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 Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 447-457

Clinical significance of inflammatory mediators in the pathogenesis of oral cancer


1 Biochemistry Research Division, The Gujarat Cancer and Research Institute, Ahmedabad, India
2 Deputy Director, The Gujarat Cancer and Research Institute, Ahmedabad, India

Date of Web Publication25-Jul-2016

Correspondence Address:
Prabhudas S Patel
Head, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Asarwa, Ahmedabad - 380 016, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.147765

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 > Abstract 


Oral cancer has become a grave problem in many parts of the globe with two.thirds of the cases occurring in developing countries. Chronic inflammation plays a prominent role in the development of oral cancer. The rationale for molecular targeted prevention of oral cancer is promising. Therefore, there are continued improvements to our understanding of the molecular connections between inflammation and oral cancer. The inflammatory mediators including nuclear factor kappa B, vascular endothelial growth factor, inflammatory cytokines, prostaglandin pathways, p53, reactive oxygen and nitrogen species, and microRNAs are major key players in the pathogenesis of oral cancer. Currently, visual cytology.based techniques and biopsy are used to detect dysplasia and early stage of oral squamous cell carcinoma. These approaches are limited in their ability to judge the severities of oral lesions and are useful only after the appearance of visual changes. Thus, traditional cytological and biopsy assays combined with testing of inflammatory biomarkers would be beneficial for the efficient early detection of oral dysplastic lesions and early stages of oral squamous cell carcinoma.

Keywords: Inflammation, molecular signature, oral cancer


How to cite this article:
Patel JB, Shah FD, Joshi GM, Patel PS. Clinical significance of inflammatory mediators in the pathogenesis of oral cancer. J Can Res Ther 2016;12:447-57

How to cite this URL:
Patel JB, Shah FD, Joshi GM, Patel PS. Clinical significance of inflammatory mediators in the pathogenesis of oral cancer. J Can Res Ther [serial online] 2016 [cited 2019 Sep 21];12:447-57. Available from: http://www.cancerjournal.net/text.asp?2016/12/2/447/147765




 > Introduction Top


Oral cancer is a major cause of morbidity and mortality worldwide. Annually 400,000 new cases of oral cancer annually have been detected in the world.[1],[2] Oral cancer is also a major health problem in the Indian subcontinent. It is the commonest cancer in the Southeast Asia and in India.[1],[3] Moreover, in western countries, it is only 3-5% of total cancers. In India, its incidence is particularly high and is frequently associated with habit of chewing paan mixed with tobacco, which contains areca nut-based carcinogens.[1] Millions of people in India are exposed to tobacco smoke or smokeless tobacco products.

Oral cancer is a multi-step process with a multifactorial etiology especially involving tobacco and alcohol use and various genetic changes. Advances in understanding of mechanism of oral carcinogenesis are necessary to improve survival curves that plateaued over the past two decades have remained among the worst of all cancer sites.[1],[3] Many research studies involving the detection of oral cancer have been conducted; however, their findings are far from being applied in the clinical setting. Currently, cytological testing is the most common mode of detection. Although various light-based visual examinations of the oral cavity have been proposed for screening oral lesions in recent decades,[4] these techniques exhibit several limitations.[4] Whereas, biochemical and molecular assays involving the oral mucosa show the greatest potential for overcoming diagnosis related limitations and would serve as excellent gold standards. It is important and necessary to apply the vast knowledge that has been obtained regarding inflammatory mediators in oral cancer in the clinical area.

Inflammation is the major hallmark of cancer. As early as in the 19th century it was perceived that cancer is linked to inflammation. This perception has waned for a long time. Previous reports have seen a renaissance of the inflammation cancer connection stemming from different lines of work and leading to generally accepted paradigm.[5] Epidemiological studies have revealed that the chronic inflammation play prominent role in the development of oral cancer. Therefore, there are continued improvements to our understanding of the molecular connections between inflammation and oral cancer. Inflammatory mediators including nuclear factor kappa B (NF-κB), vascular endothelial growth factor (VEGF), inflammatory cytokines, prostaglandins, p53, nitric oxide (NO), reactive oxygen species (ROS) and nitrogen species, and specific microRNAs (miRNAs) are major key players in pathogenesis of oral cancer.[6] The expression of these mediators is largely responsible for either a pro-tumorigenic or anti-tumorigenic inflammatory response through changes in cell proliferation, cell death, cellular senescence, DNA mutation, DNA methylation and angiogenesis. Understanding of these will provide opportunities to develop novel diagnostic and therapeutic strategies [6],[7] [Figure 1]. The present review summarize the reports on clinical significance of potential inflammatory associated molecular signature for early detection of oral dysplasia and squamous cell carcinoma.
Figure 1: Chronic inflammation alters the cellular levels of inflammatory mediators

