Abstract
Adjuvant chemoradiotherapy is a standard treatment option for glioblastoma multiforme (GBM). Despite intensive care, recurrent tumors developed during the first year are fatal for the patients. Possibly contributing to this effect, among other causes, is that therapy induces changes of polysaccharide heparan sulfate (HS) chains in the cancer cells and/or tumor microenvironment. The aim of this study was to perform a comparative analysis of heparanase (HPSE) expression and HS content in different normal and GBM brain tissues. Immunohistochemical analysis revealed a significant decrease of HPSE protein content in the tumor (12-15-fold) and paratumorous (2.5-3-fold) GBM tissues compared with normal brain tissue, both in cellular and extracellular compartments. The relapsed GBM tumors demonstrated significantly higher intertumor and/or intratumor heterogeneity of HPSE and HS content and distribution compared with the matched primary ones (from the same patient) (n = 8), although overall expression levels did not show significant differences, suggesting local deterioration of HPSE expression with reference to the control system or by the treatment. Double immunofluorescence staining of various glioblastoma cell lines (U87, U343, LN18, LN71, T406) demonstrated a complex pattern of HPSE expression and HS content with a tendency towards a negative association of these parameters. Taken together, the results demonstrate the increase of intratumor heterogeneity of HPSE protein in relapsed GBM tumors and suggest misbalance of HPSE expression regulation by the adjuvant anti-GBM chemoradiotherapy.
Highlights
Conventional anti-glioblastoma multiforme (GBM) therapy includes maximal surgical resection, followed by a combination of radiotherapy (60 Gy) and chemotherapy with temozolomide (TMZ) [1,2]
Quantitative analysis of HPSE protein content in normal human brain tissue and primary and relapsed GBM tumors was performed based on IHC staining (Figure 1, Supplemental Figure S1)
We have demonstrated that HPSE expression is significantly decreased in paratumorous tissue compared with normal brain tissue, with a further decrease of this parameter in GBM tumors
Summary
Conventional anti-glioblastoma multiforme (GBM) therapy includes maximal surgical resection, followed by a combination of radiotherapy (60 Gy) and chemotherapy with temozolomide (TMZ) [1,2]. About 70% of GBM patients develop disease relapse within one year of diagnosis [3]. Study of mechanisms underlying the development of relapse is an important way to overcome the problem and increase efficiency of the anti-GBM treatment. Normal brain ECM mainly consists of hyaluronic acid and complex polysaccharide–protein molecules of proteoglycans (PGs) bearing polysaccharide chains of chondroitin sulfate and/or heparan sulfate (HS). 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]
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