Inflammation contributes to carcinogenesis through various mechanisms such as instability in genome, changes in epigenetic events and consecutive irrelevant gene expression, increased differentiation of initiated cells, apoptotic resistance, aggressive tumour neovascularization, invasion in tumour-associated basement membrane, angiogenesis and metastasis. ROS, an effector molecule participates in host defence or acts as chemo-attractants volunteering leukocytes to wounded site, thereby prompting inflammatory reaction in tissue injured area. There are various cancer and diseases that are caused by oxidative stress followed by inflammation.
4.1 Colorectal cancer
Colorectal cancer (CRC) is a perplexing multistage disease that has numerous mutations in oncogene as well as tumor suppressor genes such as p53, adenomatous polyposis coli (APC) and K-ras mutations [43]. was found widely in western countries with the highest mortality rates of 70-80% that occurs intermittently while the rest 20-30% of the cases develop through inherited factors. These uncommon CRC cases leads to obesity, physical inactivity, changes in environmental as well as lifestyle factors of the individual etc [44, 45]. The increase in DNA oxidation and metabolic rate in CRC is mainly due to the rapid division of epithelial cells where CRC originates and lines the bowel [46]. In daughter cells, these DNA damages cannot be impaired and leads to mutation that could also result in cell cycle arrest, transcription activation, genomic instability closely linked with the initiation of carcinogenesis in colon [47]. Though, there is no history in the advancement of CRC after Inflammatory bowel disease (IBD), there is a major factor that recent inflammation and cancer prototype are being in the epidemiological studies along with its high frequency rate in IBD patients [48]. However, recent evidences stated that the ROS generation has a considerable role in cancer development [49]. The chronic inflammation in the intestine may leads to colon carcinogenesis in both type of IBD patients with Crohn’s disease (CD) and ulcerative colitis (UC) [50] (Figure 3).
UC, a chronic inflammation is represented with large number of inflammatory cell infiltrations such as neutrophils, lymphocytes, plasma cells etc. These infiltrated cells are largely to generate higher levels of ROS, thereby stimulating OS and various protein degrading enzymes. These ROS and proteolytic enzymes cause severe damages to cells, which in turn inflate inflammatory damage, which subsequently enters into intestinal mucosal necrosis and ulceration, thereby, leading it to colon [51–53].
JAK/STAT protein acts as diagnostic as well as prognostic marker that has a vital play in the development and prolonged survival of CRC that is profoundly seen during lymph node metastasis and tumor infiltration depth [54]. The oxidative modifications of Cys253 residue, dimerizes and translocate STAT3 to nucleus by signalling activation [55]. There are various other passages involved in CRC such as MAPK, Wnt/β-catenin and Notch signalling, PI3K/AKT. MAPK induces phosphorylation and activation of downstream genes including Ras through S-glutathionylation on Cys118 residue that generates higher ROS levels leading to CRC [56]. Wnt/β-catenin and Notch signalling are modulated by NOX as they are redox-sensitive and are involved in proliferation, migration and differentiation of CRC [57]. PI3K/AKT was intimately linked to CRC where it has a contact between redox balanced oncogenic signalling and metabolic modification with CRC progression. An NADPH generating enzyme called methylenetetrahydrofolate dehydrogenase (MTNFD2) was upregulated by c-Myc through KRAS downstream effectors facilitating CRC growth and metastasis that includes PI3K/AKT and ERK pathways [58]. There are two types of receptor molecules that are involved in colon carcinoma progression namely positive and negative regulators. Positive regulators include proinflammatory cytokines like IL-1, IL-6, TNF- α and proinflammatory CC- chemokines. Negative regulators such as IL-10, TIR8 (also called single immunoglobulin IL-1R molecule, SIGIRR), TGF-β, cyclooxygenase-2 (COX-2) and others like innate immune cells and signalling molecules like toll-like receptors 4 (TLR4), MyD88 and important transcription factor named NF-κB [48].
In rat colonocytes, the lower crypt cells are prone to be very sensitive to hydrogen peroxide that causes severe damage than the differentiated surface cells. These cells are proliferating which are the putative target cells of colon carcinogenesis [47]. In human with colorectal cancer, it was observed that the patients had high RS levels and malondialdehyde (MDA), a product obtained from lipid peroxidation and decline in the sodium dismutase (SOD) and glutathione (GSH) levels [59]. MDA that acts as a marker for OS enhance the CRC aggression and advancement [60].
