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Bardelčíková, A.; Šoltys, J.; Mojžiš, J. Oxidative Stress, Inflammation and Colorectal Cancer. Encyclopedia. Available online: (accessed on 14 June 2024).
Bardelčíková A, Šoltys J, Mojžiš J. Oxidative Stress, Inflammation and Colorectal Cancer. Encyclopedia. Available at: Accessed June 14, 2024.
Bardelčíková, Annamária, Jindřich Šoltys, Ján Mojžiš. "Oxidative Stress, Inflammation and Colorectal Cancer" Encyclopedia, (accessed June 14, 2024).
Bardelčíková, A., Šoltys, J., & Mojžiš, J. (2023, May 04). Oxidative Stress, Inflammation and Colorectal Cancer. In Encyclopedia.
Bardelčíková, Annamária, et al. "Oxidative Stress, Inflammation and Colorectal Cancer." Encyclopedia. Web. 04 May, 2023.
Oxidative Stress, Inflammation and Colorectal Cancer

Colorectal cancer (CRC) represents the second leading cause of cancer-related deaths worldwide. The pathogenesis of CRC is a complex multistep process. Among other factors, inflammation and oxidative stress (OS) have been reported to be involved in the initiation and development of CRC. Although OS plays a vital part in the life of all organisms, its long-term effects on the human body may be involved in the development of different chronic diseases, including cancer diseases. Chronic OS can lead to the oxidation of biomolecules (nucleic acids, lipids and proteins) or the activation of inflammatory signaling pathways, resulting in the activation of several transcription factors or the dysregulation of gene and protein expression followed by tumor initiation or cancer cell survival. In addition, it is well known that chronic intestinal diseases such as inflammatory bowel disease (IBD) are associated with an increased risk of cancer, and a link between OS and IBD initiation and progression has been reported. 

oxidative stress inflammation inflammatory bowel disease colorectal carcinoma

1. Introduction

Oxidative stress (OS) is caused by an imbalance between pro-oxidant molecules and the cell’s antioxidant capacity [1]. This imbalance leads to the damage of digestive tract cells, including DNA damage, protein aggregation, and membrane dysfunction [2][3]. It has been proven that reactive oxygen species (ROS) via interaction with cellular macromolecules, including proteins, nucleic acids, and lipids, can disrupt crucial cellular functions. For example, the oxidative damage of DNA may result in bases oxidation, single- and double-strand breaks, or the generation of abasic sites [4]. In addition, unrepaired oxidative DNA damage increases the risk of mutagenesis. These mutations can occur in important genes that regulate cell growth, such as tumor suppressor genes and proto-oncogenes, and can lead to the development of cancer [5][6].
The body’s response to the cell damage of intestinal mucosa exposed to OS is inflammation. Under physiological circumstances, the repair or replacement of inflammation-damaged or dead cells occurs. However, sites repeatedly exposed to inflammation can lead to the development of chronic inflammation and the induction of autoimmune processes [7]. The disruption of homeostasis leads to a breach in the cell integrity and loss of the defensive function in the gut mucosa. Altogether, this leads to mucosal injury and the invasion of pathogenic microorganisms [8]. In some cases, inflammation may precede or accompany tumor development [9]. On the other hand, chronic inflammation can modulate tumorigenesis through the production of reactive oxygen species (ROS). As a result of inflammation, epigenetic alterations occur that promote tumorigenesis through the production of growth factors and pro-inflammatory cytokines [10]. Growing tumors through a feedback pathway further influences the inflammatory environment by the production of cytokines and chemokines.
Oxidative stress is closely associated with inflammatory responses and it has been implicated in the propagation and exacerbation of inflammatory bowel disease (IBD) [11]. IBD is a chronic disease affecting the digestive tract, primarily the large intestine. Several oxidative stress-related IBD genetic risk loci have been identified [2]. There are two primary diseases—ulcerative colitis (UC) and Crohn’s disease (CD) [12], which differ regarding to the extent and involvement in the gastrointestinal tract. Both diseases develop from an overreaction of the immune system. In addition, the conversion of sensitive cells into neoplastically transformed cells in some patients with IBD has been observed [13][14]. Thus, carcinogenesis in the gastrointestinal tract represents a complex pathogenetic process evolving gradually and spontaneously. According to available studies, oxidative stress is significantly involved in the development of colorectal cancer (CRC) [15][16][17][18].

