Journal of Radiation and Cancer Research

REVIEW ARTICLE
Year
: 2018  |  Volume : 9  |  Issue : 4  |  Page : 147--154

Intracellular reactive oxygen species determine cancer stem cell radiosensitivity related to predictive biomarker for radiotherapy


Kaushala Prasad Mishra 
 Ex-Bhabha Atomic Research Center; Foundation for Education and Research, Mumbai, Maharastra, India

Correspondence Address:
Dr. Kaushala Prasad Mishra
Ex-Bhabha Atomic Research Center; Foundation for Education and Research, Mumbai, Maharastra
India

Abstract

Cancer cells display a higher level of reactive oxygen species (ROS) mainly due to increased metabolic activities resulting in altered redox balance. Imbalance in redox arises when the generation of ROS exceeds antioxidants defense system. ROS are generated in cells from multiple pathways, but mitochondria contribute significantly to cellular ROS pool by oxidative phosphorylation. Elevated levels of ROS are implicated in cell transformation, proliferation, and tumorigenesis. ROS-mediated signaling pathways activate pro-oncogenes which regulate cancer progression, angiogenesis, and survival. Normal cells maintain intracellular homeostasis by developing an array of enzymatic antioxidant systems such as catalase, superoxide dismutase, and glutathione peroxidase. Chemotherapy and radiotherapy exert their cytotoxic effects on tumor cells by the generation of excessive ROS. The failure of therapies is attributable to a small fraction of core cells in tumor mass called cancer stem cells (CSCs) which have self-renewal property and exhibit proliferation, differentiation, and resistance to treatments. Both normal and CSCs maintain low-ROS level ascribed to stemness. This review describes role and relevance of ROS in CSC with particular emphasis on developing predictive biomarker for outcome of cancer radiotherapy. It is pointed out that CSCs maintain lower ROS homeostasis and evade cell death by increased level of endogenous antioxidants capacity in cancer cells. Search for regulators of ROS and surface markers in CSC may render them sensitive to radiation offering new and effective strategy for cancer treatment.



How to cite this article:
Mishra KP. Intracellular reactive oxygen species determine cancer stem cell radiosensitivity related to predictive biomarker for radiotherapy.J Radiat Cancer Res 2018;9:147-154


How to cite this URL:
Mishra KP. Intracellular reactive oxygen species determine cancer stem cell radiosensitivity related to predictive biomarker for radiotherapy. J Radiat Cancer Res [serial online] 2018 [cited 2019 Mar 26 ];9:147-154
Available from: http://www.journalrcr.org/text.asp?2018/9/4/147/253997


Full Text



 Introduction



Most of the cancer cell types have been found to have a higher level of reactive oxygen species (ROS) than their normal counterparts. ROS has been shown to be associated with cancer development, metastasis, progression, and survival.[1],[2],[3],[4] Under normal physiological conditions, the generation of ROS inside cells is tightly regulated by the ROS scavenging system. Low-to-moderate level of ROS is tightly maintained in normal cells essential for their function and survival. To regulate physiologically acceptable level of ROS, cells have evolved endogenous antioxidant enzymes that can neutralize ROS by directly reacting with and accepting electrons from ROS. When ROS production outpaces its scavenging, an excessive accumulation of ROS occurs, generating redox imbalance giving rise to oxidative stress which produces damaging effects on cellular components such as proteins, lipids, and nucleotides. To counteract this, the cells have armed themselves with a large number and types of endogenous antioxidants that are specific to different species of ROS, which help to prevent pathological levels of ROS and repair oxidative damage to cellular structural molecules.[5],[6]

Researches in the past decades have shown that dietary supplements and antioxidants impart cells both ROS scavenging ability and exhibit anticancer properties. However, antioxidants may not always be safe to use since excessive intake of antioxidants could lead to adverse health issues. This work attempts to evaluate the role of ROS in cell transformation, proliferation, survival, stemness, and sensitivity to therapies with particular reference to acting as biomarker for prognosis of cancer treatments. Results from our laboratory on the potential of the combined effects of several flavonoids and ionizing radiation in cancer radiotherapy have been summarized in this context.[6],[7],[8],[9],[10] Furthermore, growing importance of ROS in maintaining stemness of normal and cancer stem cells (CSCs) with relevance to self-renewal, differentiation, and resistance to treatments have been described which may serve as marker for predictive outcome in chemotherapy and radiotherapy of cancer.

