title: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response.
abstract: Ionizing radiation represents the most effective therapy for glioblastoma (World Health Organization grade IV glioma), one of the most lethal human malignancies, but radiotherapy remains only palliative because of radioresistance. The mechanisms underlying tumour radioresistance have remained elusive. Here we show that cancer stem cells contribute to glioma radioresistance through preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity. The fraction of tumour cells expressing CD133 (Prominin-1), a marker for both neural stem cells and brain cancer stem cells, is enriched after radiation in gliomas. In both cell culture and the brains of immunocompromised mice, CD133-expressing glioma cells survive ionizing radiation in increased proportions relative to most tumour cells, which lack CD133. CD133-expressing tumour cells isolated from both human glioma xenografts and primary patient glioblastoma specimens preferentially activate the DNA damage checkpoint in response to radiation, and repair radiation-induced DNA damage more effectively than CD133-negative tumour cells. In addition, the radioresistance of CD133-positive glioma stem cells can be reversed with a specific inhibitor of the Chk1 and Chk2 checkpoint kinases. Our results suggest that CD133-positive tumour cells represent the cellular population that confers glioma radioresistance and could be the source of tumour recurrence after radiation. Targeting DNA damage checkpoint response in cancer stem cells may overcome this radioresistance and provide a therapeutic model for malignant brain cancers.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Shideng
authors.initials: S
authors.lastname: Bao
authors.forename: Qiulian
authors.initials: Q
authors.lastname: Wu
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: Yueling
authors.initials: Y
authors.lastname: Hao
authors.forename: Qing
authors.initials: Q
authors.lastname: Shi
authors.forename: Anita B
authors.initials: AB
authors.lastname: Hjelmeland
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects*; D010455:Peptides / Q000378:metabolism; D011836:Radiation Tolerance; D033581:Stem Cell Transplantation; D014183:Transplantation, Heterologous
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse