TY - JOUR

T1 - Chemotherapy-Induced Degradation of Glycosylated Components of the Brain Extracellular Matrix Promotes Glioblastoma Relapse Development in an Animal Model

AU - Tsidulko, Alexandra Y.

AU - Shevelev, Oleg B.

AU - Khotskina, Anna S.

AU - Kolpakova, Mariia A.

AU - Suhovskih, Anastasia V.

AU - Kazanskaya, Galina M.

AU - Volkov, Alexander M.

AU - Aidagulova, Svetlana V.

AU - Zavyalov, Evgenii L.

AU - Grigorieva, Elvira V.

N1 - Funding Information: Authors thank Dr. Sergey Baiborodin for help with confocal microscopy and Mr. Anton Grigoriev for providing language help and proofreading the article; the Proteomic analysis Center and the Multi-Access Center Modern Optical Systems (Federal Research Center of Fundamental and Translational Medicine, Novosibirsk, Russia), Center for Genetic Resources of Laboratory Animals (RFMEFI62119X0023), and the Microscopy Center (Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia) for granting access to the equipment. Publisher Copyright: © Copyright © 2021 Tsidulko, Shevelev, Khotskina, Kolpakova, Suhovskih, Kazanskaya, Volkov, Aidagulova, Zavyalov and Grigorieva. Publisher Copyright: © Copyright © 2021 Tsidulko, Shevelev, Khotskina, Kolpakova, Suhovskih, Kazanskaya, Volkov, Aidagulova, Zavyalov and Grigorieva.

PY - 2021/7/19

Y1 - 2021/7/19

N2 - 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.

AB - 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.

KW - chemotherapy

KW - chondroitin sulfate

KW - dexamethasone

KW - extracellular matrix

KW - glioblastoma multiforme

KW - glycosaminoglycan

KW - proteoglycan

KW - temozolomide

UR - http://www.scopus.com/inward/record.url?scp=85111941666&partnerID=8YFLogxK

U2 - 10.3389/fonc.2021.713139

DO - 10.3389/fonc.2021.713139

M3 - Article

C2 - 34350124

AN - SCOPUS:85111941666

VL - 11

JO - Frontiers in Oncology

JF - Frontiers in Oncology

SN - 2234-943X

M1 - 713139

ER -