Over the years, many therapeutic approaches have been employed targeting intracellular ROS levels which have yielded mixed outcomes. Exposure of tumor cells to radiation and drugs has been found to augment the level of ROS beyond barrier as well as express a variety of new proteins.[11],[12],[13] Evidently, analyses of expression profiles of ROS and proteins between radiation sensitive and radiation resistant tumor cells may offer a useful tool for predicting the response to radiotherapy. These lines of research may help developing molecular parameters in diagnosis and treatment of cancer with potential for insights into the progress of individualized molecular therapies of patients.

Recent research results on cancer have provided a new direction on tumor induction, progression, and therapies.[14],[15] It is commonly accepted that a small fraction (<1% of tumor mass) of self-renewing and proliferating cells called CSCs are responsible for recurrence, invasion, and prognosis.[11],[16],[17] It is noteworthy that CSCs possess lower level of ROS than in normal CSCs. It is believed that the regulation of intracellular ROS is the intrinsic feature of stem cells giving them survival advantage.[15],[18] Researchers envisage developing new strategies for effective therapies by quantifying, monitoring, and relating ROS level with the expression of surface markers on the CSC populations, both embryonic and adult.[19] It is notable that ROS regulate and maintain cell stemness which determine their survival and death. The resistance of CSC to chemo and radiotherapies is believed to be linked to maintaining low level of ROS which opens new possibilities to identify biomarkers for predicting treatment outcome[11],[20] as well as target for developing radiation and drug therapies. The role of ROS in regulating stem cell dynamics has implications for various diseases, including cancer and age-related illnesses.[21]

With the advances in genomics and proteomics, there is also increasing information about various ways in which ROS are balanced and control cellular processes. Based on microarray analyses, radioresponse-associated gene expression profiles have been reported in several cancers, including lung, head and neck, and colorectal cancers.[22] There is also increasing evidence that ROS are involved in many distinct levels of biological processes, from gene expression and protein translation to protein–protein interactions, etc.[23] They function in cellular signaling, propagating signals from one tissue to another, and in translating environmental cues into cellular responses to balance cellular inputs, such as nutrients and cytokines with appropriate cellular responses. ROS may function as a crucial tool to coordinate numerous cellular processes and adjust cellular activity to the available bioenergy sources.[24] These studies have identified genes involved with DNA repair, apoptosis, cell cycle, metastasis, and hypoxia.[25] During the disease processes, protein biomarkers are proving indicators of physiological states, and therefore, large-scale protein expression arrays are becoming increasingly popular in screening therapeutic strategies.[26] The comparison of the patterns of protein expression in radioresistant and radiosensitive head-and-neck cancer cells,[27] proteome profiles have been performed in various other cancers, including prostate, breast, rectal, and laryngeal cancers.[27],[28]

It is reported that changes in oxidation state of stem cells[29],[30],[31] might be responsible for the communication between mitochondria and the nucleus.[32],[33] Redox-mediated mitochondria-nucleus crosstalk could explain the coordination of cellular metabolism with chromatin remodeling, gene expression, cell cycling, DNA repair, and cell differentiation.[34] ROS have also been implicated in the aging process, but less is known about whether and how ROS might be involved in the aging of stem cells.[35] Since a slight alterations in ROS content may have profound effects on stem cell survival[29],[36] and elucidating mechanisms whereby ROS metabolism influences stem cell fate could reveal how stem cell aging relates to age-associated diseases. This review endeavors to focuses on addressing the relevance of ROS to CSC fate and usefulness of ROS in association with CSC surface markers as predictive tool for the outcome of radiotherapy and other treatment modalities.

