Letter | Published:

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

Nature volume 444, pages 756760 (07 December 2006) | Download Citation



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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    et al. Brain and other central nervous system cancers: recent trends in incidence and mortality. J. Natl Cancer Inst. 91, 1382–1390 (1999)

  2. 2.

    et al. Outcome and patterns of failure following limited-volume irradiation for malignant astrocytomas. Radiother. Oncol. 20, 99–110 (1991)

  3. 3.

    et al. Identification of human brain tumour initiating cells. Nature 432, 396–401 (2004)

  4. 4.

    et al. Cancerous stem cells can arise from pediatric brain tumours. Proc. Natl Acad. Sci. USA 100, 15178–15183 (2003)

  5. 5.

    et al. Identification of a cancer stem cell in human brain tumours. Cancer Res. 63, 5821–5828 (2003)

  6. 6.

    et al. Direct isolation of human central nervous system stem cells. Proc. Natl Acad. Sci. USA 97, 14720–14725 (2000)

  7. 7.

    et al. Isolation and characterization of tumourigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 64, 7011–7021 (2004)

  8. 8.

    , & A microtubule-associated protein antigen unique to mitotic spindle microtubules in PtK1 cells. J. Cell Biol. 96, 424–434 (1983)

  9. 9.

    et al. Human cortical glial tumours contain neural stem-like cells expressing astroglial and neuronal markers in vitro.. Glia 39, 193–206 (2002)

  10. 10.

    et al. Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427, 740–744 (2004)

  11. 11.

    & Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255, 1707–1710 (1992)

  12. 12.

    , , & Cell division tracking and expansion of hematopoietic long-term repopulating cells. Leukemia 13, 499–501 (1999)

  13. 13.

    et al. Flow cytometric quantification of apoptosis and proliferation in mixed lymphocyte culture. Cytometry A 51, 107–118 (2003)

  14. 14.

    Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev. 15, 2177–2196 (2001)

  15. 15.

    DNA structure dependent checkpoints as regulators of DNA repair. DNA Repair 1, 983–994 (2002)

  16. 16.

    & The DNA damage response: putting checkpoints in perspective. Nature 408, 433–439 (2000)

  17. 17.

    & Cell-cycle checkpoints and cancer. Nature 432, 316–323 (2004)

  18. 18.

    et al. Requirement of protein phosphatase 5 in DNA-damage-induced ATM activation. Genes Dev. 18, 249–254 (2004)

  19. 19.

    et al. ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses. Nature 411, 969–974 (2001)

  20. 20.

    , , & Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu. Rev. Biochem. 73, 39–85 (2004)

  21. 21.

    et al. Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing. Environ. Mol. Mutagen. 35, 206–221 (2000)

  22. 22.

    & Replication protein A and γ-H2AX foci assembly is triggered by cellular response to DNA double-strand breaks. Exp. Cell Res. 300, 320–334 (2004)

  23. 23.

    et al. Inhibition of the G2 DNA damage checkpoint and of protein kinases Chk1 and Chk2 by the marine sponge alkaloid debromohymenialdisine. J. Biol. Chem. 276, 17914–17919 (2001)

  24. 24.

    et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907–913 (2005)

  25. 25.

    et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864–870 (2005)

  26. 26.

    et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res. 66, 7843–7848 (2006)

  27. 27.

    et al. Isolation of neural stem cells from the postnatal cerebellum. Nature Neurosci. 8, 723–729 (2005)

Download references


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.

Author information


  1. Department of Surgery,

    • Shideng Bao
    • , Qiulian Wu
    • , Yueling Hao
    • , Qing Shi
    • , Anita B. Hjelmeland
    •  & Jeremy N. Rich
  2. Preston Robert Tisch Brain Tumor Center,

    • Shideng Bao
    • , Qiulian Wu
    • , Roger E. McLendon
    • , Yueling Hao
    • , Qing Shi
    • , Anita B. Hjelmeland
    • , Darell D. Bigner
    •  & Jeremy N. Rich
  3. Department of Pathology,

    • Roger E. McLendon
    •  & Darell D. Bigner
  4. Department of Radiation Oncology,

    • Mark W. Dewhirst
  5. Department of Medicine, and,

    • Jeremy N. Rich
  6. Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA

    • Jeremy N. Rich


  1. Search for Shideng Bao in:

  2. Search for Qiulian Wu in:

  3. Search for Roger E. McLendon in:

  4. Search for Yueling Hao in:

  5. Search for Qing Shi in:

  6. Search for Anita B. Hjelmeland in:

  7. Search for Mark W. Dewhirst in:

  8. Search for Darell D. Bigner in:

  9. Search for Jeremy N. Rich in:

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Corresponding author

Correspondence to Jeremy N. Rich.

Supplementary information

PDF files

  1. 1.

    Supplementary Notes

    This file contains Supplementary Tables and Supplementary Figures 1–17.

Word documents

  1. 1.

    Supplementary Methods

    This file contains additional details of the methods used in this study.

  2. 2.

    Supplementary Figure Legends

    Text to accompany Supplementary Figures 1–17

About this article

Publication history






Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.