4.2 Breast cancer
Breast cancer (BC) is one of the most common cause of mortality in women. It is diagnosed by dysregulation in various molecular pathways and the sensitivity differences in the treatment aids in the survival of the inmates [44, 61]. Chronic inflammation promotes various cellular related changes that initiates ROS production and enhances cell proliferation [62]. OS has a considerable play in breast cancer associated with dysfunctional adiposity and produces higher levels of ROS through various metabolic ways in obese and type 2 diabetes inmates [63, 64]. Chronic inflammation is a type of cytokine-activated oxidative stress that initiates carcinogenesis in breast by producing instability in genome which takes it into malignant transformation where high frequency of DNA damage is linked with metastatic cancer cells increasing the growth and tumorigenic potential [65–67].
Gain in weight and obesity are of significant factor in post-menopausal women to predict the estrogen-dependent breast cancer (EDBC) [68]. Adipokines secreted from adipose tissue along with inflammatory cytokines and polypeptides are involved in EDBC initiation [69]. In overweight and obese women, concentration of leptin, TNF-α and IL-6 correlates with body mass index (BMI) and directly promotes carcinogenesis and all these are found in estrogen receptor (ER+) patients [70] (Figure 4).
Recent insights provide evidences that various pro-inflammatory cytokine (COX-2, IL1-b, IL-8, TNF-α) expression are convoluted in pathogenesis of BC [71]. These pro-inflammatory cytokine does not directly promote carcinogenesis through obesity related factors either it activates by insulin resistance or by the modification of aromatase activity in adipose tissue [72, 73]. Also, breast cancer development is associated with higher COX-2 levels and ROS production with increased levels of estrogen [74]. It has been stated that IL-8 simulated secretion aids in both invasion and angiogenesis enhancing tumor growth by causing disturbance to immune system [75]. Il-6, an inflammatory cytokine is involved directly in the stimulation of NF-κB/STAT3 and induces insulin resistance [76, 77]. This insulin resistance will downregulate the insulin-like growth factor (IGF) binding proteins that enhances the IGF-1 bioavailability and initiates tumor development in breast [78]. Additionally, necrosis, inflammation and immune response in tumor cells are related with TNF-α [79]. Frequent cases of worsenning BC, higher expression of TNF-α and IL1-b activates epithelial to mesenchymal transition and stimulates movement and adhesion [80]. ROS derived from IL1-b increases malignancy in breast cancer patients by improving cell proliferation and differentiation [81].
Because of weight gain, insulin resistance, IGF-1, inflammatory and metabolic changes, induces oxidative stress which damages nucleic acids, proteins, lipids, in turn activates Akt/PI3K/mTOR signalling which acts as a major pathway in promoting tumour growth, progression and modulating the receptor function of estrogen which is strictly associated with lipid, glucose metabolism for energy and regulation of autophagy [82–86]. The endocrine resistance mechanism is found in ER and PI3K/Akt/mTOR signalling and in ER+ MCF-7 cells, tamoxifen resistance is closely related with OS that increases JNK and c-Jun phosphorylation along with enhanced AP-1 activity. Both these resistance blockade stimulates anti-tumor activity in breast cancer models [87, 88].
Doxorubicin is an anthracycline used in BC treatment generates ROS by disrupting replication mechanism of DNA by binding to topoisomerase II leading to DNA damage [89]. Another drug called Paclitaxel stabilizes microtubules by modifying cell division causing cell mortality [90]. Both these drugs cause oxidative stress and 50% cytotoxic chemotherapy treatment develop resistance to breast cancer [91]. In BC patients, status of oxidative stress is reported by putative markers derived from lipid peroxidation process namely malondialdehyde, 8-F2-isoprostanes and 4-hydroxinoenal [92].
4.3 Lung cancer
Lung cancer (LC) is the top most killer cancer that is highly invasive, found both in men and women in United States of America (US) that causes higher mortality per year than the other next four highest deadliest cancer such as colon, breast, pancreas and prostate cancer death [93] according to International Agency for Research on Cancer. There are numerous types of lung cancers include adenocarcinoma, squamous cell carcinoma, SCLC and NSCLC [94].
