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Chemotherapy-Induced Degradation of Glycosylated Components of the Brain Extracellular Matrix Promotes Glioblastoma Relapse Development in an Animal Model

Authors :
Alexandra Y. Tsidulko
Oleg B. Shevelev
Anna S. Khotskina
Mariia A. Kolpakova
Anastasia V. Suhovskih
Galina M. Kazanskaya
Alexander M. Volkov
Svetlana V. Aidagulova
Evgenii L. Zavyalov
Elvira V. Grigorieva
Source :
Frontiers in Oncology, Vol 11 (2021)
Publication Year :
2021
Publisher :
Frontiers Media S.A., 2021.

Abstract

Adjuvant chemotherapy with temozolomide (TMZ) is an intrinsic part of glioblastoma multiforme (GBM) therapy targeted to eliminate residual GBM cells. Despite the intensive treatment, a GBM relapse develops in the majority of cases resulting in poor outcome of the disease. Here, we investigated off-target negative effects of the systemic chemotherapy on glycosylated components of the brain extracellular matrix (ECM) and their functional significance. Using an elaborated GBM relapse animal model, we demonstrated that healthy brain tissue resists GBM cell proliferation and invasion, thereby restricting tumor development. TMZ-induced [especially in combination with dexamethasone (DXM)] changes in composition and content of brain ECM proteoglycans (PGs) resulted in the accelerated adhesion, proliferation, and invasion of GBM cells into brain organotypic slices ex vivo and more active growth and invasion of experimental xenograft GBM tumors in SCID mouse brain in vivo. These changes occurred both at core proteins and polysaccharide chain levels, and degradation of chondroitin sulfate (CS) was identified as a key event responsible for the observed functional effects. Collectively, our findings demonstrate that chemotherapy-induced changes in glycosylated components of brain ECM can impact the fate of residual GBM cells and GBM relapse development. ECM-targeted supportive therapy might be a useful strategy to mitigate the negative off-target effects of the adjuvant GBM treatment and increase the relapse-free survival of GBM patients.

Details

Language :
English
ISSN :
2234943X
Volume :
11
Database :
Directory of Open Access Journals
Journal :
Frontiers in Oncology
Publication Type :
Academic Journal
Accession number :
edsdoj.51ec4338a983464d874d2e3e6aa66255
Document Type :
article
Full Text :
https://doi.org/10.3389/fonc.2021.713139