 Generation and Regulation of Cellular Reactive Oxygen Species



Under normal physiological conditions, the generation of ROS is tightly regulated by the ROS scavenging system in cells. ROS scavengers are antioxidant enzymes that can neutralize ROS by directly reacting with and/or accepting electrons from ROS. When ROS production outpaces ROS scavenging, an excessive accumulation of ROS occurs, leading to oxidative stress and producing damaging cellular components, including proteins, lipids, and nucleotides. To counteract this, the cell contains multiple types of antioxidants that are specific to different species of ROS, which helps to prevent pathological levels of ROS and to repair oxidative damage to cellular components. These include superoxide dismutase (SOD), catalase, peroxiredoxins, thioredoxin (TRX), glutathione peroxidase (GPX), and glutathione reductase (GR). Glutathione (GSH), a tripeptide, is one of the most abundant antioxidants synthesized by the cell. Oxidized proteins and H2O2 are reduced by GSH through the glutaredoxin and TRX system. Other key antioxidants include SOD and catalase, which reduce O2− and H2O2, respectively. The subcellular localization of antioxidants at areas of high ROS generation, such as within the mitochondria, may further enhance the efficiency of ROS scavenging.

ROS are generated from the reduction of molecular oxygen and originate at multiple locations and distinct chemical processes. Intracellular ROS exist primarily in three forms: superoxide anions (O2−), hydrogen peroxide (H2O2), and hydroxyl radicals (OH−). The superoxide anion contains an unpaired electron that imparts high reactivity and converts rapidly to H2O2 by the antioxidant enzyme SOD.[37] H2O2 can be further reduced to H2O and O2 by various cellular enzymes and antioxidants.

ROS can be detected intracellularly using a variety of methods, but most ROS assays do not distinguish between different ROS species. Although ROS were originally thought to be merely a harmful byproduct of metabolism, accumulating evidence demonstrate the role for ROS in cell fate.[38],[39] H2O2 is thought to be the main ROS species involved with intracellular signaling, and in specific contexts can act directly as a second messenger. This is due mostly to the longer half-life of H2O2 and its ability to diffuse easily through membranes relative to other types of ROS.[40]

Within the cell, ROS is produced in mitochondria electron transport chain of respiration. The primary role of the electron transport chain is to generate the proton motive force, which leads to ATP production through ATP synthase in a process known as oxidative phosphorylation. However, a tiny fraction of O2 consumed by mitochondria is converted into ROS through leakage of electron flow to O2 mainly through electron transport chain complexes.[41]

ROS levels can be maintained by removing substrates away from oxidative phosphorylation resulting in decreased mitochondrial respiration. In addition, ROS is also generated by the membrane-bound protein NADPH oxidase, which consumes NADPH to generate O2− and subsequently, H2O2.

 Reactive Oxygen Species and Molecular Targets



ROS were originally shown to have signaling properties when they were found to act as secondary messengers in growth factor, and oncogenic signaling[42],[43],[44] However, not all ROS can be employed in signaling events. Only ROS with a substrate specificity that generates reversible oxidation, such as H2O2, are likely to trigger signaling cascade in in vivo physiological settings.[43]

ROS can signal directly to proteins through amino acid oxidation, the most common reaction being oxidation of cysteine residues. ROS signaling to amino acids can cause functional changes in the range of different proteins, and thus these types of modifications have established ROS as crucial regulators of cellular signaling. Such proteins are known as redox sensors, which directly get modified by ROS and undergo conformational changes as a result of the oxidative modification. These changes influence their function, stability, subcellular localization, and interactions with other proteins.

 Redox Sensor Molecules



A growing network of proteins has been shown to act as redox sensor and get modulated by ROS. Many of these redox sensor proteins that are directly modulated by ROS in response to oxidative stress are found to be crucial regulators of stem cell survival. Among these proteins are transcription factors that have been connected to the regulation of cellular antioxidant machinery. These include members of the forkhead box O family, nuclear factor erythroid 2 (NRF2), PR domain containing 16, and the p53 (TRP53) tumor suppressor.[45],[46] Modulations of ROS and p53 activity by TRX-interacting protein may be implicated in hematopoietic stem cell (HSC) function specifically during aging.[29] Other transcription factors, such as nuclear factor κB, mediate the transactivation by ROS of hypoxia-inducible factor 1α (HIF1α).[47] Furthermore, other protein types, such as ATM (ataxia-telangiectasia mutated kinase), p38 mitogen-activated protein kinase, mammalian target of rapamycin (mTOR) and protein kinase B protein kinases, as well as the multifunctional apurinic/apyrimidinic endonuclease1/redox factor 1 protein, PTEN (phosphate and tensin homolog), and sirtuins (specifically SIRT1 and SIRT3) are also considered to be redox sensors.