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 > Nuclear Factor Kappa B and Oral Cancer Top


Nuclear factor kappa B is a ubiquitous nuclear transcription factor mapped on chromosome 11q13 that was first identified in 1986 by Sen and Baltimore. It was named by its location in the nucleus and bounded to an 11-base pair sequence in the enhancer element of the immunoglobulin kappa light chain gene in B cells. It represents a group of structurally related proteins, with five members in mammals forming dimers by combination of several proteins including NF-κB p65 (Rel A). Consistent with its role in inflammatory and immune response, incorrect regulation of NF-κB has been linked to activation of oncogenes, cytokine receptors, cell adhesion molecules and growth factors [Figure 2].[8] NF-κB is activated by ROS, cytokines, viruses, protein kinase C activators and immunological stimuli.[8] In most cells NF-κB/Rel proteins are sequestered in the cytoplasm, bound to IKBs. Upon stimulation of cells by inducers such as interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), IKBs are degraded and NF-κB is translocated to the nucleus where it modulates the expression of genes involved in inflammation, extracellular matrix degradation, cell adhesion, angiogenesis and prevention of cell death. Activation of NF-κB involves phosphorylation, followed by ubiquitination and proteosome mediated degradation of IKBs. NF-κB suppression in combination with chemotherapeutic agents is found to be useful for the adequate treatment of human salivary gland malignancies.[9],[10] Moreover, it has been reported that aberrant activation of NF-κB occurs in human malignant cells and that specific inhibition of activity leads to apoptosis.[9] It has been also documented that inhibition of NF-κB may provide a means of intervention at early as well as later stages of the transformation process in the mammary gland.[11] There are increasing evidences that the NF-κB/Rel family is important in controlling cell proliferation and oncogenesis.[11] Based on recent reports [Table 1], it is hypothesized that exposure to tobacco carcinogens stimulate proinflammatory activity of human monocytes through activation of NF-κB.
Figure 2: Inflammatory networking in cancer

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Table 1: Significance of NF-κB in oral cancer

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 > Vascular Endothelial Growth Factor and Oral Cancer Top


Oral cancer cells with different potential of lymphatic metastasis displayed distinct biological behaviors and gene expression profiles. Angiogenesis plays an important role in tumor growth and prognosis. Primary tumor cannot grow beyond 3 mm without new vessel formation. A key angiogenesis stimulator is VEGF, which promotes vessel permeability, cell proliferation and migration of endothelial cells and inhibits apoptosis.[17] VEGF overproduction by a wide spectrum of tumor cells suggested that this angiogenic factor plays an important role in tumorigenesis. Expression of VEGF was an independent prognostic factor in patients with breast cancer, colon cancer and esophageal squamous cell carcinoma.[18] A tumor specimen from cancer patients showed an association between poor prognosis and/or low survival rates and VEGF overexpression.[19] As documented recently [Table 2], there is a strong evidence for the contribution of VEGF to the progressive growth of solid tumors through its effect on promoting tumor angiogenesis. Furthermore, when VEGF signaling is inhibited, tumor angiogenesis and consequently, tumor growth are impaired.
Table 2: Significance of VEGF in oral cancer

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 > Interleukin-8 and Oral Cancer Top


Previous studies of in vitro human cell lines as well as malignant tumors have demonstrated that concentration of certain proinflammatory, proangiogenic cytokines such as TNF-α, IL-1, IL-6, and IL-8 are increased in oral cancer.[26],[27] It has been known that cellular genes including IL are uniquely associated with oral squamous cell carcinoma. These cytokines have also been linked with increased tumor growth and metastasis, and could thus contribute to the pathogenesis of oral disease. Elevated concentrations of IL-8 in cell line supernatants, tumor specimens, and the serum of patients with oral squamous cell carcinoma have also been documented.[28] Recent studies [Table 3] have documented that salivary levels, as well as gene polymorphisms of IL-8 and environmental carcinogens, might be highly related to the risk of oral cancer. Therefore, it is important to study association between inflammation and oral squamous cell carcinoma development through the potential mediator, IL-8.
Table 3: Significance of IL-8 and COX-2 in oral cancer

