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A Radical Bailout Strategy for Cancer Stem Cells

2009; Elsevier BV; Volume: 4; Issue: 3 Linguagem: Inglês

10.1016/j.stem.2009.02.008

1934-5909

Zuzana Tóthová, D. Gary Gilliland,

Ubiquitin and proteasome pathways

In a recent issue of Nature, Diehn et al., 2009Diehn 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. et al.Nature. 2009; (Published online February 4, 2009)https://doi.org/10.1038/nature07733Crossref PubMed Scopus (1651) Google Scholar demonstrate that breast cancer stem cells (CSCs) maintain lower levels of reactive oxygen species (ROS) than their nontumorigenic counterparts. Their studies provide a link between the management of ROS by CSCs and enhanced tumor radioresistance. In a recent issue of Nature, Diehn et al., 2009Diehn 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. et al.Nature. 2009; (Published online February 4, 2009)https://doi.org/10.1038/nature07733Crossref PubMed Scopus (1651) Google Scholar demonstrate that breast cancer stem cells (CSCs) maintain lower levels of reactive oxygen species (ROS) than their nontumorigenic counterparts. Their studies provide a link between the management of ROS by CSCs and enhanced tumor radioresistance. In 1956, Denham Harman proposed the "free radical theory of aging," hypothesizing that cumulative effects of ROS on DNA, proteins, and membranes determine the life span of an organism (Harman, 1956Harman D. J. Gerontol. 1956; 11: 298-300Crossref PubMed Scopus (6049) Google Scholar). In addition, it is now well established that many adult tissues require stem cells for their maintenance, and organismal longevity is thought to be dependent in part on the maintenance of different tissue stem cell pools. It has thus been suggested that effective management of ROS in normal tissue stem cells may contribute to their fitness, and hence the life span of the organism. But what might happen if this investment in ROS management by normal stem cells were commandeered by a renegade group of cells with the capacity to initiate and propagate cancer? Might this engender systemic collapse of the entire organism? In the hematopoietic stem cell (HSC) compartment, protection from oxidative stress is critical for the maintenance of self-renewal. For example, mice deficient in the Atm kinase or FoxO1, FoxO3, and FoxO4 transcription factors exhibit elevated ROS levels in the HSC compartment that result in a rapid extinction of HSCs. Furthermore, the demise of these mutant HSCs can be reverted by in vivo antioxidant therapy (Ito et al., 2004Ito K. Hirao A. Arai F. Matsuoka S. Takubo K. Hamaguchi I. Nomiyama K. Hosokawa K. Sakurada K. Nakagata N. et al.Nature. 2004; 431: 997-1002Crossref PubMed Scopus (913) Google Scholar, Miyamoto et al., 2007Miyamoto K. Araki K.Y. Naka K. Arai F. Takubo K. Yamazaki S. Matsuoka S. Miyamoto T. Ito K. Ohmura M. et al.Cell Stem Cell. 2007; 1: 101-112Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar, Tothova et al., 2007Tothova Z. Kollipara R. Huntly B.J. Lee B.H. Castrillon D.H. Cullen D.E. McDowell E.P. Lazo-Kallanian S. Williams I.R. Sears C. et al.Cell. 2007; 128: 325-339Abstract Full Text Full Text PDF PubMed Scopus (1170) Google Scholar), indicating a causal link between ROS and HSC longevity. However, protection of HSC from the accumulation of ROS is abandoned with the transition of HSC to myeloid progenitors. This developmental transition is associated with an ∼100-fold increase in ROS, and enables the mature progeny of non-self-renewing myeloid progenitors to engage their role as professional generators of ROS with bactericidal intent (Tothova et al., 2007Tothova Z. Kollipara R. Huntly B.J. Lee B.H. Castrillon D.H. Cullen D.E. McDowell E.P. Lazo-Kallanian S. Williams I.R. Sears C. et al.Cell. 2007; 128: 325-339Abstract Full Text Full Text PDF PubMed Scopus (1170) Google Scholar). Diehn et al. now extend this paradigm into the realm of epithelial tissue stem cells. In their elegant report, the authors demonstrate developmental regulation of ROS levels in the context of mammary epithelial stem cells and their progeny. They convincingly demonstrate that human and mouse breast CSCs, similar to their normal tissue counterparts, maintain low levels of ROS that afford radioprotection, providing a possible explanation for tumor recurrence with therapy (Diehn et al., 2009Diehn 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. et al.Nature. 2009; (Published online February 4, 2009)https://doi.org/10.1038/nature07733Crossref PubMed Scopus (1651) Google Scholar). Diehn et al. made the initial observation that a population of murine mammary repopulating unit (MRU)-enriched cells harbors lower levels of ROS and mitochondrial superoxide than do murine mammary progenitor cells, further emphasizing the importance of low levels of physiologic oxidative stress among different tissue stem cell compartments. They extended these findings to breast CSCs and addressed whether CSCs also have mechanisms that protect them from detrimental effects of oxidative stress. There are several reasons why this issue may be of particular relevance to CSCs. First, the cell of origin of CSCs may influence the levels of ROS and the transcriptional programs available for ROS management. For example, if a CSC population arose from committed progenitors in either the breast epithelial compartment or the myeloid progenitor compartment, endogenous ROS would be predicted to be higher than if CSCs arose from a stem cell. Second, CSCs demonstrate activation of signaling pathways that result in increased production of ROS and extinction of normal stem cells, such as the PI3K/AKT axis that results in inactivation of FoxO. Thus, CSCs may have mechanisms for protection from ROS, either through activation or reactivation of physiologic mechanisms that maintain low levels of ROS, or development of resistance to predicted detrimental effects of high ROS on self-renewal of CSCs. Diehn et al., 2009Diehn 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. et al.Nature. 