Review Article
Oxidative stress, inflammation, and cancer: How are they linked?
Introduction
Oxidative stress is defined as an imbalance between production of free radicals and reactive metabolites, so-called oxidants or reactive oxygen species (ROS), and their elimination by protective mechanisms, referred to as antioxidants. This imbalance leads to damage of important biomolecules and cells, with potential impact on the whole organism [1]. ROS are products of a normal cellular metabolism and play vital roles in the stimulation of signaling pathways in plant and animal cells in response to changes in intra- and extracellular environmental conditions [2]. Most ROS are generated in cells by the mitochondrial respiratory chain [3]. During endogenous metabolic reactions, aerobic cells produce ROS such as superoxide anion (O2−), hydrogen peroxide (H2O2), hydroxyl radical (OH•), and organic peroxides as normal products of the biological reduction of molecular oxygen [4]. The electron transfer to molecular oxygen occurs at the level of the respiratory chain, and the electron transport chains are located in the membranes of the mitochondria [5], [6]. Under hypoxic conditions, the mitochondrial respiratory chain also produces nitric oxide (NO), which can generate reactive nitrogen species (RNS) [3]. RNS can further generate other reactive species, e.g., reactive aldehydes—malondialdehyde and 4-hydroxynonenal—by inducing excessive lipid peroxidation [7]. Proteins and lipids are also significant targets for oxidative attack, and modification of these molecules can increase the risk of mutagenesis [8].
Under a sustained environmental stress, ROS are produced over a long time, and thus significant damage may occur to cell structure and functions and may induce somatic mutations and neoplastic transformation [9], [10]. Indeed, cancer initiation and progression have been linked to oxidative stress by increasing DNA mutations or inducing DNA damage, genome instability, and cell proliferation [11].
The skin, for example, is chronically exposed to both endogenous and environmental pro-oxidants because of its interface function between the body and the environment, and to protect the skin against this overload of oxidant species, it needs a well-organized system of both chemical and enzymatic antioxidants [12]. The lungs, which are directly exposed to oxygen concentrations higher than in most other tissues, are protected against these oxidants by a variety of antioxidant mechanisms [13]. Furthermore, aging, which is considered an impairment of body functions over time, caused by the accumulation of molecular damage in DNA, proteins, and lipids, is also characterized by an increase in intracellular oxidative stress due to the progressive decrease in intracellular ROS scavenging [14]. Acting to protect the organism against these harmful pro-oxidants is a complex system of enzymatic antioxidants (e.g., superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase, catalase) and nonenzymatic antioxidants (e.g., glutathione (GSH), vitamins C and D) [15] (Fig. 1).
ROS are involved in a wide spectrum of diseases, including chronic inflammation (Table 1), and in a wide variety of cancers (Table 2).
Chronic inflammation is induced by biological, chemical, and physical factors and is in turn associated with an increased risk of several human cancers [54]. The link between inflammation and cancer has been suggested by epidemiological and experimental data [55], [56] and confirmed by anti-inflammatory therapies that show efficacy in cancer prevention and treatment [57]. The fact that continuous irritation over long periods of time can lead to cancer had already been described in the traditional Ayurvedic (meaning “the science of long life”) medical system, written as far back as 5000 years ago [58]. Whether this irritation is the same as what Rudolf Virchow referred to as inflammation in the 19th century is uncertain [59]. Virchow first noted that inflammatory cells are present within tumors and that tumors arise at sites of chronic inflammation [60]. This inflammation is now regarded as a “secret killer” for diseases such as cancer. For example, inflammatory bowel diseases such as Crohn disease and ulcerative colitis are associated with increased risk of colon adenocarcinoma [61], [62], [63], and chronic pancreatitis is related to an increased rate of pancreatic cancer [64].
The exact mechanisms by which a wound-healing process turns into cancer are topics of intense research [57], [65], and possible mechanisms include induction of genomic instability, alterations in epigenetic events and subsequent inappropriate gene expression, enhanced proliferation of initiated cells, resistance to apoptosis, aggressive tumor neovascularization, invasion through tumor-associated basement membrane, and metastasis [66]. How oxidative stress modulates these different stages of inflammation-induced carcinogenesis is the focus of this review.
Section snippets
Inflammatory network
The sources of inflammation are widespread and include microbial and viral infections; exposure to allergens, radiation, and toxic chemicals; autoimmune and chronic diseases; obesity; consumption of alcohol; tobacco use; and a high-calorie diet [60], [67]. In general, the longer the inflammation persists, the higher the risk of cancer. Two stages of inflammation exist, acute and chronic inflammation. Acute inflammation is an initial stage of inflammation (innate immunity), which is mediated
Pro-oxidant network
After an inflammatory stimulus, initiation of carcinogenesis mediated by ROS may be direct (oxidation, nitration, halogenation of nuclear DNA, RNA, and lipids) or mediated by the signaling pathways activated by ROS. With the help of the mitochondrial respiratory chain, aerobic organisms are able to attain a far greater energy production efficiency compared with anaerobic organisms. However, one disadvantage of aerobic respiration is continuous electron leakage to O2 during mitochondrial ATP
Cellular transformation
Chronic inflammation has been linked to various steps involved in carcinogenesis, including cellular transformation, promotion, survival, proliferation, invasion, angiogenesis, and metastasis [65], [142]. How oxidative stress is involved in these various steps is discussed in the following sections.
