TY - JOUR
T1 - Immunohistochemical Detection of Neural Stem Cells and Glioblastoma Stem Cells in the Subventricular Zone of Glioblastoma Patients
AU - Hira, Vashendriya V. V.
AU - Molenaar, Remco J.
AU - Breznik, Barbara
AU - Lah, Tamara
AU - Aronica, Eleonora
AU - van Noorden, Cornelis J. F.
N1 - Funding Information: The authors thank Jasper Anink and Theo Dirksen from the Department of (Neuro)Pathology of the Amsterdam UMC at the location Academic Medical Center in The Netherlands for their technical assistance. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was financially supported by the Dutch Cancer Society (KWF; UVA 2014-6839 and UVA 2016.1-10460; V.V.V.H., R.J.M., C.J.F.V.N.), the Slovenian Research Agency (Project J3-2526; CJFVN, BB, TL), the European Program of Cross-Border Cooperation for Slovenia-Italy Interreg TRANS-GLIOMA (Program 2017; T.L.), the IVY Interreg Fellowship (V.V.V.H.), and the Slovenian Research Agency (Program P10245; T.L., and Postdoctoral project Z3-1870 to B.B.), and R.J.M. was supported by the Fondation pour la Recherche Nuovo-Soldati 2019. Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was financially supported by the Dutch Cancer Society (KWF; UVA 2014-6839 and UVA 2016.1-10460; V.V.V.H., R.J.M., C.J.F.V.N.), the Slovenian Research Agency (Project J3-2526; CJFVN, BB, TL), the European Program of Cross-Border Cooperation for Slovenia-Italy Interreg TRANS-GLIOMA (Program 2017; T.L.), the IVY Interreg Fellowship (V.V.V.H.), and the Slovenian Research Agency (Program P10245; T.L., and Postdoctoral project Z3-1870 to B.B.), and R.J.M. was supported by the Fondation pour la Recherche Nuovo-Soldati 2019. Publisher Copyright: © The Author(s) 2021. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/5
Y1 - 2021/5
N2 - Glioblastoma usually recurs after therapy consisting of surgery, radiotherapy, and chemotherapy. Recurrence is at least partly caused by glioblastoma stem cells (GSCs) that are maintained in intratumoral hypoxic peri-arteriolar microenvironments, or niches, in a slowly dividing state that renders GSCs resistant to radiotherapy and chemotherapy. Because the subventricular zone (SVZ) is a major niche for neural stem cells (NSCs) in the brain, we investigated whether GSCs are present in the SVZ at distance from the glioblastoma tumor. We characterized the SVZ of brains of seven glioblastoma patients using fluorescence immunohistochemistry and image analysis. NSCs were identified by CD133 and SOX2 but not CD9 expression, whereas GSCs were positive for all three biomarkers. NSCs were present in all seven samples and GSCs in six out of seven samples. The SVZ in all samples were hypoxic and expressed the same relevant chemokines and their receptors as GSC niches in glioblastoma tumors: stromal-derived factor-1α (SDF-1α), C-X-C receptor type 4 (CXCR4), osteopontin, and CD44. In conclusion, in glioblastoma patients, GSCs are present at distance from the glioblastoma tumor in the SVZ. These findings suggest that GSCs in the SVZ niche are protected against radiotherapy and chemotherapy and protected against surgical resection due to their distant localization and thus may contribute to tumor recurrence after therapy.
AB - Glioblastoma usually recurs after therapy consisting of surgery, radiotherapy, and chemotherapy. Recurrence is at least partly caused by glioblastoma stem cells (GSCs) that are maintained in intratumoral hypoxic peri-arteriolar microenvironments, or niches, in a slowly dividing state that renders GSCs resistant to radiotherapy and chemotherapy. Because the subventricular zone (SVZ) is a major niche for neural stem cells (NSCs) in the brain, we investigated whether GSCs are present in the SVZ at distance from the glioblastoma tumor. We characterized the SVZ of brains of seven glioblastoma patients using fluorescence immunohistochemistry and image analysis. NSCs were identified by CD133 and SOX2 but not CD9 expression, whereas GSCs were positive for all three biomarkers. NSCs were present in all seven samples and GSCs in six out of seven samples. The SVZ in all samples were hypoxic and expressed the same relevant chemokines and their receptors as GSC niches in glioblastoma tumors: stromal-derived factor-1α (SDF-1α), C-X-C receptor type 4 (CXCR4), osteopontin, and CD44. In conclusion, in glioblastoma patients, GSCs are present at distance from the glioblastoma tumor in the SVZ. These findings suggest that GSCs in the SVZ niche are protected against radiotherapy and chemotherapy and protected against surgical resection due to their distant localization and thus may contribute to tumor recurrence after therapy.
KW - glioblastoma
KW - glioblastoma stem cell
KW - neural stem cell
KW - niche
KW - subventricular zone
KW - therapy-resistance
UR - http://www.scopus.com/inward/record.url?scp=85101074538&partnerID=8YFLogxK
U2 - https://doi.org/10.1369/0022155421994679
DO - https://doi.org/10.1369/0022155421994679
M3 - Article
C2 - 33596115
SN - 0022-1554
VL - 69
SP - 349
EP - 364
JO - Journal of Histochemistry and Cytochemistry
JF - Journal of Histochemistry and Cytochemistry
IS - 5
ER -