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Inflammation is the immediate response of immune system to tissue injury and infections. This is the only mechanism to repair damaged tissue and is tightly regulated process and unresolved inflammation leads to several disorders. This review mainly focuses on the chronic inflammation induced tumerigenesis.
Inflammation is a 1st line of defence mechanism that is broadly defined as a nonspecific response to tissue malfunction and it acts to eliminate the pathogenic intruder and help repairing the damaged tissue. The distinctive feature of inflammatory responses is that damage to the host is unavoidable. It is beneficial to the host in short term and detrimental if it is not regulated. A large set of diseases have cellular and molecular evidence for inflammation. These include chronic arterial and venous disease (Ross R. 1999, Schmid-Sch onbein GW,2001), myocardial ischemia (Entman ML, 1991), acute cerebral stroke and Alzheimer's chronic disease (Jean WC,1998), and more recently cancer (Karin M,2005; Philip M,2004). It is the only known mechanism for tissue repair post injury.
What is inflammation?
Inflammation is a biological immune reaction in response to disrupted tissue homeostasis (Medzhitov 2008). Infection by microbial invaders is often thought to be the major culprit that promotes inflammatory responses. However, injury or trauma and exposure to foreign particles are also potent activators of inflammation, suggesting that this response evolved as a general adaptation mechanism for coping with damaged or malfunctioning tissue (Matzinger 2002). The primary function of inflammation is to rapidly destroy or isolate the underlying source of the disturbance, remove the damaged tissue, and then restore tissue homeostasis (Medzhitov 2008, Soehnlein & Lindbon 2010). It is the only known mechanism for tissue repair post injury.
Molecular mechanism of inflammation:
Inflammation consists of four components such as inflammatory inducers, sensors , mediators and finally the target tissue which are affected by mediators of inflammation. The 1st step of inflammation involves, the recognition of inflammatory inducer such as DAMPS or alarmins which are components from damaged tissue and PAMPS which are molecules present on the pathogen surface are recognized by sensors such as TLRs and the intracellular NOD-like receptors (NLRS) (Lange et al. 2001, Proell et al. 2008). Activation of the TLR signaling pathway results in the activation of NF-kB (Ghosh et al. 1998). NF-kB expression induces the expression of pro inflammatory cytokines such as IL-6, interleukin-1-beta (IL-1Î²), tumor necrosis factor-alpha (TNF-Î±), and other chemokines which are mediators and mediates further recruitment of leukocytes such as neutrophils and monocytes to the site of injury. Then recruited neutrophils release noxious chemicals such as ROS and RNS and various proteinases from cytoplasmic granules via degranulation process. The molecules are very toxic and cause destruction of both the host and the pathogen and essentially remove microbial disturbance (Nathan 2002). The produced pro inflammatory cytokines further suppress cell death and promote epithelial cell proliferation. Infiltrated monocytes and neutrophils secretes VEGF to induce neovascularisation (Lewis et al., 2000), which provides neutrients and oxygen to the remodelled tissue (Bao et al., 2009). These immune responses can be further modulated by adaptive immune system components such as lymphocytes. T lymphocytes play a key role in the modulation of inflammation under pro-inflammatory cytokine milieu thereby causing inflammation associated chronic disorders. The critical step in the control of inflammation is its resolution phase which depends on several anti inflammatory mediators such as IL10, TGFÎ², lipoxins and prostaglandins (1,14). These molecules mainly impart regulation of inflammation (1,14). The resolution of inflammation also requires the apoptosis of leukocytes and phagocytic clearance by local macrophages. This process of phagocytic clearance is intimately linked to the down-regulation of macrophage activation and promotes the release of other anti-inflammatory mediators such as TGF-b. In this process macrophage migration through the lymphatics (17) results in the presentation of antigen to lymphocytes in the lymphatics and makes potent protective immune responses. Inflammation associated with wound healing is usually self-limiting and the disregulation of endogenous anti-inflammatory mechanisms (1) and defective resolution phase or the persistence of an inflammatory stimulus can lead to chronic inflammation and its associated abnormalities and this is the case in some of the tumorigenesis processes.
