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Biosci. Rep. (2012) / 32 / 1–15 (Printed in Great Britain) / doi 10.

1042/BSR20100136

Multifaceted link between cancer and inflammation
Gautam SETHI*1 , Muthu K. SHANMUGAM*, Lalitha RAMACHANDRAN*, Alan Prem KUMAR*† and Vinay TERGAONKAR‡1
*Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore, †Cancer Science Institute of Singapore, National University of Singapore, 28 Medical Drive, Singapore 117456, Singapore, and ‡Institute of Molecular and Cellular Biology (A*STAR), 61 Biopolis Drive, Singapore 138673, Singapore

' Synopsis
Increasing evidence from epidemiological, preclinical and clinical studies suggests that dysregulated inflammatory response plays a pivotal role in a multitude of chronic ailments including cancer. The molecular mechanism(s) by which chronic inflammation drives cancer initiation and promotion include increased production of pro-inflammatory mediators, such as cytokines, chemokines, reactive oxygen intermediates, increased expression of oncogenes, COX-2 (cyclo-oxygenase-2), 5-LOX (5-lipoxygenase) and MMPs (matrix metalloproteinases), and pro-inflammatory transcription factors such as NF-κ B (nuclear factor κ B), STAT3 (signal transducer and activator of transcription 3), AP-1 (activator protein 1) and HIF-1α (hypoxia-inducible factor 1α ) that mediate tumour cell proliferation, transformation, metastasis, survival, invasion, angiogenesis, chemoresistance and radioresistance. These inflammation-associated molecules are activated by a number of environmental and lifestyle-related factors including infectious agents, tobacco, stress, diet, obesity and alcohol, which together are thought to drive as much as 90 % of all cancers. The present review will focus primarily on the role of various inflammatory intermediates responsible for tumour initiation and progression, and discuss in detail the critical link between inflammation and cancer. Key words: activator protein 1 (AP-1), hypoxia-inducible factor 1α (HIF-1α ), matrix metalloproteinase (MMP), nuclear factor κ B (NF-κ B), oncogene, signal transducer and activator of transcription 3 (STAT3)

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INTRODUCTION

Bioscience Reports

Inflammation is a complex process that involves widespread changes in cellular and molecular components of physiology. Although controlled inflammation is a necessary process required for an array of processes including tissue repair, wound healing and for defence against invading foreign pathogens, chronic, uncontrolled inflammation is harmful and has now been linked to a number of human ailments [1,2]. The critical role of chronic inflammation in cancer was first proposed by Rudolf Virchow in 1863, when he observed the presence of leucocytes in neoplastic tissues [3,4]. Virchow postulated that an inflammatory milieu promotes a cellular environment that drives the initiation and development of carcinogenesis [1,5].

Within the tumour microenvironment, a network of various pro-inflammatory mediators participate in a complex signalling process that facilitates extravasations of tumour cells through the stroma, thereby promoting tumour progression [6,7]. While acute inflammation is primarily a self-limiting process and has potential therapeutic consequences, prolonged chronic inflammation is mostly detrimental [2,8]. Chronic inflammation is now dubbed by the popular press as a ‘secret killer’ and has been widely associated with diseases such as atherosclerosis, rheumatoid arthritis, multiple sclerosis, asthma, Alzheimer’s disease and various cancers [1,3,4]. It is a well-accepted paradigm now that environment- and lifestyle-related factors play a critical role in development of 90 % of all cancers [4,9]. For example, almost 30 % of all cancers have been attributed to tobacco smoke, 35 % to diet,