2. Colorectal Carcinoma as a Multilevel Cancer Disease

The inflammatory processes induced by oxidative stress can lead to mitochondrial and neurodegenerative diseases, diabetes, chronic diseases, and aging [19][20]. In addition, it leads to the development of tumorigenesis and tumor angiogenesis processes, which are promoted by free radicals, especially ROS [21]. Increased cancer risk is associated with chronic intestinal diseases [15]. The pathogenesis of colorectal cancer is a complex multistep process that results from long-term inflammation, exposure to infectious agents, or other stressors [22].
IBD is common worldwide, and the number of cases is increasing yearly. While the incidence in children is becoming more frequent, men and women are affected equally [23]. This chronic disease persists throughout life; periods of remission are observed when symptoms are minimal or not existent, and then there are periods of flare-ups when symptoms are most noticeable. Currently, no treatment would completely stop these diseases [24]. Modern medicine aims to achieve the longest possible periods of remission and, in case of flare-ups, suppress the symptoms with symptomatic treatment [25].

2.1. Oxidative Stress in Colorectal Cancer Pathogenesis

CRC is a multifactorial disease in which several factors play a significant role. Although the cause of CRC is not yet defined, research results confirm the influence of lifestyle factors, including diet, smoking, stress, alcohol and toxins. Oxidative stress leads to inflammatory reactions of the intestinal mucosa, genetic predisposition, altered intestine immune reaction, and, last but not least, dysbiosis—changes in the composition of the intestinal microbiota [26][27], which are considered an integral part of the CRC development [28].
Many studies confirm the influence of free radicals on the initiation, promotion [29] and formation of IBD [2], and also in the process of multistage carcinogenesis [30]. Oxidative stress in intestinal mucosal cells almost certainly plays a key role in the pathogenesis of CRC. Free radical-induced oxidative damage can result in the activation of metabolic pathways, during which other proteins affecting the processes of cell proliferation and inflammation are created.
The effects of oxidative stress on the cells of the colon mucosa could be divided into three levels: (a) the level of biological membranes (oxidation of lipids), (b) the level of the nucleus (oxidative DNA damage), and (c) the level of proteins and carbohydrates. At the same time, products of oxidative damage by free radicals represent potential indicators or markers of CRC outcome [15].
Lipid peroxidation, the main feature of oxidative stress, promotes cell destruction at the level of phospholipid cell membranes. The endoplasmic reticulum is a reservoir of calcium ions, which escape into the cytoplasm due to the peroxidation of membrane lipids. As a result, there is a loss of control over the activity of Ca2+-dependent enzymes, whose activity is controlled by the levels of calcium ions in the cytoplasm [31]. Moreover, increased levels of Ca2+ ions in the cytoplasm stimulate the NO synthase (NOS) to produce the NO, which induces oxidative damage [32]. Mitochondrial lipids are extremely important for maintaining structural integrity and mitochondrial functions [33], where oxidative damage to mitochondrial membranes disrupts cell energy metabolism [34]. Damage to the phospholipid bilayer of the cytoplasmic membrane of colon cells leads to malfunctions of membrane receptors, the release of small molecules into the extracellular environment, and subsequent membrane rupture. As a result of lipid peroxidation by free radicals, the structure of fatty acids is damaged and their function is lost. In addition to the formation of by-products such as gaseous alkanes—ethane, propane, pentane, and hexane, lipid peroxidation produces highly toxic aldehydes, ketones, hydroxy aldehydes and epoxides. Elevated levels of ethane, methane and pentane have been detected in patients with Crohn’s disease and ulcerative colitis [35].
The final product of lipoperoxidation is malondialdehyde (MDA), which reacts with DNA to form MDA–DNA complexes. MDA–DNA complexes have been shown to have pro-mutagenic properties and induce mutations in oncogene/tumor suppressor genes in human tumors [36][37].
Enzymes such as lipooxygenase and cyclooxygenase are involved in oxidative stress as well. Lipooxygenase ensures the synthesis of hydroperoxides, while cyclooxygenase ensures the synthesis of endoperoxides, from which prostaglandins are formed [38]. Cholesterol derivatives have significant pro-inflammatory and pro-apoptotic effects. Free radicals oxidize cholesterol to form oxysterols (7α-OH or 7β-OH), which are further oxidized to 7-keto-cholesterol and toxic C-5 and C-6 oxygenated derivatives of cholesterol [39].
As oxidation products of lipids and carbohydrates, ROS, RNS, and metal ions participate in protein oxidation. Proteins with a side chain composed of amino acids containing sulfur atoms (methionine, cysteine) are easily oxidizable. While the oxidation of cysteine produces disulfides, the oxidation of methionine produces methionine sulfoxide. Hydroxyl radicals activate the peptide bond, forming carbon radicals that react with oxygen [40], which creates an alkyl peroxyl radical, an alkyl peroxide or an alkyl radical. These radicals also oxidize other places on the polypeptide chain [41].
Free radicals (ROS/RNS), ionizing radiation, and transition metals may directly damage the DNA/RNA. Oxidative DNA damage results in DNA strand breaks, DNA fragmentation, and base mismatches, leading to unwanted mutations [42]. These are subsequently repaired by a system of repair enzymes that cut out and simultaneously replace the damaged bases with new bases. Non-specific endonucleases remove the entire chain. Specific DNA glycosylases remove one specific damaged base. The oxidation of DNA also changes the primary structure of DNA, the exchange or loss of bases and the formation of cross-links [43].

