1. Department of Radiation Oncology,
2. Stanford Institute for Stem Cell Biology and Regenerative Medicine,
3. Department of Pediatrics Division of Stem Cell Transplantation,
4. Department of Otolaryngology—Head and Neck Surgery,
5. Department of Surgery,
6. Departments of Pathology and Developmental Biology,
7. Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA
8. Department of Bioengineering and Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA
9. Department of Medical Oncology and Therapeutics Research,
10. Department of Surgery,
11. Department of Pathology, City of Hope National Medical Center, Duarte, California, California 91010, USA
12. These authors contributed equally to this work.

Correspondence to: Michael F. Clarke^2,7 Correspondence and requests for materials should be addressed to M.F.C. (Email: mfclarke@stanford.edu).

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 cells^{1, 2} and haematopoietic stem cells and early progenitors^{3, 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 killing^{7, 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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