, которые наиболее ин-тенсивно изучаются и в нашей лаборатории [61][62][63][64].…”

Overexpression of Annexin A2 Promotes Proliferation by Forming a Glypican 1 / c-Myc Positive Feedback Loop: Prognostic Significance in Human Glioma

“…Furthermore, the higher expression of GPC1 has been suggested to predict poor prognosis of glioblastoma through examining the expression of GPC1 in 53 patients [20]. However, in another study with 31 cases, analysis showed no association between GPC1 expression and any clinical parameters of glioblastoma patients, including OS and tumor grade [21]. Collectively, these results suggest that GPC1 alone might be inappropriate to act as a strong and stable prognostic indicator for glioma, although GPC1 was implicated in the proliferation of glioma cells.…”