2.2. Mechanisms of CRC Development Induced by Oxidative Stress

Preclinical and clinical research has identified the primary mechanisms by which free radicals contribute to the development of CRC. The development of CRC is a multistep process of transforming a healthy intestinal cell into an abnormal one, where one mutation is not enough to cause the CRC. The direct oxidizing of bases, sugar components, and proteins associated with DNA causes mutations where free radicals, via transcription factors Nrf2 and NF-κB, intervene with inflammation and carcinogenesis [44][45][46]. The activation/inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2), activated by free radicals, is considered effective in CRC prevention and treatment [44]. Its activation inhibits oxidative stress and inflammation, resulting in the prevention CRC development [44]. The primary function of Nfr2 is the regulation of cytoprotective and antioxidant gene expression. Under normal conditions, Nrf2 is in a complex with the inhibitory proteins Keap1 via the ETBE and DLG domains. Keap1 proteins enable the ubiquitination of the Nrf2 protein and, subsequently, its degradation in the proteasome. Keap1 proteins represent a regulatory mechanism by which the amount of Nrf2 in the cell’s cytoplasm is regulated. Protein modifications play a key role in adaptation to oxidative stress by activating antioxidant or metabolic programs to counteract ROS metabolism [47][48].
The promoter hypermethylation of Keap1 leads to a reduction of Keap1 expression and Nrf2 accumulation in the nucleus of patients with CRC [49]. As a result of oxidative stress, Keap1 proteins dissociate from Nrf2 and enter the nucleus. Nrf2, together with the small sMAF (small musculoaponeurotic fibrosarcoma oncogene homolog) protein, induces the transcription of antioxidant response elements (ARE) [50] and leads to the expression of more than 500 target genes, including antioxidant enzymes [51][52] such as NAD(P)H: quinone oxidoreductase-1 (NQO1), heme oxygenase (HO-1), superoxide dismutase 1 (SOD), and catalase (CAT); and enzymes involved in glutathione metabolisms such as glutathione S-transferase (GST), glutathione peroxidase (GPX) and others [53][54]. Nfr2 eliminates ROS through the upregulation of enzymes involved in the induction and synthesis of antioxidant molecules [53]. Heme oxygenase 1 (HO-1) catalyzes the degradation of heme to iron, biliverdin and carbon monoxide (CO) [40]. CO suppresses the nuclear translocation of NF-κB p65, which plays a central role in the inflammation process [55][56]. Its activation leads to the production of pro-inflammatory cytokines (TNFα, IL-1β, IL-6), chemokines (MCP-1, MIP-1, RANTES, eoxantin, IL-8), transcription factors (Jnk, Erk, p38), inflammation mediators (COX-2), antimicrobial peptides and adhesive molecules (ICAM-1, VCAM-1, ELAM) [57]. Therefore, by inhibiting the nuclear translocation of NF-κB, there is a decrease in the intracellular level of pro-inflammatory cytokines.
On the other hand, overexpression of Nrf2 can promote colorectal tumor growth. The aberrant activation or accumulation of Nrf2 is connected with malignant progression, chemotherapy resistance, and poor prognosis [58][59]. Therefore, if the tumor has already occurred, Nrf2 inhibitors are administered as anticancer agents. Effective Nrf2 inhibitors are brusatol [60], chrysin [61], trigonelline [62], ascorbic acid [63] and retinoic acid [64]. Luteolin, as an inhibitor of Nrf2, reverses the sensitivity of colorectal cancer cells to chemotherapeutic agents [65].
Nrf2 is probably also an important inhibitor of metalloproteinases (MMPs). While in humans, Nrf2 activation inhibits MMP-7, and in Nrf2-deficient mice, the level of MMP-3 is higher than in controls [66]. At the same time, the Nrf2-deficient mice are more susceptible to benzo[α]pyrene-induced tumor formation [67]. The pathogenesis of CRC is closely related to oxidative DNA damage and the production of pro-inflammatory cytokines, overexpression of Nrf2, expression of metastasis-associated colon cancer 1 (MACC1), and stimulation of MMP production via TNFα [68]. Long-term stimulation of the intestinal epithelium by inflammatory cytokines and persistent activation of NF-κB are involved in the development of chronic inflammation and the initiation of carcinogenesis. The immune system responds to signaled inflammation by activating T-cells and infiltration of inflammatory neutrophils into the mucosal layer of the intestine. Neutrophils