Evidence linking chronic inflammatory response with cancer:
In 1863, Rudolf Virchow observed the presence of leukocytes in transformed tumor tissue and he was the 1st person to provide the link between cancer and inflammation. Nearly about 10 years there were no evidence on inflammation role in cancer. In the 19th century, clinical studies provided evidence that most of the tumors arose at the chronic inflammatory site and substantiated this finding with observation of inflammatory cells in tumor samples (Balkwill, F. & Mantovani,2001). Studies using animal models provided further evidence for the role of inflammation in the carcinogenesis. Clinical studies regarding the use of aspirin and non steroidal anti inflammatory drugs in humans suggested a strong relationship between chronic inflammation and cancer. About 20% of deaths from cancers were reported to be associated with infections and inflammation. Inflammation plays a crucial role in the development of cancer and inflammatory environment is essential for its progression (Mantovani et al., 2008). The association of inflammation with infections increases the risk of cancer. Inflammatory bowel disease which is a result of chronic intestinal inflammation due to pathological immune response to gut flora causes increases the susceptibility to colorectal cancer. IBD patients are also susceptible to various other types of cancers like hepatocarcinoma, lymphoma, leukemia and a number of other tumors (Bernstein CN, 2001). Other than infection induced inflammation associated cancers, tumors can be caused by chronic inflammation triggered as a result of tissue damage brought about by irradiation, mechanical (Wall BM, 2001) and chemical agents (Ameille J, 2011) or genetic defects (Rebours V, 2009). Obesity triggered inflammation also increases the risk of cancers (Takahashi et al, 2010). DNA damge due to chemical carcinogen DEN leads necrotic cell death which results in the chronic inflammation induced tumorigenesis of hepato cellular carcinoma. During necrotic cell death, DAMPs or alarmins such as HMGB1 and ATP released and activate TLR4 and stimulates the release of proinflammatory cytokines which causes chronic inflammation which consequently induces tumorigenesis (Maeda et al., 2005; Sakurai et al., 2008). Chronic inflammation also increases the risk of lymphomas and leukemia (Chiorazzi et al., 2005). The inflammatory trigger for this beneficial response is also the cause of necrotic death of cancer cells, resulting in the release of HMG-B1 and ATP, which together activate TLR4 and the inflammasome to stimulate the production of IL-1b, which is critical for adaptive antitumor immunity (Ghiringhelli et al., 2009). Based on all these evidences, inflammation has added as a 7th hall mark in the list os hall marks of cancer (1,2).
Inflammation in tumorigenesis:
If wound occurs repeatedly, inflammation fails to resolve, which resulting in the deregulation of tissue repair. The unrepaired wound or in exposure to carcinogen, leads to transformation of tumor. Inflammation not only important in the tumorigenesis, but also in each step of cancer development such as tomor promotion, progression and metastasis to other organs ((DeNardo et al., 2009; Luo et al., 2007). Tumor also creates inflammatory environment for its progression and metastasis (Kim et al., 2009; Luo et al., 2007). The molecules released from necrotic cell death due to local tissue injury are the initial triggers of chronic inflammation; thereby play a roli in tumor initiatio as well as tumor progression.Initial triggers of injury-induced inflammation, necrotic cell death is of particular importance. Link local injury and cell death to induction of inflammation and cytokine production and can thereby impact tumor initiation as well as early tumor promotion. Exposure to environmental toxins such as asbestos, tobacco smoke and silica particals cause death of lung epithelium and thereby chronic inflammation (Dostert et al., 2008) and lung cancer ((Takahashi et al., 2010) by inducing oncogene ativation.DEN exposure induced cell death associated chronic inflammation also impart in hepato carcinoma. Lipid accumulation in the hepatocytes of fatty liver patients causes cell death and chronic inflammation and induces tumor formation in combination with toxic stimuli (Tuncman et al., 2006).DAMPS are the cellular components released during necrotic cell death are HMGB1, DNA, RNA, ATP and s100A8 and A9 molecules (Ghir-inghelli et al., 2009; Sakurai et al., 2008) and are recognised by and activate macrophages and DC and also mediate leukocyte infiltration to that particular site of tissue damage ((Zitvogel et al., 2010).
