|Year : 2014 | Volume
| Issue : 4 | Page : 274-279
Role of cytokines in oral malignancies
Shabnam Unus, Sarangarajan Ramabadran, Preeti Lakshmi, Narasimham, Nandhini Gunasekaran, Rajkumar Krishnan
Department of Oral and Maxillofacial Pathology and Oral Microbiology, SRM Dental College, Ramapuram, Chennai, Tamil Nadu, India
|Date of Web Publication||20-Nov-2014|
Department of Oral and Maxillofacial Pathology and Oral Microbiology, SRM Dental College, Ramapuram - 600 089, Chennai, Tamil Nadu
Cytokines are nonstructural proteins, which act as molecular messengers in the movement of various inflammatory cells, as well as in inducing growth and regeneration in the surrounding microenvironment. The inflammatory cytokine network, which influences growth, proliferation, and differentiation of cells in normal health and healing has also been found to induce tumorigenesis and tumor progression. A detailed study of the role of cytokines in various cancers has brought out many facts regarding the mechanisms and sequence of events that has eventually led to cancer. A study of these cytokines in tumorigenesis will throw further light on its usefulness in early detection of oral cancer and its potential as a therapeutic target in cancer therapy.
Keywords: Cytokines, inflammation, tumorigenesis, tumour microenvironment
|How to cite this article:|
Unus S, Ramabadran S, Lakshmi P, Narasimham, Gunasekaran N, Krishnan R. Role of cytokines in oral malignancies. SRM J Res Dent Sci 2014;5:274-9
|How to cite this URL:|
Unus S, Ramabadran S, Lakshmi P, Narasimham, Gunasekaran N, Krishnan R. Role of cytokines in oral malignancies. SRM J Res Dent Sci [serial online] 2014 [cited 2020 Feb 18];5:274-9. Available from: http://www.srmjrds.in/text.asp?2014/5/4/274/145159
| Introduction|| |
Cytokines are small nonstructural proteins with their molecular weights ranging from 8 to 40,000 Daltons.  They are usually glycoproteins and have been initially called by various nomenclatures such as monokines, lymphokines, chemokines, etc. However, the term cytokine has been accepted to be the best descriptive. 
Cytokines act as molecular messengers that allow the immune cells to act in a co-ordinated and a self-limited way.  They help in the movement of inflammatory cells towards the site of inflammation as well as they have a growth-inducing influence on various surrounding cells in the microenvironment. Cytokines play an important role in tissue repair and healing in the areas of inflammation by triggering collagen synthesis and re-epithelization.  The various cytokines and their functions are enlisted in [Table 1] 
| Role of cytokine in health and diseases|| |
Inflammation is the vascular response of mammalian living tissue to injury. It is characterized by increased blood flow and vascular permeability along with the accumulation of fluid, production of inflammatory mediators such as cytokines and by the development of specific humoral and cellular immune responses to the pathogen(s) present at the site of tissue injury. This will lead to systemic body responses such as fever, hypotension, and synthesis of acute phase proteins, leukocytosis, and cachexia. Cytokines are main categories of soluble factors that mediate these responses. 
| Cytokines in acute inflammation|| |
Acute inflammation is a rapid and self-limiting process. There are several chemical mediators which are induced in a tightly regulated sequence, and immune cells move in and out of the affected area, destroying infectious agents, repairing damaged tissue, and initiating a specific and long-term response to the pathogen. Cytokines play key roles in mediating acute inflammatory reactions. The cytokines involved in early phase of acute inflammation are interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), IL-6, IL-11, IL-8, and granulocyte-macrophage colony stimulating factor (GM-CSF). Of these, IL-1 (α and β), IL-6 and TNF are extremely potent inflammatory molecules: They are the primary cytokines that mediate acute inflammation. 