The polycomb group member BMI1 is another protein that regulates stem cell function, modulates ROS levels and is crucial for mitochondrial function.[48],[49],[50] However, whether BMI1 is also directly modulated by ROS or whether BMI1 regulates mitochondria in HSCs remains to be determined.

It is noteworthy that the redox-sensing property of many, if not all, of the proteins discussed above was established in somatic cells and often in cultured lines; whether these reactions also occur in primary stem cells or have a similar outcome remains to be established. As well as a role in redox regulation, ROS might also function to alter the epigenetic landscape, which plays a particularly pertinent role in regulating stem cell fate.[51],[52],[53] Many metabolic intermediates are necessary substrates for the posttranslational modifications of histones that together establish the epigenetic landscape of stem cells. As the activity of glycolysis and oxidative phosphorylation can directly influence ROS, leading to changes in the concentrations of various metabolic intermediates might represent a potential mechanism of ROS-mediated epigenetic regulation, albeit indirect.[54] For example, acetylation of the lysine tails of histones cannot occur without acetyl CoA, the TCA cycle metabolite, while deacetylation by sirtuin proteins (SIRTs) requires activation by nicotinamide adenine dinucleotide.

 Reactive Oxygen Species in Cancer Signaling



ROS are involved in each stage of carcinogenesis such as initiation, promotion, and progression.[55] It is observed that cancer cells produce more ROS than normal cells due to various mechanisms.[56] The increased levels of intracellular ROS, due to its reactivity, can cause damage to DNA, lipids, carbohydrates, and proteins. In fact, researchers have exploited increased ROS in cancer cells as an effective approach to selectively kill cancer cells without causing significant toxicity to normal cells.[57],[58] The intrinsic mechanisms of intracellular ROS increase may arise from accelerated metabolism, oncogene activation, tumor suppressor gene inactivation, and mitochondrial dysfunction. The increase in ROS was shown directly due to Bcr-Abl, as it could be blocked by the small-molecule tyrosine kinase inhibitor ST1571. Increased ROS seems possible through activation of the PI3K/mTOR pathway because inhibition of PI3K or mTOR attenuates the Bcr-Abl-induced ROS.[15] Likewise, the activation of c-Myc was able to increase ROS without the induction of apoptosis, while the treatment with antioxidant NAC decreased the number of c-Myc-induced hMre11 signals and improved cell survival after c-Myc activation.[59] Furthermore, tumor suppressor gene p53 decreases ROS by upregulating the transcription of antioxidant protein TIGAR, p53-induced glycolysis and apoptosis regulator. It is further found that splenocytes and thymocytes of p53−/− mice exhibited elevated level of ROS than in wild-type mice. ROS is involved in signaling mechanism, tumorigenesis process and response to radiation and chemotherapies.

 Reactive Oxygen Species Drive Cell Survival/cell Death



Cellular metabolism is the balance of catabolic and anabolic processes that involve the chemical conversion of carbon substrates to generate energy in the form of ATP and to produce macromolecular precursors in the form of nucleotides, lipids, and amino acids (anabolic). The balance of catabolic and anabolic processes can shift cellular process depending on the task being executed. Cellular processes such as growth and proliferation require mostly anabolic processes to generate building blocks for DNA, protein, and membranes.

One of the major pathways by which metabolism can influence signaling pathways is through alterations of ROS levels. In turn, ROS can directly react with various proteins, such as kinases, phosphatases, or transcription factors, to alter processes that regulate cell cycle progression, apoptosis, quiescence, or differentiation.[60],[61] Furthermore, ROS can directly modify metabolic enzymes or proteins that participate in nutrient-sensing pathways to direct the metabolic processes.[62]

 Reactive Oxygen Species in Self Renewal and Stemness



After the identification of CSC in leukemia,[63] they have been frequently identified and isolated in a number of solid tumors.[56],[63] The stem cells, whether normal or malignant, display self-renewal, and differentiation properties. The observed heterogeneity in cancer tissue such as morphology, cell surface antigens, and gene expression suggests that tumor treatment may depend on effective CSCs elimination. It is generally recognized that stemness of cancer cells may form a vital target for new treatment strategy. Stemness of cancer cells has low level of ROS and show resistance to therapies which warrants deeper studies for developing new strategy for achieving improved clinical outcome in treatment settings. The focus of research is progressing to manipulate intracellular ROS and antioxidant levels for establishing a useful predictive protocol in cancer chemotherapy and radiotherapy.

