TY - JOUR

T1 - Heparan sulfate accumulation and perlecan/HSPG2 up-regulation in tumour tissue predict low relapse-free survival for patients with glioblastoma

AU - Kazanskaya, Galina M.

AU - Tsidulko, Alexandra Y.

AU - Volkov, Alexander M.

AU - Kiselev, Roman S.

AU - Suhovskih, Anastasia V.

AU - Kobozev, Vyacheslav V.

AU - Gaytan, Alexei S.

AU - Aidagulova, Svetlana V.

AU - Krivoshapkin, Alexei L.

AU - Grigorieva, Elvira V.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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.

AB - 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.

KW - Glioblastoma

KW - Glypican-1

KW - Heparan sulfate

KW - Perlecan/HSPG2

KW - Proteoglycan

KW - Syndecan-1

KW - NERVOUS-SYSTEM

KW - LOCALIZATION

KW - PROTEOGLYCANS

KW - GLYCOSAMINOGLYCANS

KW - ANGIOGENESIS

KW - GLIOMA-CELL INVASION

KW - BRAIN-DEVELOPMENT

KW - IN-VITRO

KW - EXTRACELLULAR-MATRIX

KW - EXPRESSION

UR - http://www.scopus.com/inward/record.url?scp=85040327766&partnerID=8YFLogxK

U2 - 10.1007/s00418-018-1631-7

DO - 10.1007/s00418-018-1631-7

M3 - Article

C2 - 29322326

AN - SCOPUS:85040327766

VL - 149

SP - 235

EP - 244

JO - Histochemistry and Cell Biology

JF - Histochemistry and Cell Biology

SN - 0948-6143

IS - 3

ER -