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Chemotherapy-Induced Degradation of Glycosylated Components of the Brain Extracellular Matrix Promotes Glioblastoma Relapse Development in an Animal Model
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-t...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327169/ https://www.ncbi.nlm.nih.gov/pubmed/34350124 http://dx.doi.org/10.3389/fonc.2021.713139 |
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author | Tsidulko, Alexandra Y. Shevelev, Oleg B. Khotskina, Anna S. Kolpakova, Mariia A. Suhovskih, Anastasia V. Kazanskaya, Galina M. Volkov, Alexander M. Aidagulova, Svetlana V. Zavyalov, Evgenii L. Grigorieva, Elvira V. |
author_facet | Tsidulko, Alexandra Y. Shevelev, Oleg B. Khotskina, Anna S. Kolpakova, Mariia A. Suhovskih, Anastasia V. Kazanskaya, Galina M. Volkov, Alexander M. Aidagulova, Svetlana V. Zavyalov, Evgenii L. Grigorieva, Elvira V. |
author_sort | Tsidulko, Alexandra Y. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8327169 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-83271692021-08-03 Chemotherapy-Induced Degradation of Glycosylated Components of the Brain Extracellular Matrix Promotes Glioblastoma Relapse Development in an Animal Model Tsidulko, Alexandra Y. Shevelev, Oleg B. Khotskina, Anna S. Kolpakova, Mariia A. Suhovskih, Anastasia V. Kazanskaya, Galina M. Volkov, Alexander M. Aidagulova, Svetlana V. Zavyalov, Evgenii L. Grigorieva, Elvira V. Front Oncol Oncology 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. Frontiers Media S.A. 2021-07-19 /pmc/articles/PMC8327169/ /pubmed/34350124 http://dx.doi.org/10.3389/fonc.2021.713139 Text en Copyright © 2021 Tsidulko, Shevelev, Khotskina, Kolpakova, Suhovskih, Kazanskaya, Volkov, Aidagulova, Zavyalov and Grigorieva https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Tsidulko, Alexandra Y. Shevelev, Oleg B. Khotskina, Anna S. Kolpakova, Mariia A. Suhovskih, Anastasia V. Kazanskaya, Galina M. Volkov, Alexander M. Aidagulova, Svetlana V. Zavyalov, Evgenii L. Grigorieva, Elvira V. Chemotherapy-Induced Degradation of Glycosylated Components of the Brain Extracellular Matrix Promotes Glioblastoma Relapse Development in an Animal Model |
title | Chemotherapy-Induced Degradation of Glycosylated Components of the Brain Extracellular Matrix Promotes Glioblastoma Relapse Development in an Animal Model |
title_full | Chemotherapy-Induced Degradation of Glycosylated Components of the Brain Extracellular Matrix Promotes Glioblastoma Relapse Development in an Animal Model |
title_fullStr | Chemotherapy-Induced Degradation of Glycosylated Components of the Brain Extracellular Matrix Promotes Glioblastoma Relapse Development in an Animal Model |
title_full_unstemmed | Chemotherapy-Induced Degradation of Glycosylated Components of the Brain Extracellular Matrix Promotes Glioblastoma Relapse Development in an Animal Model |
title_short | Chemotherapy-Induced Degradation of Glycosylated Components of the Brain Extracellular Matrix Promotes Glioblastoma Relapse Development in an Animal Model |
title_sort | chemotherapy-induced degradation of glycosylated components of the brain extracellular matrix promotes glioblastoma relapse development in an animal model |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327169/ https://www.ncbi.nlm.nih.gov/pubmed/34350124 http://dx.doi.org/10.3389/fonc.2021.713139 |
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