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Open AccessArticle

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

1
Institute of Molecular Biology and Biophysics FRC FTM, 2/12, Timakova str., 630117 Novosibirsk, Russia
2
Novosibirsk State University, 1, Pirogova str., 630090 Novosibirsk, Russia
3
Meshalkin National Medical Research Centre, 15, Rechkunovskaya str., 630055 Novosibirsk, Russia
4
Novosibirsk State Medical University, 52, Krasny Prospect, 630091 Novosibirsk, Russia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(4), 1301; https://doi.org/10.3390/ijms21041301
Received: 31 December 2019 / Revised: 7 February 2020 / Accepted: 12 February 2020 / Published: 14 February 2020
(This article belongs to the Special Issue Molecular Biology of Brain Tumors)
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. View Full-Text
Keywords: glioblastoma multiforme; adjuvant chemoradiotherapy; disease relapse; heparan sulfate; heparanase expression; intratumor heterogeneity glioblastoma multiforme; adjuvant chemoradiotherapy; disease relapse; heparan sulfate; heparanase expression; intratumor heterogeneity
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Suhovskih, A.V.; Kazanskaya, G.M.; Volkov, A.M.; Tsidulko, A.Y.; Aidagulova, S.V.; Grigorieva, E.V. Chemoradiotherapy Increases Intratumor Heterogeneity of HPSE Expression in the Relapsed Glioblastoma Tumors. Int. J. Mol. Sci. 2020, 21, 1301.

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