Researches witnessed that tobacco inhaling contributes as an important risk factor where active smoking is dangerous while passive smoking causes some extend to LC (Doll and Hill, 1950). Smoking, an important factor causes pulmonary inflammation that activates macrophages, decreases neutrophils clearance and initiates oxidative stress [95, 96]. Along with smoking, there are various factors contributes to LC such as ambient air pollution especially particulate matter (PM), coal and waste burning indoor air pollutants from non-ventilated kitchens, carcinogenic metals like Cd, Ni, As, Cr, ionizing radiation like α, γ-rays. Other carcinogenic factors include industrial toxic exposures such as iron and steel founding, rubber production, diesel fumes and silica dusts and organic chemicals with carcinogenic potential such as dioxins and polychlorinated compounds that attributes for lung cancer when the individual had long term exposure to these carcinogens [97]. All the above-mentioned extrinsic factors after long term exposure initially promotes oxidative stress followed by chronic inflammation. Inmates with lung cancer, there is a huge level of OS and inflammation in bronchial epithelium [98].
LC development involves various stages namely initiation, promotion and development [99]. In the first stage of initiation, inflammation causes direct damage to DNA causing mutation or erratic effect stimulated by variety of enzymes generating ROS leading to DNA and protein damage. Secondly, during promotion of LC, oxidative stress initiates the formation of focal lesions causing invasive cancers. Progression is the last stage where malignant cells are formed from neoplastic clones. c-Jun and c-Fos re oncogenes induced by ROS generated from inflammatory cells. Also, higher expression of c-Jun was witnessed in LC individuals [100] (Figure 5).
A variety of TF such as NF-κB, AP-1 (activator protein), p53 (tumor suppressor gene), HIF-1α, PPAR-γ (peroxisome proliferator-activated receptor gamma), Wbt/β-catenin, Nrf2 (nuclear factor erythroid 2-related factor 2) are triggered by OS having a considerable role in initiation and promotion of LC [101, 102]. All these TF overexpresses various other genes namely genes of growth factor, inflammatory cytokines, cell-cycle regulatory molecules and anti-inflammatory molecules. Thereby, OS stimulated inflammatory pathways transforms normal cell to tumor cell, enhancing its durability, proliferation, differentiation, angiogenesis, chemoresistance and radioresistance. Therefore, OS, chronic inflammation and LC are closely related [103–105].
4.4 Alzheimer’s disease
Alzheimer’s disease (AD) is a complex neurodegenerative disease. It is often linked with aged-dementia and extensive neuronal loss in hippocampus, amygdala, enterorhinal and neocortex regions which is separated into familial AD (FAD) and sporadic forms [106, 107]. Various genes involved with the accretion of fibrillar proteins. Example: extra-cellular amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs) have been identified and it leads to death after 3-9 years of diagnosis. These genes are a direct causative forms during the early-onset of the disease. Example: Amyloid precursor protein (APP) gene (chromosome 21) and presenilin (PS) genes 1 and 2 (chromosomes 14 and 1). Mutations identified on the APP, PS1 or PS2 genes result in amyloidogenesis means, the increased production of β-amyloid peptide [108]. The symptoms are dysfunction ranging from slow to progressive cognitive skills, decline in memory, language disturbances and physical disabilities [109].
Besides the pathological expression in AD, diseased brain evidences are reported caused as substantial damage due to brain atrophy, chronic inflammation, oxidative stress, extracellular and intracellular deposition of Aβ and NFTs respectively leading to neurodegeneration [110]. When the natural antioxidant, glutathione level becomes low and the neural membranes contain a higher ratio of polyunsaturated fatty acids, the neurons become extremely vulnerable to free radicals and the brain metabolism will require a considerable amount of oxygen [111]. Studies from both dead and live patients, along with transgenic mouse models, shows insights of the bridge between ROS, inflammation and AD. Several surrogate markers of ROS-mediated injury are found to be greatly enlarged in the brain and cerebrospinal fluid of AD patients. A few, such markers mentioned are 1) LPO - malondialdehyde, 4-hydroxynonenal, F2-isoprostanes 2) protein oxidation - protein carbonyls, nitrotyrosine 3) DNA oxidation - 8-hydroxy-2'-deoxyguanosine, respectively [112]. Insulin regulates appetite, glucose level and homeostasis of lipid in hypothalamus of the brain. So, when insulin signaling and transport of glucose is disrupted, it predominantly causes AD [113, 114] (Figure 6).