Experimental evidence suggests that chronic inflammation has effect on all stages of cancer. The connection between inflammation and cancer can be explained as 2 pathways: extrinsic and intrinsic path ways. The inflammation associated with cancer initiation is defined as intrinsic when the mechanisms that are involved in cell transformation, most typically oncogene over expression or mutation, are also responsible for the activation of a pro-inflammatory program. By contrast, extrinsic inflammation is activated by the tissue's response to the malignant cells, and it is most prominently mediated by the infiltrating inflammatory cells (Allavena P,2008). DNA damage, Oncogene activation (Mantovani et al., 2008), inactivation of tumor suppressor p53 (Komarova et al., 2005) lead to the tumor promoting pro-inflammatory cytokines which can further increase the cancer risk. Hepatocellular carcinoma is developed mainly due to chronic inflammation induced by injury and necrotic cell death and chronic alcohol consumption, viral infections, or exposure to environmental toxins (El-Serag and Rudolph,2007. Inflammatory responses are also necessary for the induction, promotion and development of skin cancer upon repetitive exposure to UV radiation and toxic chemicals cause skin injury, cell death which results in the tumor promoting chronic inflammation (Rudolph and Zelac, 2004). In case of prostate cancer, inflammatory leukocytes such as macrophage secreted IL-1 converts an drogen-receptor antagonist into an agonist which can t stimulates onco genes transcription. Chronic inflammation triggered by the colonic irritant dextran sodium sulfate (DSS) may induce DNA damage that gives rise to colitis and then colonic adenomas (Meira et al., 2008). Chronic inflammation can affect all stages of cancer such as cancer intiation, promotion and progression and metastasis. The inflammatory environment, which consists of an increase in cytokines, chemokines and reactive oxygen and nitrogen species, results in DNA mutations, epigenetic changes and genomic instability that can contribute to tumor initiation (Karin and Greten, 2005, Hahn,M.A. et al. 2008). Chronic inflammation promotes onset of cancer and development through
the production of reactive oxygen species (ROS) and RNS, which cause DNA damage and DNA mutations that contribute to genetic instability and the malignant cell proliferation (2)
the production of proinflammatory cytokines which enhance prolipheration of altered cells and inhibt apoptosis and positive feedback effect on the generation of ROS.
the production of angiogenic factors such as VEGF, which can promote neovascularisation of tumor (7)
the production of matrix metalloproteases, which can promote invasion and metastasis (8).
It can causes dysfunctioning of cell-mediated antitumor immunity (9).
Components of inflammation induced tumorigenesis:
Reactive oxygen species:
No one single mutation is sufficient to transform cells, it has been suggested that an inflammatory microenvironment can be capable of increasing mutation rates, in addition to enhancing the proliferation of mutated cells. Activated inflammatory cells serve as sources of reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI) that are capable of inducing DNA damage and genomic instability. ROS cause DNA damage which results in the activation of oncogenes and instability of the genome. Nitrous Oxide (NO) leads to cancer associated inflammation by means of inactivating DNA repair machinery (M. Jaiswal, 2000)). ROS and RNS can cause inactivation of tumor suppressor genes (W. Hu, Z. Feng, 2002) and also inactivate retinoblastoma protein in case of colon cancer (L. Ying, 2007). ROS can cause necrotic cell death there by increasing the risk of inflammation and inflammation associated cancers (M.C. Chang,2007, B. Halliwell,2007).
Key cytokines in the inflammation induced tumorigenesis:
Cytokines consists of both pro-inflammatory and anti inflammatory properties. Most of the cytokines produced during inflammation are proinflammatory cytokines. The balance between these two types of cytokines have an important role in inflammation associated tumorigenesis (Lin,W.W, 2007).
The pro-inflammatory cytokine tumor necrosis factor-a (TNF-a) is a key player in chronic inflammation. TNF-Î± is important in cancer as it acts as a tumor initiator by stimulating the production of ROS and RNS that lead to DNA damage and mutations,which promote tumors by promoting cell proliferation and reduced cell death (Di Girolamo et al., 1997; Szlosarek et al., 2006).
IL-6 is another major pro-inflammatory cytokine that participates in inflammation associated tumorigenesis [S. Rose-John,2007] and regulates the expression of genes involved in cell cycle progression and supression of apoptosis, via the JAK-STAT signaling pathway . lL6 is important in colitis associated colorectal cancer development by promoting the survival of the neoplastic colon epithelial cells ((Bollrath et al., 2009)10,30,31,50,51). It also plays a role in promoting growth and tumorigenesis of cancer cells through altering the epigenome and promotes colon tumorigenesis through DNA methyltransferase 1 (DNMT1)-mediated tumor suppressor gene silencing (53). Clinical evidences suggested that its increased level has been associated with pathogenesis of various cancers [W. Cozen, P.S2004; H. Kai, Y 2005; M.R. Schneider, 2000].
