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

Abstract

Metabolism of oxygen, while central to life, also produces reactive oxygen species (ROS) that have been implicated in processes as diverse as cancer, cardiovascular disease, and aging. It has recently been shown that central nervous system stem cells 1, 2 and hematopoietic stem cells and early progenitors [3][4][5][6] contain lower levels of ROS than their more mature progeny and that these differences appear to be critical for maintaining stem cell function. We hypothesized 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 # To whom correspondence should be addressed. mfclarke@stanford.edu. * Contributed equally.Author Contributions M.D. and R.W.C. contributed equally to this work. M.D, R.W.C., N.L., T.K., M.J.D., A.K., D.Q., J.S.L., L.A., and M.W. performed the experiments. B.J., M.J.K, I.W., F.W., G.S., C.G., B.P., J.S., and S.K.L. aided in human tumor 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.Author Information Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. Given the conservation of low ROS levels in several types of normal tissue stem cells, we hypothesized that CSCs in some tumors may also contain lower concentrations of ROS than their non-tumorigenic progeny. In order to investigate ROS biology in human CSCs, we began by examining the expression of genes involved in ROS metabolism in primary human breast CSCs and NTCs. Using microarray data from human breast CSC-enriched populations and NTCs 13 and a curated list of genes involved in ROS metabolism 5 (see methods), Gene Set Enrichment Analysis (GSEA) 14 revealed that the expression of ROS genes was highly overrepresented in the CD44 + CD24 -/low Lin -breast CSC-enriched population compared to NTCs (p<0.001; Supplementary Fig. S2). The ROS genes identified as the core enriched genes by GSEA included a number of important antioxidant genes (Supplementary Table 2). Thus, gene expression profiles of human breast CSC-containing populations suggest that they contain higher levels of antioxidant defense systems than NTCs. NIH Public AccessNext, we directly assessed ROS levels in human tumor subpopulations. To do this the CD44 + CD24 -/low Lin -breast CSC-enriched population and the corresponding "Not CD44 + CD24 -/low " Lin -NTC population were purified from surgically resected breast tumors ( Supplementary Fig. S3). DCF-DA staining revealed that the CSC-enriched population in the human breast tumors we examined contained significantly lower levels of prooxidants than the NTC population. In some breast tumors, the vast majority of cells in the CSC-containing fraction displayed a low ROS phenotype compared to NTCs (Fig. 1e) while ...

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Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

“…It seems that multiple molecular mechanisms regulate GSC radioresistance, perhaps with intertumoral variation. Interestingly, decreased radiosensitivity in breast cancer stem cells has been linked to lower levels reactive oxygen species (ROS) (Diehn et al, 2009) or enhanced activity of Wnt/β-catenin signaling (Woodward et al, 2007). Although these mechanisms have not been reported in GSCs, they give hope that several molecular regulators may be targeted synergistically in GSCs in order to effectively overcome radioresistance.…”

Extracellular ATP reduces tumor sphere growth and cancer stem cell population in glioblastoma cells

“…The concept of cancer stem cells (CSCs) brought a change of paradigm in cancer biology and therapeutics [2,3], suggesting that specifically targeting these cells for destruction [4] or differentiation [5] may be the best therapeutic strategy to follow for several aggressive types of cancers. This, however, may not be easy, since CSCs have shown to present less reactive oxygen species [6] and to be more resistant to ionizing radiation [7], vincristine [8], hypoxia, and other chemotherapeutics [9] when compared to nonCSCs. Treatment with some of these agents increased the proportion of CSCs, which may be an explanation for more aggressive recurrence [7].…”