2009; (Published online February 4, 2009)https://doi.org/10.1038/nature07733Crossref PubMed Scopus (1651) Google Scholar provide evidence that the former is the case in the context of mammary CSCs. First, gene set enrichment analysis (GSEA) using microarray expression data sets derived from human breast CSC-enriched populations (ESA+CD44+CD24−/low Lin−) or nontumorigenic breast cancer cells ("NTCs," CD24+Lin−) shows that genes involved in ROS metabolism, including glutathione peroxidase 1 and 4, superoxide dismutase 2, and catalase, are enriched in CSCs. Furthermore, enrichment of antioxidant gene expression correlates with lower levels of ROS in human breast CSC-enriched populations relative to NTCs, although ROS expression levels were heterogeneous within both populations of cells. In addition, a CSC-enriched population derived from an MMTV-Wnt1 murine model of spontaneous breast cancer exhibits lower overall levels of ROS than NTCs. However, transplantation of both low-ROS and high-ROS CSC-enriched populations gives rise to tumors, and a higher tumor-forming efficiency was noted in the high-ROS group. These data are somewhat perplexing and argue that in this setting, levels of ROS do not correlate with transplantability of the CSC population. This finding also stands in contrast with the hematopoietic system, at least in the context of nonmalignant HSCs (Ito et al., 2006Ito K. Hirao A. Arai F. Takubo K. Matsuoka S. Miyamoto K. Ohmura M. Naka K. Hosokawa K. Ikeda Y. Suda T. Nat. Med. 2006; 12: 446-451Crossref PubMed Scopus (995) Google Scholar, Tothova et al., 2007Tothova Z. Kollipara R. Huntly B.J. Lee B.H. Castrillon D.H. Cullen D.E. McDowell E.P. Lazo-Kallanian S. Williams I.R. Sears C. et al.Cell. 2007; 128: 325-339Abstract Full Text Full Text PDF PubMed Scopus (1170) Google Scholar). Although deleterious effects of ROS include induction of DNA damage and genetic instability, certain ROS also regulate a variety of cellular functions (reviewed in Veal et al., 2007Veal E.A. Day A.M. Morgan B.A. Mol. Cell. 2007; 26: 1-14Abstract Full Text Full Text PDF PubMed Scopus (1109) Google Scholar). To assess the physiological relevance of low levels of ROS in breast CSCs, Diehn et al., 2009Diehn 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. et al.Nature. 2009; (Published online February 4, 2009)https://doi.org/10.1038/nature07733Crossref PubMed Scopus (1651) Google Scholar examined the propensity of breast CSC-enriched populations to develop DNA damage after ionizing radiation (IR). They observed that CSC-enriched populations accumulate fewer DNA single- and double-strand breaks after in vitro and in vivo irradiation. In addition, the decrease in DNA damage correlates with increased persistence of the CSC-enriched population, consistent with the model that ROS modulates radioresistance of the CSC population. Furthermore, radioprotection in the CSC-enriched population is linked to expression of genes involved in glutathione synthesis, including glutamate cysteine ligase (Gclm), glutathione synthetase (Gss), and FoxO1, but not FoxO4, Hif1α, or Epas1. In addition, depletion of GSH in CSC via treatment with buthionine sulphoximine (BSO) results in decreased colony-forming ability and radiosensitization (Figure 1). In contrast, pretreatment with the antioxidant tempol protects NTCs from radiation-induced death to the same extent as that of the CSC-enriched population. Additional key mediators of ROS induction and genomic stability identified in other tissue stem cell contexts also warrant further investigation, including ATM, FoxO3, p53, p66Shc, NRF2-ARE, and p38MAPK, among others. In addition, it will be of interest to determine the contribution of microenvironmental regulation of ROS and genomic instability in this context. For example, expression of matrix metalloproteinase-3 (MMP3) in breast tumors is implicated in increased production of ROS with resultant DNA damage and genomic instability (Radisky et al., 2005Radisky D.C. Levy D.D. Littlepage L.E. Liu H. Nelson C.M. Fata J.E. Leake D. Godden E.L. Albertson D.G. Nieto M.A. et al.Nature. 2005; 436: 123-127Crossref PubMed Scopus (933) Google Scholar). Microenvironmental contribution to these processes could potentially explain the heterogeneity in ROS levels that was observed in the CSC-enriched population in the aforementioned experiments. Finally, it remains to be determined whether differential expression of ROS in breast CSCs versus NTCs may serve additional regulatory functions. For example, ROS has been implicated in activation of signaling pathways in response to cytokines, such as differentiation or induction of apoptosis. Taken together, these intriguing findings suggest that the self-renewal potential of CSCs in different tissues may be exquisitely sensitive to levels of reactive oxygen, and that the redox state may be intimately linked to resistance to IR. If so, this liability might represent a CSC "Achilles' heel" for future therapeutic exploitation. Indeed, there is evidence suggesting that treatment of human AML stem and progenitor cells with parthenolide, a naturally occurring molecule that induces ROS, preferentially targets AML cells and induces robust apoptosis (Guzman et al., 2005Guzman M.L. Rossi R.M. Karnischky L. Li X. Peterson D.R. Howard D.S. Jordan C.T. Blood. 2005; 105: 4163-4169Crossref PubMed Scopus (537) Google Scholar). It remains to be seen whether CSCs in other tissue compartments maintain low levels of ROS or whether they utilize other protective mechanisms to "bail out" the population from metabolic debts accumulated over time. A more thorough mechanistic understanding of these observations may inform the pursuit of improved therapeutic targeting of this critical tumor cell population.