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 > Prostaglandin Molecular Pathway and Oral Cancer Top


The smoke or smokeless products contain thousands of chemical constituents including major alkaloid (nicotine) and minor alkaloids (noricotine, anabasine, anatabine, etc). The formation of tobacco specific nitrosamines like 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanol occur from nicotine, nornicotine, anabasine by the reaction with nitrite.[40] NNK bioactivation leads to the production of ROS,[41] which are known to activate NF-κB that acts as positive regulatory element of cyclooxygenase (COX)-2 expression [42],[43],[44] [Figure 3]. Both, COX-1 and COX-2 are the key enzymes in the synthesis of prostaglandins. They catalyze the same reaction of arachidonic acid to prostaglandin 5-hydroxy analogue. The two forms of COX, COX-1 and COX-2 have different biological role. The constitutively expressed COX-1 is known to carry out “housekeeping” functions including the production of prostaglandin under normal physiological conditions. In contrast, the COX-2 protein is normally absent in most tissues. COX-2 expression can be induced by inflammatory mediators including cytokines mitogens, growth factors, oncogenes and carcinogens. Over expression of COX-2 is seen in several neoplastic tissues including oral cancer.[45] Previous reviews [46],[47] have explained that COX-2 metabolized NNK more effectively than COX-1. It has been suggested that ingredients of areca nut play a critical role in the pathogenesis of oral submucous fibrosis and oral cancer via their stimulatory effects on the prostagalndin through COX-2 production and associated tissue inflammatory responses.[48] Recent reports [Table 3] have indicated that chronic inflammation is one of the characteristics of oral lichen planus. COX-2 is an important molecule showing close relation to inflammation, carcinogenesis and angiogenesis.
Figure 3: Pathway of cyclooxygenase induction by 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone in U937 macrophages

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 > P53 Expression and Oral Cancer Top


p53 is the most widely studied tumor suppressor gene in a wide variety of solid tumors. The wild-type p53, a 53 kD short-lived nuclear phosphoprotein, is essential for normal cell growth and eventual suppression of a malignant phenotype. Inactivation of p53 induces development of malignancy. The mutant p53 loses its anti-proliferative properties favoring a deregulation of cellular multiplication with the accumulation of genetic aberrations. Mutations stabilize the p53 protein and extend its half-life to such an extent that may trigger humoral immune reaction releasing anti-p53 antibodies into the circulation. Recent reports suggest [Table 4] that expression of p53 would be a valuable tool for the study of early events in oral carcinogenesis.
Table 4: Significance of p53 and NO in oral cancer

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 > Nitric Oxide and Oral Cancer Top


The discovery in 1987 that NO accounted for the bioactivity of endothelium-derived relaxing factor, rapidly led to an explosion of information on the physiological and pathological role of this molecule. Half-life of NO is very short (3-30 s). It is an inorganic free radical gas, containing an odd number of electrons and can form a covalent link with other molecules by sharing a pair of electrons. NO is generated from the terminal guanido nitrogen atom of L-arginine by various NADPH dependent enzymes called NO synthase (NOS) located in various tissues, and play an active role in free radical and tumor biology.[56],[58] The three main isoforms of NOS are neuronal (nNOS), inducible (iNOS) and endothelial (eNOS). In general, nNOS and eNOS are expressed constitutively in neurons and endothelial cells, respectively, while; iNOS are expressed during pathogenesis of several diseases.

