Glioma stem cells promote radioresistance by preferential activation of the DNA damage response

Shideng Bao, Qiulian Wu, Roger E. McLendon, Yueling Hao, Qing Shi, Anita B. Hjelmeland, Mark W. Dewhirst, Darell D. Bigner and Jeremy N. Rich ()
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Shideng Bao: Department of Surgery
Qiulian Wu: Department of Surgery
Roger E. McLendon: Preston Robert Tisch Brain Tumor Center
Yueling Hao: Department of Surgery
Qing Shi: Department of Surgery
Anita B. Hjelmeland: Department of Surgery
Mark W. Dewhirst: Department of Radiation Oncology
Darell D. Bigner: Preston Robert Tisch Brain Tumor Center
Jeremy N. Rich: Department of Surgery

Nature, 2006, vol. 444, issue 7120, 756-760

Abstract: Abstract Ionizing radiation represents the most effective therapy for glioblastoma (World Health Organization grade IV glioma), one of the most lethal human malignancies1, but radiotherapy remains only palliative2 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 cells3,4,5,6, 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.

Date: 2006
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DOI: 10.1038/nature05236

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