Chapter One - Reactive Oxygen Species in Normal and Tumor Stem Cells

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Abstract

Reactive oxygen species (ROS) play an important role in determining the fate of normal stem cells. Low levels of ROS are required for stem cells to maintain quiescence and self-renewal. Increases in ROS production cause stem cell proliferation/differentiation, senescence, and apoptosis in a dose-dependent manner, leading to their exhaustion. Therefore, the production of ROS in stem cells is tightly regulated to ensure that they have the ability to maintain tissue homeostasis and repair damaged tissues for the life span of an organism. In this chapter, we discuss how the production of ROS in normal stem cells is regulated by various intrinsic and extrinsic factors and how the fate of these cells is altered by the dysregulation of ROS production under various pathological conditions. In addition, the implications of the aberrant production of ROS by tumor stem cells for tumor progression and treatment are also discussed.

Introduction

About 2.5 million years ago, cyanobacteria evolved to gain the ability to produce oxygen (O2) as a by-product of photosynthesis. O2 is a paramagnetic gas that readily reacts with other elements like hydrogen, carbon, copper, and iron. As O2 accumulated, it is thought to have converted the early reducing atmosphere into an atmosphere more conducive to oxidation reactions. Also, as atmospheric O2 levels rose, many new organisms evolved and flourished after developing antioxidant defense systems to protect against the toxicity of by-products related to O2 metabolism. Moreover, early aerobic organisms continued evolving to become multicellular organisms by taking selective advantage of efficient O2 utilization in various vital metabolic processes, such as employing O2 as the terminal electron acceptor for mitochondrial electron transport chain (ETC) activity during oxidative phosphorylation (OXPHOS), allowing for the efficient production of energy (Halliwell & Gutteridge, 2007).

However, utilizing O2 in many essential metabolic processes by living systems came at an evolutionary price, because O2 metabolism can lead to the production of reactive oxygen species (ROS) (Boveris, 1977, Buettner, 1993, Chance et al., 1979, Forman and Kennedy, 1974, Forman and Kennedy, 1975, Fridovich, 1978). Fortunately, living systems are normally maintained in a nonequilibrium steady-state that is highly reducing and is exemplified by the reduced glutathione (GSH)/glutathione disulfide (GSSG) redox couple that oscillates between about − 200 and − 240 mV (Schafer & Buettner, 2001). This highly reducing intracellular environment keeps steady-state ROS at relatively low levels that oscillate with changes in metabolic activity, which can communicate normal shifts in oxidative metabolism to signaling and gene expression pathways that control many diverse cellular functions including cell proliferation, circadian rhythms, differentiation, immunological functions, tissue remodeling, and vascular reactivity (Beckman and Koppenol, 1996, Kessenbrock et al., 2010, Menon and Goswami, 2007, Oberley et al., 1980, Oberley et al., 1981, Reuter et al., 2010, Rutter et al., 2001). If the metabolic production of ROS exceeds the capacity of the endogenous antioxidant defense systems, oxidative stress can occur (Sies, 1991, Spitz et al., 2004). Depending on the severity of oxidative stress, an organism may adapt by increasing its antioxidant capacity, increasing the capacity to repair oxidative damage, or shifting metabolic processes away from oxidative metabolism towards glycolytic metabolism. If the cellular adaptive processes that are induced in response to chronic metabolic oxidative stress cannot mitigate the accumulation of oxidative damage to critical biomolecules, potentially pathological conditions can develop due to increasing oxidative damage to DNA, proteins, and lipids. It is this gradual accumulation of oxidative damage to critical biomolecules that is believed to contribute to most if not all degenerative diseases associated with aging and cancer (Droge, 2002, Finkel, 2005).

Although all cells in an organism can be affected by the accumulation of oxidative damage, the effects of ROS on stem cells (or pluripotent cells) in most self-renewing tissues are of particular interest to the processes of aging and cancer development because of their undifferentiated state and longevity of replicative potential (Kobayashi and Suda, 2012, Oberley et al., 1980, Oberley et al., 1981, Shyh-Chang, Daley and Cantley, 2013). Stem cells can exist in a completely undifferentiated state, such as pluripotent embryonic stem cells (ESCs), or can be more committed to a particular lineage in a tissue as tissue stem cells or adult stem cells (ASCs). All normal stem cells appear to be highly sensitive to oxidative stress because of their relatively undifferentiated state with a long division potential for accumulating genetic damage. Accumulation of oxidative damage in normal stem cells can lead to cell transformation and tumorigenesis or cause tissue injury, loss of function, enhanced senescence, and loss of division potential associated with degenerative diseases associated with aging (Shyh-Chang, Daley, et al., 2013). Therefore, in this chapter, we will focus our discussions on the role of metabolic ROS in stem cell physiology and pathology and discuss strategies to exploit the differences in normal and tumor stem cell (TSC) sensitivities to oxidative stress for selectively protecting normal ASCs while sensitizing TSCs including leukemia stem cells (LSCs) and cancer stem cells (CSCs) to oxidative damage induced during leukemia and cancer therapy.

Section snippets

Common biological ROS

ROS is a collective term for oxygen-containing species that are more reactive than molecular O2. The most likely ROS to be produced initially during the metabolism of O2 by living systems were proposed to derive from the superoxide anion (O2) because it represents the one-electron reduction product of O2 (Boveris, 1977, Buettner, 1993, Chance et al., 1979, Fridovich, 1978). O2 is a relatively weak oxidant but is an excellent reductant for transition metal ions such as Fe+ 3, Mn+ 3, and Cu+ 2

Types of major normal stem cells

As concluded by Leydig “Omne vivum ex vivo (all life [is] from life),” life neither ends nor begins but continues (Sell, 2004). A new life is formed by the union of an oocyte and a sperm after fertilization, which generates the first stem cell, for example, the zygote, in an organism. The zygote is a totipotent stem cell. It undergoes cleavage, proliferation, and differentiation to produce pluripotent ESCs and multipotent trophoblast stem cells. ESCs continue proliferating and differentiating

TSCs

Like their normal tissue counterparts, tumors contain phenotypically and functionally heterogeneous populations of tumor cells (Beck and Blanpain, 2013, Nguyen et al., 2012). These cells are structured in a hierarchical manner in some, but not all, tumors (Magee et al., 2012). Undifferentiated tumor cells that are at the apex of the hierarchy have the ability to propagate the tumor by generating all of the cells in a tumor, including undifferentiated and differentiated tumor cells and other

Conclusion

Oxidative stress resulting from an increase in ROS production and/or a reduction in antioxidant capacity has been implicated in the pathogenesis of many diseases and aging. Although all cells in an organism can be affected by oxidative stress, the effects of ROS on stem cells have the greatest impact on the body, because they have the ability to self-renew and generate/replenish all other cells for the life span of the organism. Unfortunately, stem cells are more sensitive to oxidative stress

Acknowledgments

We apologize to the authors whose contributions were not directly cited owing to space limitations. The authors thank the previous and current members of Dr. Zhou's Laboratory for their work and support and Gareth Smith and Shawn Roach for their graphic design assistance. The research conducted in Dr. Zhou's Laboratory was supported in part by grants from the National Institutes of Health (R01-CA122023 and AI080421) and a grant from the Edward P. Evans Foundation and the Arkansas Research

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