| Cytokines in chronic inflammation|| |
Chronic inflammation may develop following acute inflammation and may last for weeks to months, or for years. During this phase of inflammation, cytokine interactions result in monocyte chemo-taxis to the site of inflammation where macrophage activating factors, such as interferon-g (IFN-g), monocyte chemoattractant protein-1 (MCP-1), and other molecules activate the macrophages, while migration inhibition factors, such as GM-CSF and IFN-γ, retain them at the inflammatory site.  These macrophages contribute to the inflammatory process by chronically elaborating low levels of IL-1 and TNF. The cytokines known to mediate chronic inflammatory processes can be divided into those participating in humoral inflammation, such as IL-4, IL-5, IL-6, IL-7, IL-13 and those contributing to cellular inflammation such as IL-1, IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, IFNs, transforming growth factor-β (TGF-β), TNF-α and-β.
| Cytokines in healing and regeneration|| |
Clearance of debris, foreign agents, and/or infectious organisms promotes resolution of inflammation, apoptosis, and the ensuing repair response that encompasses overlapping events involved in granulation tissue, angiogenesis, and re-epithelialization.  Keratinocyte proliferation is mediated by the local release of growth factors, with a parallel up-regulation of growth factor receptors, including TNF-α, epidermal growth factor (EGF), keratinocyte growth factor and TGF.
It is recently found out that TGF-β1 stimulates migration of keratinocytes, possibly by integrin regulation and/or provisional matrix deposition. TGF-β, and TGF-β2 are potent inhibitors of keratinocyte proliferation. TGF-β3 is required to down regulate TGF-β1 and TGF-β2. Once the contact is established with opposing keratinocytes, mitosis and migration stop, the cells differentiate into a stratified squamous epithelium above a newly generated basement membrane.  Granulation tissue forms below the epithelium and is composed of inflammatory cells, fibroblasts and newly, forming vessels. This initial restructuring of the damaged tissue serves as a temporary barrier against the hostile external environment, and is mainly aided by cytokines along with the other transductory signal molecules like vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). 
Cytokines play an important role in regulating fibroblast function, such as proliferation, migration and matrix synthesis, and it is the balance of these mediators that is likely to play a key role in regulating the initiation and progression of scarring in any fibrotic disease.  It has been shown that subcutaneous perfusion of TNF-α induces a local proliferation of fibroblasts, capillaries and epidermal cells, with a significant increase in hydroxyproline.  Other studies have shown that both IL-1β and TNF-α stimulate the collagenase synthesis. ,, However, Chou et al. 1996  have shown that TNF-α inhibits adherence and phagocytosis of collagen; thus suggesting that inhibition of the collagen phagocytic pathway may contribute to fibrosis.
| Cytokines at the cross roads of inflammation and malignancy|| |
Rudolf Virchow, the founder of cellular pathology, was the first to formulate an association between chronic inflammation and development of cancer in 1863. Nowadays it is generally accepted that up to 25% of human malignancies are related to chronic inflammation due to viral and bacterial infections. 
Cytokines play an important role in tissue repair and healing in the areas of inflammation by triggering collagen synthesis and re-epithelization.  Any dis-regulation in this process will cause persistence of inflammation leading to cancer. 
Based on the natural history of certain diseases and epidemiological studies, a strong association has been established between chronic inflammatory conditions and eventual tumor appearance.  According to Virchow's hypothesis, "inflammatory infiltrate might be the origin of cancer in sites of chronic inflammation, which include lymphocytes, macrophages and dendritic cells. 
According to Pryton Rous, cancer develops from "sub threshold neoplastic states" caused by viral/chemical carcinogens that induce somatic changes. These sub threshold changes (now referred as initiation), involve irreversible DNA alterations and can persist in otherwise normal tissue indefinitely until the occurrence of a second type of stimulation (now referred as promotion) which are induced by inflammatory cytokines, growth promoting factors or even chemical substances at the site of chronic inflammation. 
According to Mantovani et al.,  the connection between tumorigenesis and inflammation is mediated via intrinsic and extrinsic pathways. The intrinsic pathway is activated by genetic alterations. These alterations comprise mutation-driven proto-oncogene activation, chromo-somal rearrangement/amplification, and inactivation of tumor suppressor genes. Transformed cells secrete inflammatory mediators and thus generate an inflammatory microenvironment. The extrinsic pathway is driven by inflammation or infections that increases the risk for the development of cancer in organs. 
| Mechanism by which cytokines induce malignancies|| |
An inflammatory cytokine network may influence survival, growth, mutation, proliferation, differentiation, and movement of both tumor and stromal cells. Moreover, these cytokines can regulate communication between tumor and stromal cells, and tumor interactions with the extracellular matrix.