Nitric oxide has mutagenic properties. Long-term exposure of cells to high NO concentrations resulting from iNOS induction during chronic inflammation have an active role in carcinogenesis.[56],[58] Mutagenesis by NO can occur through several mechanisms [60],[61] [Figure 4]. DNA damage due to deamination of nucleic acid bases has been shown in cell-free systems, bacteria, and macrophages. Transition and/or transversion of nucleic acid bases (e.g. G: C→ A:T, G: C→C: G, G: C.→ C: G, G: C→ A:T) by reactive NO products has been documented in plasmid DNA. Further, inactivation of DNA repair enzymes (e.g. alkyltransferase and DNA ligase) can occur owing to the high affinity of reactive NO species for amino acids containing thiol residues.[61] It has been reported that NO may promote carcinogenesis by inactivating the tumor suppressor oncoprotein p53. Cells are containing wild-type p53, when exposed to excess NO, accumulated p53 protein with a concomitant loss of its DNA binding activity. This has been attributed to nitration of tyrosine residues in the protein. Further, mutation of p53 may occur in a high NO environment. A positive correlation between total NOS activity and the prevalent form of p53 mutation (G: C→ A: T at CpG dinucleotides) was reported in 27 head and neck carcinoma.[62] Recent reports [Table 4] have shown that high production of NO through iNOS expression have a significant role in oral carcinogenesis.
Figure 4: Role of nitric oxide in carcinogenesis

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 > Reactive Oxygen Species and Oral Cancer Top


The free radicals generated during chewing and smoking of tobacco causes oxidative stress, which has been defined as a disturbance in the balance between the production of ROS and antioxidants defenses. The ROS damages various cellular targets including DNA, proteins and lipids, which leads to tissue injury. Cellular antioxidant enzymes normally protect the cells from toxic effects of the ROS. Hence, defensive mechanisms play a vital role in etiology of oral cancer. The first line of defense; antioxidants enzymes are superoxide dismutase (SOD) and catalase. SOD converts O2 − to H2O2, which is converted to H2O with the help of catalase. SOD and catalase are potent enzymatic antioxidants known to play an important role in combating oxidative stress.[63] These antioxidants help in quenching the free radicals and ROS, produced during detoxification or in response to carcinogen exposure. Besides, second line of defense; detoxification pathway enzymes like glutathione-S-transferase (GST) including GSTM1 and GSTT1 and glutathione reductase (GR) also play important role in determining individual's susceptibility to develop oral cancer [63],[64] [Figure 5]. Glutathione is also an important antioxidant. Biothiols, the major components of GSH, are extraordinarily efficient antioxidant, protecting the cell against consequence of damage-induced by free radicals.[64] Recent reports [Table 5] have documented that genetic susceptibility is considered as one of the factors responsible for pathogenesis of oral cancer.
Figure 5: (a) Prevention against reactive oxygen species by antioxidant enzymes (b) susceptibility to oral cancer against tobacco carcinogen compounds

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Table 5: Significance of antioxidants/detoxification enzymes in oral cancer

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 > Micornas as Mediators of Inflammation in Oral Cancer Top


MicroRNAs are a recently discovered class of regulatory molecules that have a convincing role in inflammation and cancer. miRNAs regulate the translation of specific genes. The first miRNAs, Lin-4 was discovered in cenorhabdits elegans in 1993 and was found to regulate development timing and cell fate specification. In 2000, miRNAs were found to be conserved in vertebrates and over the last decade miRNAs have been shown to be involved in nearly every cellular and development process examined.[6]

MicroRNAs are short, noncoding RNA molecules (22 nucleotides) that bind the to 3'UTR of mRNA and regulate posttranscriptional gene expression in many cancers, including oral squamous cell carcinoma. Increased plasma miRNA (miR-31) has been previously reported in association with oral squamous cell carcinoma. The overexpression of miR-21, miR-24, and miR-31 in plasma has been reported in oral cancer. In addition, miR-181b and miR-34 overexpression has been reported in association with oral leukoplakia. Oral precancer has been linked to the under expression of miR-125b and mir-100. Sasahira et al. have shown that miR-126 might be a useful as diagnostic and therapeutic target in oral quamous cell carcinoma.[76]


 > Inhibition of Pro-Inflammatory Pathways by Curcumin Top


Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant, commonly known as turmeric. Curcumin has been used extensively in Ayurvedic medicine for centuries as it is nontoxic and has a variety of therapeutic properties including antioxidant, analgesic, and inflammatory and antiseptic activity. Much of the interest to medical research lies within the ability of curcumin to counteract the generation and subsequent effects of ROS and nitrogen free radicals, typically manifesting from damaged cells. Curcumin can impose desirable effects upon multiple targets within the inflammatory cascade and its related signaling pathways [77] [Figure 6]. It has been also known that curcumin inactivates NF-κB, an important transcription factor regulating cellular activity, particularly with respect to stress and injury. NF-κB activation appears to be crucial in the relationship between inflammation and the development of cancer. Inactivation of NF-κB by curcumin in turn leads to reduced expression of COX-2 and down-regulation of cytokines including TNF and IL and a reduction in chemokines TNF-α and NO production consequently reducing tissue damage.[77]
Figure 6: The multi-targeted effects of curcumin on inflammatory mediaotors