 Hypoxia, Reactive Oxygen Species, and Surface Markers in Cancer Stem Cell



Solid tumors possess hypoxic niche due to poor vasculature and resulting low oxygen level promotes tumor growth and favors survival of aggressive malignant cells.[64] Hypoxia in neoplastic mass is considered a prognostic indicator of poor treatment outcome and contributes to developing metastasis and cancer progression.[65],[66] In many human cancers, under hypoxic conditions, the hypoxia-inducible factor, (HIF-1α), is found overexpressed which dimerizes with HIF-1 β and translocates into the nucleus. Thus, HIF-1 activates transcription of genes involved in the mechanisms of cancer biology, such as angiogenesis, cell survival, glucose metabolism, and invasiveness offering a target for a selective cancer therapy.[66] Several genes associated with the hypoxic response in normal cells, such as Glut1, Serpin B9, and vascular endothelial growth factor, are upregulated in CSCs. In addition, hypoxia induces the expression of Sox2 and Oct4 genes relevant in stem cell function.[67] Recently, it has been shown that Sox2 with Sox4 play a vital role in the maintenance of stemness in CSCs.[68]

Hypoxia has been demonstrated to induce epithelial-mesenchymal transition (EMT), which promotes invasion and metastasis of cancer cells.[69] During EMT, epithelial cells undergo several biochemical alterations that allow the acquisition of the mesenchymal phenotype enabling cancer cells to evade and colonize at remote locations.[70] EMT-inducers, including transforming growth factor-β and hypoxia, trigger changes in gene expression by complex signaling pathways. It is found that an early event of EMT is the increased expression of the mesenchymal marker, vimentin, and the transcriptional downregulation of E-cadherin. Several cancer reports have demonstrated that EMT is involved in generating cells with properties of stem cells.[71] This suggests that hypoxia-induced EMT may affect CSCs or induce stem-like cells from more differentiated progenitors determining an increase of CSC population responsible for early systemic cancer dissemination and metastasis formation. Studies have shown a functional connection in low-oxygen tension, ROS production, and EMT.[72] ROS can favor EMT but antioxidants can attenuate hypoxia-induced EMT and metastasis dissemination in cancer cells, the maintenance of low ROS levels is crucial to preserve CSC self-renewal and stemness.

It is notable that, in contrast to cancer cells in which ROS levels are increased, CSCs generally maintain low ROS, exhibiting redox patterns that are similar to the corresponding normal stem cells. It is reported that ROS levels are lower in human and murine breast CSCs compared to non-stem breast cancer cells and that the pharmacological depletion of ROS scavengers in CSCs markedly decreases their clonogenicity and shows radiosensitivity.[73] A pioneering study showed that it is possible to use CD34+/CD38− cell surface markers to separate cells into AML CSCs and non-CSCs populations that differ in their self-renewal capacity in vitro and tumorigenicity in vivo. In the CNS, CD133 is believed to be the marker for CSCs in different types of brain tumor. The subpopulation of CD133+ tumor cells is enriched after radiation in gliomas.[74] Gastrointestinal CSCs with a high level of CD44 expression have shown an enhanced capacity of reduced GSH synthesis and defense against ROS by the activation of cystine-glutamate exchange transporter. Therefore, since EMT is a reversible and redox-dependent phenomenon, it is likely that ROS could also stimulate mesenchymal–epithelial transition regulating differentiation of CSCs toward non-stem cancer cells.

Oxidative stress caused by the cellular accumulation of ROS is intrinsically detrimental to CSCs, which have evolved antioxidant systems to protect against ROS increase. Therefore, understanding of redox regulation mechanisms is essential to develop rational therapies that specifically target CSCs.