In the initial phase of tumor development, inflammatory mediators such as cytokines, reactive oxygen species, and reactive nitrogen species derived from tumor-infiltrating immune cells induce epigenetic alterations in premalignant lesions and silence tumor suppressor genes.  During tumor promotion, immune cells secrete cytokines and chemokines that act as survival and proliferation factors for malignant cells. The angiogenic switch is critical for an adequate supply of tumor cells with oxygen, nutrition, growth, and survival factors.  During tumor progression and metastasis, both tumor cells and immune cells produce cytokines and chemokines leading to an increase in cell survival, motility, and invasiveness. Epithelial-mesenchymal transition, a crucial process in tumor invasiveness and metastasis, is also promoted.
Mechanisms by which cytokines and chemokines may facilitate cancer growth, invasion and metastasis can be summarized as follows:
- DNA damage via reactive oxygen
- Inhibition of DNA repair via reactive oxygen
- Functional inactivation of tumor suppressor genes
- Autocrine/paracrine growth and survival factors for malignant cells
- Induction of vascular permeability and extravasation of fibrin/fibronectin
- Tissue remodeling via induction/activation of matrix metalloproteinases
- Control of tumor-cell migration, direct and indirect
- Control of leukocyte infiltrate
- Modulation of cell: Cell adhesion molecules
- Subversion of host immune responses
- Stimulation of angiogenesis and angiogenic factor production. 
| Cytokines and tumour microenvironment|| |
Interactions between malignant and nontransformed cells create the tumor microenvironment (TME). The nonmalignant cells of the TME have a dynamic and tumor-promoting function at all stages of carcinogenesis.  Intercellular communication between these cells is driven by cytokines, chemokines, growth factors, and matrix remodeling enzymes.
The inflammatory microenvironment of tumors is characterised by the presence of host leukocytes both in the supporting stroma and in tumor areas. Tumor infiltrating lymphocytes may contribute to cancer growth and spread, and to the immunosuppression associated with malignant disease. Macrophages are also found in considerable numbers in the tumor microenvironment.
With regards to macrophages and cancer two things are to be noted:
- Accumulation of macrophages in tissues of chronic inflammation apparently promotes cancer initiation and progression and
- A high density of tumor associated macrophages (TAMs) in tumor tissues often correlates with poor prognosis for cancer patients.
Experimental evidence indicates that depending on the stimuli, monocytes can differentiate into pro-inflammatory (M1) or antiinflammatory (M2) macrophages. TAMs resemble M2 macrophages and are generally thought to promote tumor progression due to their inability to induce T-cell activation along with their elevated expression of scavenger and mannose receptors and the release of pro-tumorigenic factors such as TGF-β1, IL-10, pro-angiogenic factors and MMPs. Moreover, elevated levels of IL-10 and TGF-β1 found in the tumor micro environment are believed to mediate a conversion from M1 to M2 macrophages. 
Tumour associated macrophages are required for tumor cell migration, invasion, and metastasis formation. TAMs promote the angiogenic switch, neovascularization as well as malignant transition of the tumor cells by secretion of specific proangiogenic factors (VEGF, IL-1β, TNF-α, angiogenin, semaphorin 4D), or indirectly through the release of MMP-9. 
| Cytokines in oral premalignant and malignant conditions|| |
The emergence of cytokines as a marker for detecting malignancies has made us realize the importance of inflammation-mediated carcinogenesis in oral premalignant disorders as well as in oral cancer. Within the oral cavity, the best example of inflammation mediated premalignant disorder is oral lichen planus (OLP). Chronic trauma in the oral cavity were also associated with oral carcinogenesis in some recent studies and case reports.
Brailo et al. 2012  reported increased levels of IL-6 and TNF-α in patients with cancer and premalignant lesions such as OLP and oral submucous fibrosis. Increased salivary IL-6 and TNF-alpha might play a certain role in oral leukoplakia. Pekiner et al. 2012  found higher serum levels of IL-10 and low serum IL-2 levels in patients with OLP and concluded that, OLP could be a result of a delayed type hypersensitivity. Liu et al. 2014  in his study found out that, OLP patient showed high-level IL-4 expression profile in both serum and saliva. Serum IL-4 level in the erythematous/ulcerative group was significantly higher than that in the reticular group. Serum levels of IL-4 were significantly and positively correlated with the salivary levels. These results provide more evidence for cytokine-predominant immune imbalance in OLP, as well as the potential of IL-4 as the biomarker for monitoring severity of OLP.