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Curcumin's potent anti-oxidant and free-radical quenching properties play an important role in the inhibitory effects of the compound on the initial stages of carcinogenesis. Curcumin's inhibitory effect on carcinogenesis has been demonstrated in several animal models of various tumor types including oral cancer, mammary carcinoma and intestinal tumors.[78] It has been shown that curcumin has the ability to suppress UV irradiation-induced DNA mutagenesis.[78] In addition to the inhibitory effects on the production of NO and the ability to scavenge DNAdamaging superoxide radicals, curcumin also affects both the Phase I and Phase II enzymes of the hepatic cytochrome p450 enzyme system involved in the oxidation and detoxification of toxic substances. Curcumin has been shown to inhibit the Phase I enzymes (including cytochrome p450 isoforms and p450 reductase) which are induced in response to toxin exposure and create a host of carcinogenic metabolites that contribute to DNA adduct formation during the oxidation of such substances.[79] Conversely, curcumin induces the Phase II enzymes involved in detoxification of toxic metabolites (including GST, glutathione peroxidase and GR).[80]

Current molecular pathway based therapies in clinical trials for oral squamous cell carcinoma are documented in [Figure 7].[78] It has been known that platinum-based agents form the backbone of the standard chemotherapeutic regimens for oral cancer. Cisplatin (cis-diamminedichloroplatinum) is a widely used drug in the class of platinum-based chemotherapies (which also includes carboplatin and oxaliplatin). The platinum compounds work by the formation of DNA crosslinks within cells, leading to apoptosis and cellular senescence. The efficacy of cisplatin in squamous cell carcinoma is greatly increased when combined with other chemotherapeutic agents, such as taxanes (paclitaxel and docetaxel) and 5-fluorouracil. There is significant interest in potentially using curcumin as an adjuvant agent in combination with standard platinum-based chemotherapy for the treatment of malignant tumors. It was also reported that CAL27 and UMSCC-1 cell lines demonstrated an increased growth suppressive effect in cells treated with a combination of liposomal curcumin and cisplatin, both in vitro as well as in mouse xenograft tumor models.[78] Khafif et al. has also compared the effects of curcumin and single-dose radiation alone and in combination in the squamous cell carcinoma cell lines SCC-1, SCC-9, A431 and KB.In vitro growth suppression with either curcumin or radiation was observed in all the four cell lines, and the combination of both therapies resulted in an additive growth suppressive effect.[81]
Figure 7: Current molecular pathway based therapies in oral squamous cell carcinoma

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 > Conclusion Top


The World Health Organization has emphasized recently that early detection and prevention are major objectives for reducing oral cancer cases worldwide.[4] In India, oral cancer is a major health challenges for scientists, clinicians and policy makers.[82] It is well said, “Prevention is better than cure and prevention is cheaper than cure”. Currently, visual cytology-based techniques and biopsy are being used by clinicians to detect dysplasia and early stage of oral squamous cell carcinoma. These approaches are limited in their ability to judge the severities of the oral lesion and are useful only after the appearance of visual changes. Therefore, tradition cytological and biopsy techniques combined with inflammatory associated molecular signatures testing would be beneficial for the efficient early detection of oral dysplastic lesion and early stages of oral squamous cell carcinoma.


 > Acknowledgments Top


The authors would like to acknowledge the Gujarat Cancer Society and Directorate Medical Education and Research, Gujarat state for financial supports in various project related to the topic.

 
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  >Abstract>Introduction>Nuclear Factor K...>Vascular Endothe...>Interleukin-8 an...>Prostaglandin Mo...>P53 Expression a...>Nitric Oxide and...>Reactive Oxygen ...>Micornas as Medi...>Inhibition of Pr...>Conclusion>Acknowledgments>Article Figures>Article Tables
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