Association of reactive oxygen species levels and radioresistance in cancer stem cells
Open accessAbstract
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 and haematopoietic stem cells and early progenitors 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, 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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Targets of the Nrf2 gene, such as HMOX1, facilitate cancer development because they counteract the effect of oxidative stress in transformed cells.
“It has been recently reported that targets of the Nrf2 gene, such as HMOX1, facilitate cancer development because they counteract the effect of oxidative stress in transformed cells55.”
From ROS in cancer therapy: the bright side of the moon (2020) · cites this paper as [55]
The paper’s Abstract (no page given) reports that antioxidant defenses help breast cancer stem cells survive oxidative stress: depleting glutathione reduced colony formation and increased radiosensitivity. It does not identify Nrf2 or HMOX1 as responsible, or establish that they facilitate cancer development in transformed cells. (LLM, conf=0.86)
Experimental — accuracy not yet measuredROS can mediate the deleterious effects of radiation and contribute to DNA damage and activation of senescence pathways in cells.
“reactive oxygen species (ROS) can mediate the deleterious effects of radiation and contribute to DNA damage and the activation of senescence pathways in cells (Diehn et al., 2009; Kuilman et al., 2010; Sonis, 2009; Spitz et al., 2004).”
From mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis (2012) · cites this paper as Diehn et al., 2009
Generation of ROS is an important mediator of cellular alterations caused by radiation exposure, including mucositis.
“The generation of ROS is also an important mediator of the cellular alterations caused by radiation exposure (Diehn et al., 2009; Sonis, 2009; Spitz et al., 2004), including mucositis (Citrin et al., 2010; Cotrim et al., 2007; Cotrim et al., 2005).”
From mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis (2012) · cites this paper as Diehn et al., 2009
Cellular ROS levels increase upon the differentiation of both neural and epithelial stem cells.
“Cellular ROS levels also increase upon the differentiation of both neural and epithelial stem cells 44–46.”
From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [46]
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- Authors
- Diehn, M., Cho, R. W., Lobo, N. A., Kalisky, T., Dorie, M. J., Kulp, A. N., Qian, D., Lam, J. S., Ailles, L. E., Wong, M., Joshua, B., Kaplan, M. J., Wapnir, I., Dirbas, F. M., Somlo, G., Garberoglio, C., Paz, B., Shen, J., Lau, S. K., Quake, S. R., Brown, J. M., Weissman, I. L., & Clarke, M. F.
- Affiliations
- Stanford Medicine (US)
- Institute for Stem Cell Biology and Regenerative Medicine (US)
- City Of Hope National Medical Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Clarke, Michael F.
- ORCID
- Venue
- Nature
- Published
- 2009-04
- Volume
- 458
- Issue
- 7239
- Pages
- 780-783
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2778612
- OpenAlex
- W2118758371
- Cited by
- 2,555
- References
- 33
- Citations by year
- 2026: 62 · 2025: 86 · 2024: 113 · 2023: 156 · 2022: 194 · 2021: 182 · 2020: 166 · 2019: 162 · 2018: 147 · 2017: 189 · 2016: 169 · 2015: 168 · 2014: 157 · 2013: 156 · 2012: 160
- FWCI
- 73.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (R01CA100225, U54CA126524)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- reactive oxygen species, cancer stem cells, radioresistance (biology), breast cancer, radiotherapy, mammary epithelial stem cells, DNA damage, radical scavengers, radiosensitization, clonogenicity
- MeSH terms
- Animals, Breast Neoplasms, Cells, Cultured, DNA Damage, Female, Humans, Mice, Inbred C57BL, Radiation Tolerance, Neoplastic Stem Cells, Gene Expression, Reactive Oxygen Species, Mammary Glands, Human, Mice
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