@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 = "Funding Information: 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 Vetenskapsr{\aa}det (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 ). Funding Information: 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 Vetenskapsr{\aa}det (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). 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 = "Academic Press Inc.",
number = "1",
}