TNF-Î± along with IL-6 contributes to obesity-mediated inflammation induced tumorigenesis and cancer promotion in HCC (Park et al., 2010) and IL6 deficient showed reduced risk of HCC in response to the chemical procarcinogen DEN, and the increased production of IL-6 accounts for the much higher HCC load in males (Naugler et al., 2007).
A number of oncoproteins (Ras, Myc, RET) are known to activate signaling pathways leading to the production of proinflammatory cytokines and chemokines (IL-6, IL-8, IL-1b, CCL2, CCL20) (Mantovani et al., 2008). IL-6 is of particular importance, as it acts both in paracrine and autocrine manners, IL-6-deficient mice are resistant to induction of multiple myeloma (Hodge et al., 2005).
IL17 is a pro-inflammatory cytokine produced by TH17 subtype of T cells has recently been recognized as a key player in inflammation and cancer [W.W. Lin, M,2007]. The role of IL-17 in inflammation-associated cancer is in tumor intiation and angiogenesis. Number of studies provided evidence for the increased levels of IL-17-in different types of cancers such as HCC [E. Tartour, F 1999;], human non-small cell lung cancer [M. Numasaki, 2005], fibrosarcoma [M. Numasaki, J, 2003].
Key transcription factors in inflammation induced tumerigenesis:
Inflammatory mediators activate oncogenic transcription factors such as NF-kB and STAT3, both of which play critical roles in linking inflammation and carcinogenesis. Constitutively induced aberrant NF-kB activation aid in a variety of inflammatory diseases, asthma, including rheumatoid arthritis, atherosclerosis, inflammatory bowel disease (135, 136).The transcription factor NF-kB is triggered in response to infectious agents and pro-inflammatory cytokines, resulting in the altered expression of many genes, which ultimately provides an environment that can promote tumorigenesis if an immune response is uncontrolled (65). It has a mojor role in linking inflammation to cancer because of proinflammatory cytokines, such as IL-6 and TNF-a (134) and MMPs, COX-2, and iNOS (130). NF-nB plays role in tumor development by stimulating cell proliferation via inducing the expression of proto onco genes such as c-Myc and growth factor genes, and cyclin D1 (128,147, 148) and inhibit tumor suppressor genes and it also contribute to genomic instability by promoting the roduction of reactive oxygen species, which have a potential to cause DNA damage andmutations (128) and its the antiapoptotic activity prevents mutated pretumorigenic cells to be eliminated (128).
The transcription factor STAT3 is induced by many cytokines, including IL-6, and by growth factors, such as epidermal growth factor (68,69). Active STAT3 is increased during inflammation and is constitutively activated in many cancers., in a mouse model of colitis, IL-6 activated STAT3 to promote tumorigenesis. The critical role of STAT3 in this process was demonstrated by inhibiting STAT3 in the intestinal epithelial cells, which resulted in inhibition of CAC induction and growth (31, 65). SOCS3, an inhibitor of STAT3 that is itself regulated by DNA methylation, provides an additional layer of regulation to this transcription factor. If the DNA methylation pattern of SOCS3 is altered, persistent activation of STAT3 can also result (51,70). Therefore, the transcription factors NF-kB and STAT3, which are activated during inflammation, provide key links between inflammation and cancer.
Cells in inflammation induced tumerigenesis:
Tumour associated macrophages accounts for the major components of infiltrated leukocytes (Mantovani A, 1992) and are an important source of pro-inflammatory cytokines and further facilitate the leukocyte infiltration and chronic inflammation, there by promoting cancer progression. They also secrete pro-angiogenic factor vascular endothelial growth factor (VEGF) and promotes neo vascularisation and metastasis also. Neutrophils and mast cells also infiltrate the tumor tissue. Neutrophils are the major cell types responsible for generating a chronic inflammatory microenvironment by producing ROS and RNS and proteolytic enzymes.
Myeloid derived dendritic suppressor cells (MDSC):
MDSC are immature myeloid cells which are precursors of DC, macrophages and granulocytes. Clinical evidence suggested that the number of myeloid derived suppressor cells (MDSC), which are CD1b/Gr-1 double positive cells in mice, is increased in cancer patients and tumor bearing mice [47,48,49,50].
