High density is a property of slow-cycling and treatment-resistant human glioblastoma cells

Hanna Sabelström; David A. Quigley; Trenten Fenster; Daniel J. Foster; Clara A.M. Fuchshuber; Supna Saxena; Edith Yuan; Nan Li; Francesca Paterno; Joanna J. Phillips; Charles David James; Börje Norling; Mitchel S. Berger; Anders I. Persson

doi:10.1016/j.yexcr.2019.03.003

High density is a property of slow-cycling and treatment-resistant human glioblastoma cells

Hanna Sabelström, David A. Quigley, Trenten Fenster, Daniel J. Foster, Clara A.M. Fuchshuber, Supna Saxena, Edith Yuan, Nan Li, Francesca Paterno, Joanna J. Phillips, Charles David James, Börje Norling, Mitchel S. Berger, Anders I. Persson^*

^*Corresponding author for this work

Neurological Surgery

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

Abstract

Slow-cycling and treatment-resistant cancer cells escape therapy, providing a rationale for regrowth and recurrence in patients. Much interest has focused on identifying the properties of slow-cycling tumor cells in glioblastoma (GBM), the most common and lethal primary brain tumor. Despite aggressive ionizing radiation (IR) and treatment with the alkylating agent temozolomide (TMZ), GBM patients invariably relapse and ultimately succumb to the disease. In patient biopsies, we demonstrated that GBM cells expressing the proliferation markers Ki67 and MCM2 displayed a larger cell volume compared to rare slow-cycling tumor cells. In optimized density gradients, we isolated a minor fraction of slow-cycling GBM cells in patient biopsies and tumorsphere cultures. Transcriptional profiling, self-renewal, and tumorigenicity assays reflected the slow-cycling state of high-density GBM cells (HDGCs) compared to the tumor bulk of low-density GBM cells (LDGCs). Slow-cycling HDGCs enriched for stem cell antigens proliferated a few days after isolation to generate LDGCs. Both in vitro and in vivo, we demonstrated that HDGCs show increased treatment-resistance to IR and TMZ treatment compared to LDGCs. In conclusion, density gradients represent a non-marker based approach to isolate slow-cycling and treatment-resistant GBM cells across GBM subgroups.

Original language	English (US)
Pages (from-to)	76-86
Number of pages	11
Journal	Experimental Cell Research
Volume	378
Issue number	1
DOIs	https://doi.org/10.1016/j.yexcr.2019.03.003
State	Published - May 1 2019

Funding

We thank patients for giving their consent and the staff at the UCSF Neurosurgery Tissue Core for providing human GBM biopsies from patients undergoing surgery. We also thank Eunice Wan for excellent assistance with microarray processing. A.I.P. acknowledges financial support from NIH / NINDS ( U54CA163155 , R21NS088114 ), American Brain Tumor Association Collaboration Grant supported by Humor to Fight the Tumor, the Loglio Collaborative , the TDC Foundation , and the Guggenhime Endowment Fund . H.S. was supported by fellowships from Vetenskapsrådet (the Swedish Research Council ), the European Molecular Biology Organization (EMBO), the Foundation BLANCEFLOR Boncompagni Ludovisi , and the ABTA Basic Research Fellowship in memory of Joel A. Gingras, Jr. J.J.P acknowledges support from NIH/NINDS ( 1R01 NS081117 ). We thank patients for giving their consent and the staff at the UCSF Neurosurgery Tissue Core for providing human GBM biopsies from patients undergoing surgery. We also thank Eunice Wan for excellent assistance with microarray processing. A.I.P. acknowledges financial support from NIH/NINDS (U54CA163155, R21NS088114), American Brain Tumor Association Collaboration Grant supported by Humor to Fight the Tumor, the Loglio Collaborative, the TDC Foundation, and the Guggenhime Endowment Fund. H.S. was supported by fellowships from Vetenskapsrådet (the Swedish Research Council), the European Molecular Biology Organization (EMBO), the Foundation BLANCEFLOR Boncompagni Ludovisi, and the ABTA Basic Research Fellowship in memory of Joel A. Gingras, Jr. J.J.P acknowledges support from NIH/NINDS (1R01 NS081117).

Keywords

Cancer
Glioblastoma
Glioma
Slow-cycling
Stem cell
Tumor

ASJC Scopus subject areas

Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.yexcr.2019.03.003

Cite this

Sabelström, H., Quigley, D. A., Fenster, T., Foster, D. J., Fuchshuber, C. A. M., Saxena, S., Yuan, E., Li, N., Paterno, F., Phillips, J. J., James, C. D., Norling, B., Berger, M. S., & Persson, A. I. (2019). High density is a property of slow-cycling and treatment-resistant human glioblastoma cells. Experimental Cell Research, 378(1), 76-86. https://doi.org/10.1016/j.yexcr.2019.03.003

@article{071745c1f17747c481d75a8aab399361,

title = "High density is a property of slow-cycling and treatment-resistant human glioblastoma cells",

abstract = "Slow-cycling and treatment-resistant cancer cells escape therapy, providing a rationale for regrowth and recurrence in patients. Much interest has focused on identifying the properties of slow-cycling tumor cells in glioblastoma (GBM), the most common and lethal primary brain tumor. Despite aggressive ionizing radiation (IR) and treatment with the alkylating agent temozolomide (TMZ), GBM patients invariably relapse and ultimately succumb to the disease. In patient biopsies, we demonstrated that GBM cells expressing the proliferation markers Ki67 and MCM2 displayed a larger cell volume compared to rare slow-cycling tumor cells. In optimized density gradients, we isolated a minor fraction of slow-cycling GBM cells in patient biopsies and tumorsphere cultures. Transcriptional profiling, self-renewal, and tumorigenicity assays reflected the slow-cycling state of high-density GBM cells (HDGCs) compared to the tumor bulk of low-density GBM cells (LDGCs). Slow-cycling HDGCs enriched for stem cell antigens proliferated a few days after isolation to generate LDGCs. Both in vitro and in vivo, we demonstrated that HDGCs show increased treatment-resistance to IR and TMZ treatment compared to LDGCs. In conclusion, density gradients represent a non-marker based approach to isolate slow-cycling and treatment-resistant GBM cells across GBM subgroups.",