produce large amounts of ROS/RNS, whose high local concentration damages other cells of the intestinal mucosa [69]. TNFα together with IL-1β stimulates matrix metalloproteinase (MMP) production and simultaneously regulates the COX-2 overexpression in the early stages of carcinogenesis [70]. IL-6 activates the JAK/STAT pathways, leads to the inhibition of apoptosis and, together with TNFα, promotes angiogenesis and tumor growth [71]. Oxidative DNA damage represents the beginning of the transformation of intestinal epithelial cells. The subsequent activation of oncogenic genes provides cells with advantages in the form of unregulated proliferation, growth, resistance to apoptosis and survival [72].
The inflammatory environment contributes to tumor initiation by producing reactive oxygen/nitrogen species or epigenetic changes (e.g., DNA methylation, histone modifications or changes in chromatin organization) that can play a role in carcinogenesis by silencing the expression of tumor suppressor genes and activating oncogenic signaling [73][74]. It also promotes tumorigenesis by providing growth factors and pro-inflammatory cytokines [10]. The environment of chronic inflammation as a result of the ROS signaling function provides transformed cells with suitable conditions (energy source and metabolites) to initiate carcinogenesis. The resulting effect of ROS on tumor initiation and promotion is related to quantity, location and duration [47].
Under normal conditions, ROS regulate many signal transduction pathways. In general, tumor cells have a higher level of ROS than healthy cells. On the other hand, cancer cells tend to produce higher levels of antioxidants to counteract the damaging effects of ROS. This suggests that maintaining a certain level of ROS is essential for cancer cells to function properly [75]. Thus, while low levels of ROS can promote cell proliferation and invasion, excessive levels of ROS cause oxidative damage to proteins, lipids, RNA and DNA, which in turn induces cell death [76][77][78]. As a result of metabolic abnormalities and oncogenic signaling, the protective mechanism against the persistent oxidative stress of the tumor cell is activated. This redox adaptation reaction of cancer cells results in drug resistance [15].
Screening of oxidative stress markers and antioxidants in colorectal cancer patients suggests the existence of a protective mechanism for the tumor cell. The study of Burwaiss et al. [79] analyzed ROS in tumor cells in adjacent surrounding tumor tissues from patients with colorectal cancer and adjacent normal tissues. They found that the tumor’s oxidant and antioxidant levels were significantly lower than those in the surrounding tumor tissue and control healthy tissue. In addition, Indran and co-workers [80] reported reduced both basal and H2O2-induced ROS production in HeLa cells with overexpressed human telomerase reverse transcriptase (hTERT), indicating a possible link between hTERT and OS in cancer cells. hTERT is a significant characteristic of CRC and has a crucial role in the maintenance and the synthesis of chromosomal ends—telomeres [81][82]. Telomerase has non-telomeric function and supports growth factor-independent growth [83][84]. Elevated telomerase activity is reported in almost all human cancers [84]. The transcription factor YBX1 (cancer-related gene) upregulates the activation of the Nrf2 gene promoter in the presence of hTERT, which reduces ROS in CRC cells, thus promoting cancer progression [85]. Increased telomerase activity in cancer has been shown to promote resistance to apoptosis.
In addition to controlling the cellular processes of free radical regulation by inhibiting oxidative stress and inflammation, new Nrf2 target genes have been identified as being involved in the inhibition of cell proliferation and the induction of apoptosis [46].
The activation of antioxidant enzymes is the primary cell defense mechanism. The overall increase in SOD activity is a response to tissue protection against oxidative damage under conditions of inflammation and oxidative stress in the pathogenesis of IBD. Accordingly, SOD levels in the peripheral blood of IBD patients are already being used as bio-markers of oxidative stress [86]. Both SOD1 and SOD2 protect against spontaneous tumorigenesis, and although they have been described as tumor suppressors, they can also be upregulated during tumorigenesis [87].


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