Cancer is a multistage process defined by at least three stages: initiation, promotion, and progression [143], [144], [145]. Oxidative stress interacts with all three stages of this process. During
Tumor cell survival
One of the key characteristics of tumor cells is their increased ability to survive compared with normal cells. ROS are reported to be tumorigenic by virtue of their ability to increase cell proliferation, survival, and cellular migration. ROS can induce DNA damage, leading to genetic lesions that initiate tumorigenicity and subsequent tumor progression. On the other hand, ROS can also induce cellular senescence and cell death and can therefore function as antitumorigenic agents. Whether ROS
Tumor cell proliferation
Uncontrolled tumor cell proliferation requires the up-regulation of multiple intracellular signaling pathways, including cascades involved in survival, proliferation, and cell cycle progression. The most significant effects of oxidants on signaling pathways have been observed in the MAPK/AP-1 and NF-κB pathways [170]. The induction of redox-sensitive pathways during tumor cell proliferation is necessary because cell division presents tremendous energy requirements and the production of
Tumor cell invasion
Oxygen radicals may augment tumor invasion and metastasis by increasing the rates of cell migration. During transformation into invasive carcinoma, epithelial cells undergo profound alterations in morphology and adhesive mode, resulting in a loss of normal epithelial polarization and differentiation and a switch to a more motile, invasive phenotype. For example, treatment of mammalian carcinoma cells with hydrogen peroxide before intravenous injection into mice enhances lung metastasis
Tumor cell angiogenesis
Solid tumors induce an angiogenic response by the host blood vessels to form a new vascular network for the supply of nutrients and oxygen [217]. This neovascular response is partly responsible for tumor growth and metastatic spread [218], [219]. Angiogenesis in tumors is controlled by the so-called “angiogenic switch,” which allows the transition from low invasive and poorly vascularized tumors to highly invasive and angiogenic tumors. To increase further in size, tumor cells express a set of
Chemoresistance
Despite many decades of research, the mechanisms underlying chemoresistance are still poorly understood. There is growing evidence that the inflammatory tumor microenvironment modulates not only cancer development but also cancer responsiveness and resistance to conventional anticancer therapies [238]. Experimental studies have led to the identification of various cancer cell-intrinsic resistance mechanisms, e.g., activation and/or overexpression of drug transporter proteins (e.g.,
Radioresistance
Acquired tumor radioresistance can be induced during radiotherapy owing to tumor repopulation [272]. Although tumor radioresistance stands as a fundamental barrier limiting the effectiveness of radiation therapy, the exact molecular mechanisms underlying the radioadaptive response are largely unknown (Fig. 4). Olivieri et al. [273] first described an adaptive response of human lymphocytes to ionizing radiation. Since then, a substantial number of reports have made a strong case for the
Stem cell survival
Cancer stem cells (CSCs) are cancer cells that have the ability to generate tumors through the processes of self-renewal and differentiation into multiple cells. Such cells persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. The existence of CSCs may have several implications in cancer treatment, including disease identification, selection of drug targets, prevention of metastasis, and development of new intervention strategies.
The first
Stromal cell signaling
Cancer progression must involve both genetic and behavioral changes in cancer cells, and these changes are in part driven by the cancer-associated stromal cells and tumor microenvironment [298], [299]. The stromal component of the normal prostate epithelium, for example, consists of smooth muscle, fibroblasts, vascular endothelial cells, nerve cells, inflammatory cells, insoluble matrix, and soluble factors [300]. Studies by De Marzo et al. highlight the role of inflammation in prostate cancer,
Conclusion
This review clearly implicates the role of ROS in various phases of tumorigenesis. Therefore, targeting redox-sensitive pathways and transcription factors offers great promise for cancer prevention and therapy. Numerous agents that can interfere with redox cell signaling pathways have been identified [9], [312], [313]. These include nutraceuticals derived from fruits, vegetables, spices, grains, and cereals. They have been shown to suppress tumorigenesis in preclinical models. Whether these
Acknowledgments
We thank Michael Worley for carefully editing the manuscript. Dr. Aggarwal is the Ransom Horne, Jr., Professor of Cancer Research. This work was supported by a grant from the Clayton Foundation for Research (B.B.A.), a core grant from the National Institutes of Health (CA-16672), a program project grant from the National Institutes of Health (NIH CA-124787-01A2), and a grant from the Center for Targeted Therapy of the M.D. Anderson Cancer Center. Simone Reuter was supported by a grant from the
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