keywords = "Cancer, Glioblastoma, Glioma, Slow-cycling, Stem cell, Tumor",

author = "Hanna Sabelstr{\"o}m and Quigley, {David A.} and Trenten Fenster and Foster, {Daniel J.} and Fuchshuber, {Clara A.M.} and Supna Saxena and Edith Yuan and Nan Li and Francesca Paterno and Phillips, {Joanna J.} and James, {Charles David} and B{\"o}rje Norling and Berger, {Mitchel S.} and Persson, {Anders I.}",

note = "Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = may,

day = "1",

doi = "10.1016/j.yexcr.2019.03.003",

language = "English (US)",

volume = "378",

pages = "76--86",

journal = "Experimental Cell Research",

issn = "0014-4827",

publisher = "Elsevier Inc.",

number = "1",

}

Sabelström, H, Quigley, DA, Fenster, T, Foster, DJ, Fuchshuber, CAM, Saxena, S, Yuan, E, Li, N, Paterno, F, Phillips, JJ, James, CD, Norling, B, Berger, MS & Persson, AI 2019, 'High density is a property of slow-cycling and treatment-resistant human glioblastoma cells', Experimental Cell Research, vol. 378, no. 1, pp. 76-86. https://doi.org/10.1016/j.yexcr.2019.03.003

TY - JOUR

T1 - High density is a property of slow-cycling and treatment-resistant human glioblastoma cells

AU - Sabelström, Hanna

AU - Quigley, David A.

AU - Fenster, Trenten

AU - Foster, Daniel J.

AU - Fuchshuber, Clara A.M.

AU - Saxena, Supna

AU - Yuan, Edith

AU - Li, Nan

AU - Paterno, Francesca

AU - Phillips, Joanna J.

AU - James, Charles David

AU - Norling, Börje

AU - Berger, Mitchel S.

AU - Persson, Anders I.

PY - 2019/5/1

Y1 - 2019/5/1

N2 - Slow-cycling and treatment-resistant cancer cells escape therapy, providing a rationale for regrowth and recurrence in patients. Much interest has focused on identifying the properties of slow-cycling tumor cells in glioblastoma (GBM), the most common and lethal primary brain tumor. Despite aggressive ionizing radiation (IR) and treatment with the alkylating agent temozolomide (TMZ), GBM patients invariably relapse and ultimately succumb to the disease. In patient biopsies, we demonstrated that GBM cells expressing the proliferation markers Ki67 and MCM2 displayed a larger cell volume compared to rare slow-cycling tumor cells. In optimized density gradients, we isolated a minor fraction of slow-cycling GBM cells in patient biopsies and tumorsphere cultures. Transcriptional profiling, self-renewal, and tumorigenicity assays reflected the slow-cycling state of high-density GBM cells (HDGCs) compared to the tumor bulk of low-density GBM cells (LDGCs). Slow-cycling HDGCs enriched for stem cell antigens proliferated a few days after isolation to generate LDGCs. Both in vitro and in vivo, we demonstrated that HDGCs show increased treatment-resistance to IR and TMZ treatment compared to LDGCs. In conclusion, density gradients represent a non-marker based approach to isolate slow-cycling and treatment-resistant GBM cells across GBM subgroups.

AB - Slow-cycling and treatment-resistant cancer cells escape therapy, providing a rationale for regrowth and recurrence in patients. Much interest has focused on identifying the properties of slow-cycling tumor cells in glioblastoma (GBM), the most common and lethal primary brain tumor. Despite aggressive ionizing radiation (IR) and treatment with the alkylating agent temozolomide (TMZ), GBM patients invariably relapse and ultimately succumb to the disease. In patient biopsies, we demonstrated that GBM cells expressing the proliferation markers Ki67 and MCM2 displayed a larger cell volume compared to rare slow-cycling tumor cells. In optimized density gradients, we isolated a minor fraction of slow-cycling GBM cells in patient biopsies and tumorsphere cultures. Transcriptional profiling, self-renewal, and tumorigenicity assays reflected the slow-cycling state of high-density GBM cells (HDGCs) compared to the tumor bulk of low-density GBM cells (LDGCs). Slow-cycling HDGCs enriched for stem cell antigens proliferated a few days after isolation to generate LDGCs. Both in vitro and in vivo, we demonstrated that HDGCs show increased treatment-resistance to IR and TMZ treatment compared to LDGCs. In conclusion, density gradients represent a non-marker based approach to isolate slow-cycling and treatment-resistant GBM cells across GBM subgroups.

KW - Cancer

KW - Glioblastoma

KW - Glioma

KW - Slow-cycling

KW - Stem cell

KW - Tumor

UR - http://www.scopus.com/inward/record.url?scp=85062645060&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062645060&partnerID=8YFLogxK

U2 - 10.1016/j.yexcr.2019.03.003

DO - 10.1016/j.yexcr.2019.03.003

M3 - Article

C2 - 30844389

AN - SCOPUS:85062645060

SN - 0014-4827

VL - 378

SP - 76

EP - 86

JO - Experimental Cell Research

JF - Experimental Cell Research

IS - 1

ER -

High density is a property of slow-cycling and treatment-resistant human glioblastoma cells

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this