Haque et al. 2000  demonstrated increased levels of proinflammatory cytokines in patients with OSF, which may be central to the pathogenesis of OSMF. OSMF is a chronic fibrotic disease which in early stages is accompanied by chronic inflammation. IL-1β is a pro inflammatory cytokine and susceptibility of individuals to OSMF may be related to cytokines. IL-1β is known to promote fibroblastic growth activity and in addition, IL-1β also potentiates collagen synthesis.  This collagen synthesis contributes to fibrosis. These are the plausible reasons for increased levels of IL-1β in patients of oral submucous fibrosis. Khan et al. 2012  data advocates that TGF-β induced in the epithelium by areca nut acts on the fibroblasts in a pro fibrogenic manner by the induction of matrix components such as collagens. Areca nut has minimal influence on fibroblasts, it synergizes with TGF-β in activating fibroblast cells. This is very important in the context of OSF manifestation in susceptible individuals.
Tumor necrosis factor-α, a widely expressed pro-inflammatory cytokine is known to play an important role in inflammation, angiogenesis, programmed cell death, and proliferation, which are all crucial components in oral cancers.  This increase in the levels of TNF-α in potentially premalignant oral disorders and oral cancers makes it an attractive biomarker. This in turn could be quantitatively measured to detect the presence or absence of cancers and identify disorders that have high risk for transformation to malignant conditions. Rhodus et al. 2005  showed that TNF-α, IL-1α, IL-6, and IL-8 were elevated in the whole unstimulated saliva of subjects with OSCC compared with premalignant lesions and controls Gokhale et al., 2005,  showed that serum IL-8 concentrations were consistently elevated in patients with local/regional recurrent or metastatic disease and a small fraction of OSCC patients with newly diagnosed, localized disease compared to controls and that IL-8 may therefore be considered as potential marker for OSCC. IL-8 up-regulation can induce tumor cell proliferation, angiogenesis and cancer cell migration and can attract inflammatory cell infiltration, which in turn, produces a variety of factors that promote tumor angiogenesis and tumor growth. Endogenous expression of IL-8 has since been found in various human cancers.
SahebJamee et al. 2008  compared the concentration of TNF-α, IL-1α, IL-6, and IL-8 in the saliva of oral squamous cell carcinoma patients with control group and found the concentration of salivary IL-6 in oral squamous cell carcinoma patients was higher than control group. He concluded that cytokines can be used in prediction or diagnosis of oral squamous cell carcinoma. The mechanism by which IL-6 contributes to or reflects cancer progression and biology is likely due to its dual effects on tumor initiation by paracrine or autocrine mechanisms and to its additional inhibitory effects on the immune response directed against the tumor.  IL-6 inhibits dendritic cell differentiation, thus inducing immune tolerance of tumors and facilitating metastatic spread. The source of IL-6 in cancer patient's sera has been shown predominately to emanate from the tumor itself. 
It is well documented that monocyte functional abnormalities and impaired cellular immunity are frequent and early characteristics of patients with OSCC. , An interesting hypothesis is raised, which proposes that IL-6 secretion from both tumor and monocytes in the TME results in an immune-tolerant situation that allows the tumor to thrive. Yamamoto et al. 1994  examined the role of various cytokines in serum of few known oral disorders like OSCC, OLP etc. They found a significant variation in serum IL-6 of OSCC patients before and after treatment. Vucicevic Boras et al.  2005 evaluated the levels of IL-6 in saliva and serum of patients with OSCC. Elevated levels of salivary IL-6 in patients with OSCC when compared to the healthy controls were found. They concluded that higher levels of salivary IL-6 in patients with OSCC might originate from the local production, probably from carcinoma cells.
