TY - JOUR

T1 - Chemoradiotherapy increases intratumor heterogeneity of HPSE expression in the relapsed glioblastoma tumors

AU - Suhovskih, Anastasia V.

AU - Kazanskaya, Galina M.

AU - Volkov, Alexander M.

AU - Tsidulko, Alexandra Y.

AU - Aidagulova, Svetlana V.

AU - Grigorieva, Elvira V.

N1 - Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/2/14

Y1 - 2020/2/14

N2 - 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.

AB - 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.

KW - Adjuvant chemoradiotherapy

KW - Disease relapse

KW - Glioblastoma multiforme

KW - Heparan sulfate

KW - Heparanase expression

KW - Intratumor heterogeneity

KW - SURVIVAL

KW - glioblastoma multiforme

KW - intratumor heterogeneity

KW - GLYCOSAMINOGLYCANS

KW - GLIOMA

KW - heparan sulfate

KW - HEPARANASE EXPRESSION

KW - CLONING

KW - GROWTH

KW - SPALAX

KW - TARGETS

KW - adjuvant chemoradiotherapy

KW - heparanase expression

KW - UP-REGULATION

KW - disease relapse

UR - http://www.scopus.com/inward/record.url?scp=85079513783&partnerID=8YFLogxK

U2 - 10.3390/ijms21041301

DO - 10.3390/ijms21041301

M3 - Article

C2 - 32075104

AN - SCOPUS:85079513783

VL - 21

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 4

M1 - 1301

ER -