Abstract
Temozolomide (TMZ) is a conventional chemotherapy drug for adjuvant treatment of glioblastoma multiforme (GBM), often accompanied by dexamethasone (DXM) to prevent brain oedema and alleviate clinical side effects. Here, we aimed to investigate an ability of the drugs to affect normal brain tissue in terms of proteoglycan (PG) composition/content in experimental rat model in vivo. Age- and brain zone-specific transcriptional patterns of PGs were demonstrated for 8, 60, and 120 days old rats, and syndecan-1, glypican-1, decorin, biglycan, and lumican were identified as the most expressed PGs. DXM treatment affected both PG core proteins expression (mainly syndecan-1, glypican-1, decorin, biglycan, lumican, versican, brevican, and NG2) and heparan sulphate (HS)/chondroitin sulphate (CS) content in organotypic brain slice culture ex vivo and experimental animals in vivo in a dose-dependent manner. TMZ treatment did not result in the significant changes in PG core proteins expression both in normal rat brain hippocampus and cortex in vivo (although generics did), but demonstrated significant effects onto polysaccharide HS/CS content in the brain tissue. The effects were age- and brain zone-specific and similar with the age-related PGs expression changes in rat brain. Combination of TMZ with DXM resulted in the most profound deterioration in PGs composition and content in the brain tissue both at core protein and glycosaminoglycan levels. Taken together, the obtained results demonstrate that conventional anti-glioblastoma therapy affects proteoglycan structure and composition in normal brain tissue, potentially resulting in deterioration of brain extracellular matrix and formation of the favourable tumorigenic niche for the expansion of the residual glioma cells. During the TMZ chemotherapy, dose and regimen of DXM treatment matter, and repetitive low DXM doses seem to be more sparing treatment compared with high DXM dose(s), which should be avoided where possible, especially in combination with TMZ.
Highlights
Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumour (Thakkar et al, 2014; Nørøxe et al, 2017)
Low and high doses of DXM resulted in different changes in the expression of individual PGs compared with the control organotypic culture-low dose (0.01–0.5 μM) treatments increased expression levels of glypican-1 and versican core proteins (5-fold and 10fold, respectively), whereas high dose (50–200 μM) treatments suppressed syndecan-1 and biglycan expression (5-fold and 3-fold, respectively)
The results demonstrate a complex attenuation of PGs expression in normal rat brain by different DXM concentrations in the experimental model ex vivo and warrant further investigation of the effects in vivo
Summary
Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumour (Thakkar et al, 2014; Nørøxe et al, 2017). After the surgical resection of the tumour node, the main purpose of all consequent treatment strategies is to eliminate the remaining glioblastoma cells and prevent the disease relapse being a main cause of the patient’s deaths. The most dangerous trait of glioblastoma is its’ active invasion into the surrounding healthy brain tissue (Paw et al, 2015; Diksin et al, 2017), and the invasiveness of GBM cells and tumour development depend on migration capabilities of the proliferating glioblastoma cells and structure of the surrounding normal brain tissue (Song and Dityatev, 2017; Manini et al, 2018). ECM is a physical non-specific barrier but is actively involved in cell–cell and cell–matrix interactions and signalling through the numerous ligands like chemokines, growth factors, and adhesion molecules (Miyata and Kitagawa, 2017). Brain ECM composes mainly of glycosylated molecules such as proteoglycans (PGs) and glycosaminoglycans (GAGs), predominantly chondroitin sulphate PGs (CSPGs) (Silver et al, 2013; Dyck and KarimiAbdolrezaee, 2015), hyaluronic acid (HA) (Park et al, 2008; Miyata and Kitagawa, 2017), and heparan sulphate PGs (HSPGs) (Yu et al, 2017)
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