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Glioma stem cells promote
radioresistance by preferential activation of the DNA damage response
Shideng Bao1,2,
Qiulian Wu1,2, Roger E. McLendon2,3,
Yueling Hao1,2, Qing Shi1,2,
Anita B. Hjelmeland1,2, Mark
W. Dewhirst4, Darell D. Bigner2,3
and Jeremy N. Rich1,2,5,6
1Department
of Surgery, 2Preston Robert Tisch Brain
Tumor Center, 3Department of Pathology,
4Department of Radiation Oncology, 5Department
of Medicine, and, 6Department of
Neurobiology, Duke University Medical Center, Durham, North Carolina
27710, USA -- Correspondence to: Jeremy N. Rich1,2,5,6
Correspondence and requests for materials should be addressed to J.N.R.
(Email: rich0001@mc.duke.edu). -- Received 1 June 2006; Accepted
7 September 2006; Published online 18 October 2006.
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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.
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