MDSC are considered a major contributor to the profound immune dysfunction of most patients with sizable tumor burdens (26). The pro inflammatory cytokines such as IL-6 (81), IL-1 (79, 80)) and the bioactive PGE2 (44) are known to be induce accumulation of MDSC in the inflammatory site.
MDSC suppress T cell activation by multiple mechanisms. Because they are rich in intra cellular arginine levels, thy uptake arginine from surroundings which is an essential amino acid for T cell activation and there by suppress anti tumor activity of T celss (42, 45, 74).
They inhibit major anti tumor activity containing cells such as CD8+ cells by nitration of their TCR, there by these T cells cannot recognize MHC peptide complexes (57)
They also inhibit T cell infiltration of anti tumor T cells in tumor sites . The down regulation of MDSC in IL-17R-/- mice leads to increase of CD8+T cells in the inflamed skin. MDSC down-regulate L-selectin (CD62L), which are necessary for homing of naÃ¯ve T cells to lymph nodes and so that they can not encounter tumor antigen and can not get activated (E. M. Hanson, V. K. Clements).
Chronic inflammation in the tumor environment promotes tumor progression (6, 7) and the major inflammatory cells found in the chronic inflammation are TH17 cells. Increased levels of IL-17 and IL-17 producing T cells have observed in human and animal tumors [14,16,36]. IL17 is a one of the key components of inflammation induced carcinogenesis and IL17R-/- mice are resistant to chemical carcinogen induced cutaneo us cancer and leads to increased infiltration of anti tumorigenic CD8+ T cells. IL17 is a key pro-inflammatory cytokine impart in number of autoimmune diseases and inflammation associated diseases (12,13) and their increased levels were detected in cancer patients (14,15) and involved in tumor development and promotion (14,16,17,18). Exposure to mutagen DMBA and inflammation inducing TPA causes skin cancer. IL-23, a stimulatory cytokine for IL-17 production, promotes DMAB/TPA induced carcinogenesis  whereas it is inhibited in IL-17-/- mice . In experimental animals of induced inflammation models, IL17 levels were increased and IL17 mediated inflammation has tumor promoting effects (18, 36). In IL17R deficient mice, CD8+ levels were increased in infiltrates and inhibits tumor promoting inflammation. These CD8+ T cells have anti tumorigenic property and play role in the prevention of tumor development. IL-17R-/-mice, which is associated with significantly reduced leukocyte infiltrations and levels of IL-1band TNF-a. deficiency in either IL-1bor TNF-asuppresses the development of chemical induced skin carcinogenesis [23,24]. Pre-inflammation in the skin increases the susceptibility to tumors, which are rich in TH17 cells (He et al., 2012).
Tregs in cancer:
One study in a mouse tumor model demonstrated that upto 30% of Tregs located at the tumor site utilize the perforin/granzyme B pathway for suppressing antitumor responses suggesting a tumor driven induction of cytolytic Tregs (Caoet al., 2007). In another recent study, Wilms Tumor 1 (WT1) specific Treg clones from leukemia patients, upregulated granzyme B upon peptide stimulation. These cells had an nTreg-like phenotype and induced cytolysis of APCs (Leheet al., 2008). According to the concept of "immunoediting,", multiple factors generated during oncogenesis counteract the immune system, cumulatively hindering an efficient immune response and facilitating the "tumor escape" (Dunnet al., 2002). Tregs are the major cell types that can modulate immune responses in the tumor environment. These cells constitutively expressed CTLA-4 and exhibited suppressive effects by inhibiting the proliferation of conventional T cells and IFN- production. Tregs are associated with immunosuppression and anti-inflammatory activity. Under certain pro-inflammatory conditions, characterized by elevated levels of IL-6, IL-1, IL-23, and lactic acid, Tregs can switch from being anti to pro-inflammatory, IL-17 producing cells. Thus, Treg populations with contradictory functions can coexist at elevated levels in the same tumor tissue. One hypothesis is that functionally reversed Tregs may contribute to the increased risk of cancer associated inflammation at an early stage and subsequently during the progression of the disease.