Chen et al. in 1999  surveyed the expression of 14 cytokines important in the regulation of immune, inflammatory, and angiogenesis responses in well-defined and freshly cultured Head and neck squamous cell carcinoma (HNSCC) lines to detect whether these cytokines are expressed and detected in the local tumor environment and systemically. They reported that cytokines IL-1α, IL-6, IL-8, GM-CSF, VEGF, and basic FGF were expressed in tumor cell lines and these cytokines have role in proinflammatory and proangiogenic responses detected in cancer cell lines.
Jeng et al. 2003  suggested that keratinocyte inflammation is crucial for the pathogenesis of cancer and tissue fibrosis. Their study results indicated that betel quid chewing contributes to the pathogenesis of cancer and OSF by impairing T cell activation and by induction of prostaglandin-E2, TNF-α and IL-6 production, which affect oral mucosal inflammation and growth of OMF and oral epithelial cells. Jablonska et al. 1997  who studied the levels of IL-1β, IL-6, TNF, sTNF-R1 and CRP in patients with oral cancer, leukoplakia. The levels IL-1β was significantly increased in serum of patients of OSCC and leukoplakia than in controls.
Kamatani et al. 2013  showed that IL-1 beta was released from cultured OSCC cells, and it may be useful for detection of early stage OSCC. IL-1 generated by tumor cells can affect the malignant cells in an autocrine or paracrine manner, promoting the proliferation and invasiveness. IL-1 secreted by malignant cells activates microenvironment residing or infiltrating cells to produce additional IL-1, which induces the cytokine network, which results in further activation of tumor invasiveness. High levels of IL-1 at tumor sites would be expected to promote invasive potential and immunosuppression. When immunosuppression is evident at tumor sites, it hinders the development or masks the function of antitumor immunity and thus invasive growth results.
Woods et al. 1998  investigated the elaboration of IL-1α, IL-1β, IL-2, IL-4, IL-6, IFN-g, TGF-β and TNF-α mRNA in eight cell lines derived from invasive head and neck primary tumors or their metastasis. TGF-α mRNAs and IL-1α was expressed in every SCC cell line, and IL-1β and TGF-β mRNAs by all but one, IL-4 and IL-6 mRNA expression varied among all cell lines. They performed IHC analysis with IL-1β, IL-α, IL-6 on specimen from 12 patients with invasive HNSCC. They demonstrated intracellular IL-1, IL-6 in all cases of invasive SCC they concluded that aberrant elaboration of IL-1, IL-6 will lead to altered immune status in these patients.
Katakura et al. 2007  compared the level of IL-1β, IL-6 and IL-8 and osteopontin from saliva of patients with oral cancer. It was seen that the salivary levels of all cytokines were higher in patients with oral cancer as compared to that of healthy controls and suggested that cytokines may be used as a potential tool for screening oral cancer.
Understanding the cancer-specific cytokines produced locally is gaining response, since immunotherapy is often directed towards altering these cytokine expressions. , The cancer-specific and histology-independent uniform cytokine cascade is one of the manifestations of the underlying para-neoplastic systemic disease, and this hypothesis links the stage of cancer with both the functional status of the immune system and the patient's prognosis. Neutralization of this cytokine pattern could offer novel and hitherto unexplored treatment approaches for cancer. ,
| Conclusion|| |
Imbalance of cytokine networks has been implicated in the pathogenesis of various malignancies. , Their pleiotropic functions and propensity for synergistic interactions and functional redundancy render them as intriguing therapeutic targets. Cancer-related cytokines have emerged as one of the hall-marks of cancer.  Among them, TNF, IL-1, IL-6 and IL-8 act as crucial mediators of inflammation-driven tumorigenesis. Thus far then, the results of a number of studies would indicate that cytokine levels are very likely to provide useful information about the presence of disease, epithelial behavior, the local inflammatory response, and carcinogenesis. Cytokines as a screening tool for oral cancer is being pursued by several researchers, the results of which are eagerly awaited as this is likely to have a profound impact on the early detection of oral cancer, potentially resulting in early treatment and a decrease in the high levels of morbidity and mortality associated with OSCC. , Furthermore, there are indications that it may be possible to utilize our enhanced understanding of the cytokines associated with disease progression, metastases, and bone invasion to develop novel methods for the treatment of oral cancer. 
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