 Cellular Status of Reactive Oxygen Species and Radiosensitivity



Elevated levels of ROS, alteration in redox balance, and deregulated redox signaling are common hallmarks of cancer progression and resistance to treatment. Mitochondria contribute mainly in the generation of ROS during oxidative phosphorylation. Cells maintain intracellular homeostasis by developing an immense antioxidant system including catalase, SOD, and GPX. Besides these enzymes exist an important antioxidant GSH and transcription factor NRF2 which contribute in balancing oxidative stress. ROS–mediated signaling pathways activate pro-oncogenic signaling which eases in cancer progression, angiogenesis, and survival. Concomitantly, to maintain ROS homeostasis and evade cancer cell death, an increased level of antioxidant capacity is associated with cancer cells giving a clue to the importance of antioxidant-based therapies.

 Reactive Oxygen Species, Apoptosis, and Signaling



Stem cells are characterized by their ability to self-renew and their multipotent differentiation capacity. Until recently, the focus in stem cell biology has been on the adverse effects of ROS, particularly the damaging effects of ROS accumulation on tissue aging and the development of cancer, and various anti-oxidative and anti-stress mechanisms of stem cells. However, it has become increasingly clear that, in CSCs, redox status plays an important role in stem cell maintenance through regulation of the cell cycle. In contrast to cancer cells, in which ROS levels are increased, most CSCs maintain low ROS levels, exhibiting redox patterns that are similar to the corresponding normal stem cell. To fully elucidate the mechanisms involved in stem cell maintenance and to effectively target CSCs, it remains essential to understand ROS regulatory mechanisms in different cell types, for example, in normal stem cells, cancer cells, and CSCs.

 Predictive Biomarker of Radiotherapy



In a variety of human tumors of different histological origins, including glioma, prostate, cervical, breast and pancreatic cancer, Hsp90 and Her-3 proteins have been established as determinants of radiosensitivity. Notably, RR-H460 cell lines exhibited CSC characteristics, displaying several aberrant CSC markers, such as CD44, activated Notch1, Nanog, Sox-2, and β-Catenin.[74] Available results suggest a great potential for careful analysis of ROS level and surface makers in CSC which may prove unique and reliable predictive markers of prognosis of cancer patients in radiotherapy. It appears promising approach to control and enhances intracellular ROS levels in CSCs by oxidative stressors shifting the redox balance from survival advantage to death susceptible frame making them more sensitive to radiation treatment. It remains to be investigated if the expression of CSC surface markers and their quantitative estimation bears relation with the cytosolic ROS. It is seen that overexpression of β-catenin promotes CSC properties and tumorigenesis both in vitro and in vivo, suggesting an important role for the Wnt/β-catenin pathway in the regulation of CSC self-renewal.[75] Therefore, developing specific regulators for inducting CSCs dysfunction may yield highly novel approach to overcome their resistance to chemo- and radiotherapy for providing effective cancer treatment strategy. It is considered a promising strategy to eliminate CSC after radiotherapy for developing effective cancer treatment.

 Conclusions



Cancer cells face the challenges of oxidative stress. ROS are known to be involved in initiation and progression of tumors. Cancer cells normally adapt to persistent oxidative stress by regulating redox response. The role of ROS in cancer cell survival, proliferation as well as targets for chemotherapy and radiotherapy have been highlighted.[65] It is clarified that conventional cancer therapies result in a transient reduction in tumor mass by killing non-stem cancer cells but fail to eliminate CSCs. Results have shown role of hypoxia and ROS deregulation in CSC establishment and propagation. CSCs maintain low ROS level and show resistance to chemo and radiotherapy. A general agreement exists on the role of CSCs on metastases and their colonization at secondary sites. In CSCs, such adaptation is potentiated by increased antioxidant mechanisms and resulting in resistance to anticancer therapies. It is suggested that low ROS, surface markers, and sensor proteins in CSC may prove predictive in outcome of cytotoxic drug and cancer radiotherapy.

Acknowledgments

We apologize to authors whose papers we could not cite due to space limitations. I tried sincerely to refer others work liberally, but I ask for excuse if there are lapses.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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