TREM2 gene associated with sporadic AD codes for cell surface protein. The knockdown of this gene brings cognitive impairment followed by the high levels of pro-inflammatory cytokines such as IL-6 and TNF- α, and decline in anti-inflammatory cytokines namely IL-10 in senescence-accelerated mouse prone-8 (SAMP8) brain model [115]. An adaptor protein named DAP12 associates with TREM2 that serves as an important factor for survival, proliferation, chemotaxis and phagocytosis of microglia in mice [116]. Microglia- predominant immune cells, involved in the homeostasis of central nervous system (CNS) during stress, disease, trauma and pathology and also attributed to the remodeling of neuronal circuits [117–119]. Either these immune cells exert neuroprotection by the phagocytic mechanism on Aβ, subsequently the loss in function exacerbate amyloidosis followed by inflammation, synaptic loss and further leads to neuronal loss [120, 121], or the inability of the microglial to clear Aβ fails, it activates pro-inflammatory passage leading to inflammation and OS in AD [122, 123].
ROS generated in the neurons interacts with any of the biomolecule causing oxidative stress to proteins. It breaks down the metabolism process, proteostasis and redox motion in the brain by stimulating various stress-related protein kinases namely JNK, mitogen activated protein kinase (p38) and ERK1/2 or brings about oxidative modifications in redox-sensitive transcription factors [124, 125]. ROS generated from two sources serves as a major donor to the AD pathophysiology includes transition metals like Fe and Cu acts as a ligand to Aβ and also mitochondrial dysfunction.
In addition, ROS from activated microglia induces inflammatory response in the brain of AD patients where NOX has a considerable play role in AD [126, 127]. The upregulation of microglial NOX2 is triggered from multiple sources like Aβ42. Along with NOX2 derived ROS, proinflammatory cytokines, chemokines further activate microglia and causes neuronal damage through linking inflammation and oxidative damage in the pathogenesis of AD [128].
4.5 Parkinson’s disease
Parkinson's disease (PD) is recognized by the cumulative neurodegeneration of pigmented nigrostriatal dopaminergic neurons (DA) and Lewy bodies formation, which are eosinophilic inclusions comprising intracytoplasmic aggregates of α-synuclein. The clinical manifestations of PD have both motor and non-motor signs. The major motor indications of PD are akinesia (complication in starting voluntary actions), bradykinesia (leisure down of movements) and extrapyramidal rigidity (muscle groups become stiffer) [129].
The general factors behind neuronal degeneration are environmental toxins, genetic factors and oxidative stress. OS is linked with PD progression in highly oxidative conditions that generally prevail in DA. Mitochondrial dysfunction is also documented in PD. For instance, respiratory enzyme in complex-I was suppressed by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causing PD. Moreover, tetrahydrobiopterin, an endogenous compound inhibits mitochondrial complexes I and IV, causing malfunction in the electron transport chain, oxidative stress and conclusively has PD symptoms [130]. In the pathogenesis of PD, increasing recognition of neuroinflammation to have a possible role are witnessed. They are shown to be stimulated by the vulnerability to infectious particles with pro-inflammatory characteristics [131] (Figure 7).
DA loss was witnessed due to oxidative stress that progresses to PD [132]. These unstable neurons oxidize to form quinone and H2O2 in the brain of PD patients simultaneously reacting with oxygen or iron forming hydroxyl radical (OH−). Dopaminergic neurotoxicity is caused by the interaction of DA quinone synthesized from catechin epoxidation of dopamine and cysteine residues where DA is inactivated by the removal of sulfhydryl groups, interferes with dysfunction of mitochondria and protein functions is inhibited [133, 134]. Sulfhydryl groups in the proteins react with DA metabolites and form adducts which damages the intracellular thiol group, aids with the advancement of PD [135]. Also, OS causes a disproportionate in the build-up of ROS bringing mitochondrial dysfunction [136]. Recent evidence suggested that rotenone (ROT) is another major risk factors in the PD pathophysiology [137].