Molecular mechanisms of inflammation induced tumorigenesis:
The best known epigenetic modification is DNA methylation which stops the expression of genes. Stephen Baylin was the 1st person to be noticed that the methylation of DNA regions in the cancer and hypothesized that mostly tumor suppressor genes may have this modification and its activity should decrease as in the case of gene mutation. Inflammation has been linked to increased DNA methylation.during the process of inflammation; the balance between pro and anti tumerigenic inflammatory responses decides the fate of the cell. Recent evidences suggested that inflammation can affect all the 3 stages of cancer such as cancer initiation, promotion and progression.tumor initiation is the process in which normal cell becomes premalignant. Chronic inflammatory environment consista of high amount of proinflammatory cytokines, chemokines ROS,RNS which results in the DNA damage, mutation, epigenetic changes and ultimately genomic instability that leads to transformation of cell (Grivennikov,S.I 2010; Hahn,M.A. 2008). Tumor promotion is process of genetically altered cell proliferation and chronic inflammation promotes this stage by providing prosurvival signal and inhibiting apoptosis signals in the genetically altered cells. the same mechanism help in angiogenesis process also (Karin,M 2005; Grivennikov,S, 2009; Popivanova,B.K , 2008; Kujawski,M , 2008). The 3rd stage, tumor progression and metastasis which involves increased size of tumors which will get additional genetic changes and the tumors start spreading from primary site of tumor orgin to the multiple regions of the body is also influence by chronic inflammation.
Cytokine balance between proinflammatory and anti inflammatory cytokines levels have essential role in inflammation associated tumorigenesis.
TNF: a key player in the chronic inflammation and acts as intiator of cancer by promoting the ROS production leads to DNA damage and instability by inducing mutation.
IL6: IL6 plays role in caner initiation and promotion by stimulating epigenome alterations. It promotes colon cancer by DNMT1 mediated tumor suppressor gene silencing (Foran,E. 2010). All of these inflammatory mediators stimulate NFkB and STAT3 signalling cascades which play role in the oncogenic gene transcription, there by linking inflammation with tumorigenesis. STAT3 is a transcription factor induced by cytokines such as IL6 and EGF (Zhong,Z, 1994; Heinrich,P.C, 1998). Activation of STAT3 increased during inflammation and its constitutive activation is in the most of the cancer types. In colon cancers, IL6 levels are more and sufficient to stimulate constitutive STAT3 activation which promotes tumorigenesis. These two factors such as NFkB and STAT3 also provide link between inflammation and cancer. Correlation of methylation status of the genes in inflammation and malignant transformation initiation provides evidence that epigenet modifications have role in the inflammation induced tumerigenesis (Hahn,M.A, 2008; Wehbe,H, 2006; Issa,J.P, 2001: Maekita,T., 2009; Alvarez,H, 2011). This was proved by a mice model of colitis and these methylation patterns were mostly at PCG targeted genes. In human cell line model and a mice model of colitis, the oxidative stress induced DNA damage and subsequent recruitment of DNMT1 to the damaged DNA and recruits other proteins and form repressive complex which then relocalized to the CpG rich region causing methylation (O'Hagan,H.M, 2004). In colitis induced colorectal cancer, the pro inflammatory cytokine signalling stabilizes DNMT1 which methylates promoters of tumor suppressor genes which results in the neoplastic cell phenotype and this inflammation induced methylation patterns are targeted to particular genes. Baylin group showed that ROS DNA methylation at promoters by DNMT1 and which causes relocalisation of repressive protein complexes and recruit a repressive protein HDAC such as SIRT1 which inturn recruits PCG complex proteins on to the CpG methylated region and PCG complex causes H3K27 trimeethylation and complete shutdown of genes (Heather M, 2011). Studies suggesting that DNA methylation during inflammation provided protective mechanism for epithelium but prolonged exposure to proinflammatory mediators cause malignant transformation of epithelium.
