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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We thank Y. H. Sun, S. Keir, D. Satterfield, L. Ehinger and J. Faison for technical assistance; M. Cook and T. R. Dissanayake for assistance with flow cytometry; Z. Lu for assistance with fluorescent microscopy; and X.-F. Wang, H. Lin, T.P. Yao, H. Friedman and R. Wechsler-Reya for discussions. Financial support was provided by the Childhood Brain Tumor Foundation, the Pediatric Brain Tumor Foundation of the United States, Accelerate Brain Cancer Cure, a grant from the Duke Comprehensive Cancer Center Kislak–Fields Family Fund (to J.N.R.), and grants from the NIH (to J.N.R. and to D.D.B.). J.N.R. is a Damon Runyon-Lilly Clinical Investigator supported by the Damon Runyon Cancer Research Foundation and a Sidney Kimmel Foundation for Cancer Research Scholar. A.B.H. is a Paul Brazen/American Brain Tumor Association Fellow. Author Contributions Q.W., S.B., Y.H. and Q.S. did the experimental work. R.E.M. performed pathological analysis and assisted in human tumour specimen acquisition. S.B. and J.N.R. wrote the paper and designed the experiments. A.B.H., M.W.D. and D.D.B. provided intellectual input and helped with experimental design.
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Journal of Experimental & Clinical Cancer Research (2018)