Neuronal inflammation is mainly due to the microglia stimulation. Various studies stated that in PD patients with microglial overactivation, neuronal cell death was observed in substantia nigra [138, 139]. In addition, stimulated microglia are found in other regions of brain namely basal ganglia and pontine [140]. This microglia in activated form are composed of two different cells having opposite functions. The polarized microglia are of two extremes namely M1 pro-inflammatory (classically activated) and M2 anti-inflammatory (alternately activated) phenotypes [141]. M1 is morphologically altered and discharges numerous inflammatory components (TNF-α, IT-1, IL-6 and nitric oxide (NO)) leading to DA neuronal loss in PD patients [142]. M2 synthesizes anti-inflammatory cytokines (IL-4, IL-13, IL-10, TGF) via phagocytic effects that reduces inflammation and repairs the inflammatory response thereby microglia-mediated neuroinflammation plays both as positive and negative response in PD progression [143, 144]. Oxidative stress and neuroinflammation plays major role in PD through microglia-mediated neurotoxicity using two mechanisms. NOX activation induces the generation of huge extracellular ROS and also increases ROS intracellularly in microglia. This microglia-mediated OS stimulates pro-inflammatory genes generation [145].
Table 1
Oxidative stress and inflammation in certain disease and cancer and its mechanism
S. No | Diseases | Mechanism | Reference |
1. | Alzheimer’s disease | T2DM is due to resistance in insulin level playing a considerable part in Alzheimer’s disease. Chronic inflammation and OS combined with T2DM enhances the build-up of Aβ protein and tangles in neurons along with mitochondrial dysfunction leading to the formation of AD. | [145] |
2. | Parkinson’s disease | Exogenous and endogenous factors induce OS in the brain. While, neuroinflammation is due to the deposition of huge amount of proinflammatory factors through blood brain barrier. Recent studies reported that lipopolysaccharides induce chronic inflammation along with rotenone-induced ROS to stimulate the damage and create a progressive loss in dopamine neurons that leads to formation of Lewy bodies and α-synuclein accumulation causing PD. | [146] |
3. | Prion disease | It is transmissible neurodegenerative disease that is incurable caused by misfolding of cellular protein (PrPsc). Higher oxidative stress level, initiates the normal prion protein (PrPc) conversion to infectios prion protein (PrPsc). Along with PrPsc, metal ions like Cu and Fe interacts in the progression of prion disease. PrPsc accumulation in neurons enhances inflammation causing loss of function in neurons and leads to neuronal death. | [147] |
4. | Colorectal cancer | One mechanism in the pathogenesis of colon cancer, ulcerative colitis. It is a chronic inflammation caused by variety of infiltrated cells which generate ROS stimulating oxidative stress. These stress damages nucleic acids, followed by inflammatory damage and subsequently causes necrosis and ulceration in intestine, leading to the formation of colon carcinogenesis. | [148, 149] |
5. | Breast cancer | Various pro-inflammatory cytokines activate breast cancer by activating insulin resistance and modifying aromatase activity in adipose tissue. In addition, cytokines IL-1β generates ROS and enhances cell proliferation and differentiation in breast cancer cells. | [150] |
6. | Lung cancer | Chronic inflammation is stimulated by various external factors namely viruses, bacteria, smoke, pollution etc. This type of inflammation induces ROS and affects the hepatocytes, leading to the initiation and progression of LC. | [151] |
7. | Bladder cancer | Overproduction of ROS enhances proinflammatory cytokines (IL-6, TNF-α) promoting proliferation in cancer cells. Also, cytokines enhance ROS generation thereby, forming a cyclic phenomenon. Additionally, JAK/STAT-3 pathway closely related with malignant transformation of urothelial cells that progresses bladder cancer. | [152] |
8. | Gastric cancer | In gastric cancer, inflammation and OS are linked with H. pylori that damages DNA. This DNA damage induced progression of gastric cancer from normal infection stage. | [153] |