miRNA as a mediators of inflammation induced tumorigenesis:
miRNAs are small non coding RNAs and are 20-23 nucleotides in length and are involved in the regulation of transcription and translation of targeted genes. In 1993, the 1st miRNA discovered was lin-4 in C.elegans and is involved in the regulation of developmental timing and cell fate specification. miRNA expression can be induced by different mechanisms. Inflammation also has role in the induction of miRNA expression by immune cells as well as non immune cells. In inflammatory diseases like eczema, allergic diseases such as lung inflammation, inflammatory cytokine milieu increased the expression of mi21. miRNA 21 expression has also found in the colitis associated colorectal cancer. Studies provided evidence for the role of miRNAs in cancer also. Over expression in cancer model studies suggested that over expression of single miRNA155 can cause B cell tumors (Costinean,S, 2006) and over expression of let-7 reduces lung tumors (Esquela-Kerscher,A, 2008). This indicates alteration in the miRNA expression has role in the carcinogenesis. Genome wide analysis provided evidence for the some of the common oncogenic miRNA such as miR-17-5p, miR 21, miR-155, miR-20a, miR 92 and miR 106 (Iorio,M.V,2005; Lu,J.et al, 2005; Volinia,S,2006). This indicates that miRNA expression is specific to tumors and can be used as markers to detect that what kind of tumor it is. Inflammatory stimuli can alter the expression of miRNAs which are having tumor suppressor and oncogenic activity, this evidence suggest that miRNA might be mediators of inflammation induced tumorigenesis. Proinflammatory cytokines such as IL6 signaling activates STAT3 which induce the expression of miR21 (Mitchell,P.S, 2008) and their levels elevated in colitis (Wu,F.et al,2008) also which might be the reason for colitis patients are more prominent to colorectal cancer. miR - 21 targets number of tumor suppressor genes and over expression of miRNA can increase the proliferation of cells and inhibit apoptosis and its down regulated levels cause regression of tumors (Si,M.L, et al.2007). Another most important miRNA produced during inflammatory stimuli is miR - 155 (Faraoni,I, 2009). Its expression is under the control of two pro inflammatory cytokines such as TNFÎ± and IFNÎ² (O'Connell,R.M, 2007; Tili,E,2007). This miR - 155 targets SOC1 and reduces its functions that results in the nitric oxide synthase 2 expression (NOD2). miR- 155 also targets tumor P53 induced nuclear protein 1 and suppress the tumor suppressor function. All these functions lead to miR - 155 is a potent inflammation induced tumorigenesis, the best example is colitis associated colorectal cancer. Another miRNA induced during proinflammatory stimuli is miR - 146 which levels also increased in tumors.
Introduction: clinical data have provided evidence for strong association between chronic tissue injury and subsequent cancer initiation at the same time. For example liver injury due to alcohol abuse cause increased risk of hepato cellular carcinoma, gastritis due to Helicobacter pylori causes susceptibility to colorectal carcinoma, exposure to silica dust or cigarette smoking causes lung injury which promote lung cancer. How can tissue injury promote cancer? Inflammation is the only mechanism to repair tissue injury caused by infections or irritants or pollutants. But chronic injury to tissue or repeated wound formation result in the aberrant healing but chronic injury creates chronic inflammatory condition and the mediators of chronic inflammation causes DNA damage and mutations and genomic instability by epigenetic modifications. The regenerative response in this situation leads to proliferation of genetically altered cells that result in the tumor formation. Haddow suggested that "tumor production is a possible over healing" (Haddow, 1972). In this case inflammatory responses extended far beyond removal of damaged cells and protection damaged of tissue from pathogenic molecules. This review mainly focused on how tissue injury and cell death triggered inflammation contributes to tumor initiation. Cell death in tissue injury is of two types apoptosis and necrotic cell death. Apoptotic cell death is anti-inflammatory because engulfment of apoptotic bodies by phagocytic cells results in the production of anti inflammatory molecules such as TGFÎ² and IL10 (Savill et al., 2002). But there are few contradictory evidences that apoptosis also causes inflammation ((Casares et al., 2005; Fucikova et al., 2011, Apetoh et al., 2007, Udono and Srivastava, 1994) but necrotic cell death is highly inflammatory, the released components from necrotic cell death such as fragmented dsDNA, RNA, nucleotides, nucleosides, DAMP such as chromatin binding factor HMGB1, S100A8 and calreticulin are recognised by receptors on innate immune cells such as DC and macrophages results in the chemokines and cytokines production and leukocyte infiltration and creation of proinflammatory state and finally cause genetic instability in the tissue cells and the provided regenerative response leads to proliferation of genetically altered cells which result in the tumor formation.
DNA methylation inhibitors as potential anti cancer agents
Inhibitor for down stream targets of proinflammatory cytokine signalling
Epigenetic modifications has role in gene expression regulation and that is the case in tumorigenesis.
Understanging the mechanism of inflammation induced epigenetic modifecations and tumorigenesis process and we can exploit this knowledge to stop the inflammation associated diseases such as cancer though therapeutic approaches in the future.