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Association of reactive oxygen species levels and radioresistance in cancer stem cells

Nature volume 458, pages 780–783 (2009)Cite this article

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Abstract

The metabolism of oxygen, although central to life, produces reactive oxygen species (ROS) that have been implicated in processes as diverse as cancer, cardiovascular disease and ageing. It has recently been shown that central nervous system stem cells1,2 and haematopoietic stem cells and early progenitors3,4,5,6 contain lower levels of ROS than their more mature progeny, and that these differences are critical for maintaining stem cell function. We proposed that epithelial tissue stem cells and their cancer stem cell (CSC) counterparts may also share this property. Here we show that normal mammary epithelial stem cells contain lower concentrations of ROS than their more mature progeny cells. Notably, subsets of CSCs in some human and murine breast tumours contain lower ROS levels than corresponding non-tumorigenic cells (NTCs). Consistent with ROS being critical mediators of ionizing-radiation-induced cell killing7,8, CSCs in these tumours develop less DNA damage and are preferentially spared after irradiation compared to NTCs. Lower ROS levels in CSCs are associated with increased expression of free radical scavenging systems. Pharmacological depletion of ROS scavengers in CSCs markedly decreases their clonogenicity and results in radiosensitization. These results indicate that, similar to normal tissue stem cells, subsets of CSCs in some tumours contain lower ROS levels and enhanced ROS defences compared to their non-tumorigenic progeny, which may contribute to tumour radioresistance.

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Figure 1: Analysis of ROS levels in normal mammary and breast cancer stem cells and their progeny.
Figure 2: Thy1 +  CD24 +  Lin - CSC-enriched cells develop less DNA damage after irradiation than non-tumorigenic cells.
Figure 3: Enrichment of CSCs after in vivo irradiation.
Figure 4: Thy1 +  CD24 +  Lin - cells overexpress genes involved in ROS scavenging and pharmacological modulation of ROS levels affects the radiosensitivity of Thy1 +  CD24 +  Lin - and ‘not Thy1 +  CD24 + ’ Lin - cells.

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Change history

  • 09 April 2009

    The name of the coauthor Frederick M. Dirbas was corrected on 9 April 2009.

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Acknowledgements

We thank D. Spitz for helpful discussions and D. Menke, D. Rossi, and J. Seita for technical assistance. This work was supported by grants from the National Institutes of Health (M.F.C., G.S. and I.L.W.), the Virginia and D.K. Ludwig Foundation (M.F.C. and I.L.W.), the Breast Cancer Research Foundation (M.F.C.), the Machiah foundation (T.K.), the American Society for Therapeutic Radiology and Oncology (M.D.), and the Radiological Society of North America (M.D.). M.D. is a recipient of the Leonard B. Holman Research Pathway fellowship.

Author Contributions M.D. and R.W.C. contributed equally to this work. M.D., R.W.C., N.A.L., T.K., M.J.D., A.N.K., D.Q., J.S.L., L.A. and M.W. performed the experiments. B.J., M.J.K., I.W., F.D., G.S., C.G., B.P., J.S. and S.K.L. aided in human tumour tissue acquisition. G.S. designed a pre-operative protocol allowing for tissue acquisition. M.D., R.W.C. and M.F.C. designed the experiments and wrote the manuscript. S.R.Q., J.M.B. and I.L.W. provided intellectual input and aided in experimental design.

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Author notes

  1. Maximilian Diehn and Robert W. Cho: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Radiation Oncology,,

    Maximilian Diehn, Mary Jo Dorie & J. Martin Brown

  2. Stanford Institute for Stem Cell Biology and Regenerative Medicine,,

    Maximilian Diehn, Robert W. Cho, Neethan A. Lobo, Angela N. Kulp, Dalong Qian, Jessica S. Lam, Laurie E. Ailles, Manzhi Wong, Irving L. Weissman & Michael F. Clarke

  3. Department of Pediatrics Division of Stem Cell Transplantation,,

    Robert W. Cho

  4. Department of Otolaryngology—Head and Neck Surgery,,

    Benzion Joshua & Michael J. Kaplan

  5. Department of Surgery,,

    Irene Wapnir & Frederick M. Dirbas

  6. Departments of Pathology and Developmental Biology,,

    Irving L. Weissman

  7. Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA,

    Michael F. Clarke

  8. Department of Bioengineering and Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA,

    Tomer Kalisky & Stephen R. Quake

  9. Department of Medical Oncology and Therapeutics Research,,

    George Somlo

  10. Department of Surgery,,

    Carlos Garberoglio, Benjamin Paz & Jeannie Shen

  11. Department of Pathology, City of Hope National Medical Center, Duarte, California, California 91010, USA,

    Sean K. Lau

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Corresponding author

Correspondence to Michael F. Clarke.

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Competing interests

[Competing Interests: M.F.C. is a founder and consultant for Oncomed Pharmaceuticals, Inc. in Redwood City, California, USA.]

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Diehn, M., Cho, R., Lobo, N. et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458, 780–783 (2009). https://doi.org/10.1038/nature07733

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