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Abbreviations used: AP-1, activator protein 1; CCR7, CC chemokine receptor 7; COX-2, cyclo-oxygenase-2; CXCL14, CXC chemokine ligand 14; CXCR, CXC chemokine receptor; ECM, extracellular matrix; EGF, epidermal growth factor; EGFR, EGF receptor; HIF-1α , hypoxia-inducible factor 1α ; HPV, human papillomavirus; JAK, Janus kinase; IGF-1, insulin-like growth factor; Iκ B, inhibitory κ B; IKK, Iκ B kinase; IL, interleukin; 5-LOX, 5-lipoxygenase; MAPK, mitogen-activated protein kinase; MMP , matrix metalloproteinase; NF-κ B, nuclear factor κ B; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma; ROS, reactive oxygen species; SCC, squamous cell carcinoma; STAT3, signal transducer and activator of transcription 3; TAM, tumour-associated macrophage; TNF, tumour necrosis factor; VEGF, vascular endothelial growth factor. 1 Correspondence may be addressed to either of these authors (email gautam_sethi@nuhs.edu.sg or vinayt@imcb.a-star.edu.sg).

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but when its antitumour activity was tested on cancer patients. a paradoxical tumour-promoting role of TNFα became apparent [13–15]........... TNFα produced by macrophages has been implicated in inflammation and subsequent tumour development [15]...G.. is a regulatory cytokine that can induce the activation of transcription factors.... including those of B-cell lymphoma [17]................... AP-1 (activator protein 1) and HIF-1α (hypoxia-inducible factor 1α ) [8.. pancreatic cancer [21.... ovarian carcinoma [23].. The pro-inflammatory potential of TNFα has also been analysed in various animal models of cancer... breast carcinoma [20].. TNFα produced by myeloid cells promoted inflammation-associated tumours [27] and also in a chemical-induced model of colorectal cancer.. IL-1β also up-regulates HIF-1α protein through a classical inflammatory signalling pathway involving NF-κ B and COX-2.. 5-LOX (5-lipoxygenase).. IL-6... IL-1β when released by myeloma cells can induce the production of IL-6 by bone marrow stromal cells and function as an autocrine growth factor for myeloma cells [31]............. survival and angiogenesis via the JAK (Janus kinase)–STAT signalling pathway [36]........ adult T-cell leukaemia [19].... COX-2 (cyclo-oxygenase-2)........... The mechanism(s) for cancer development in the presence of chronic inflammation involves the continuous presence of cytokines.. the analysis of biopsy specimens from inflammation-associated gastric cancers has revealed that the levels of IL-1β and IL-6 are highly elevated in tumours as compared with adjacent normal mucosa [38].. Thus. Increased serum levels of IL-6 have been observed to be positively correlated with tumour burden in colorectal cancer patients with high significance [40].. At present. megakaryoblastic leukaemia [18]...... in CLL (chronic lymphocytic leukaemia) patients... In the present review... Endogenous and exogenous TNFα showed an enhancement of metastasis in an experimental fibrosarcoma metastasis model [28]............................16]. It has been reported that acidic pH can induce elevation in IL-8 expression in human ovarian cancer cells and transcription factors.... enhanced angiogenesis and metastasis [11]. In another study.... MMPs (matrix metalloproteinases) and activation of important transcription factors such as NF-κ B (nuclear factor κ B) and STAT3 (signal transducer and activator of transcription 3). a potent angiogenic factor required for tumour growth and metastasis [32]... it has been found that... the pro-inflammatory role of TNFα has been linked to all steps involved in tumorigenesis... we will focus on the role of various pro-inflammatory mediators in cancer and provide novel insights into the intricate link between chronic inflammation and cancer.. direct evidence for the role of IL-1β in human cancer has been found in multiple myeloma.. IL-6 is another major pro-inflammatory cytokine that has been implicated in inflammation-associated carcinogenesis [34.. RCC (renal cell carcinoma) cell lines containing mutant p53 have been found to produce higher levels of IL-6 than those containing wild-type p53 [37]......... An overproduction of IL-6.... Moreover..... Sethi and others 14–20 % to obesity..... Also............. the TNFα gene was found to be expressed in 45 of 63 biopsies of human epithelial ovarian cancer [23]... TNFα has been reported to be produced by a wide variety of tumour cells.... For example. 2 C The Authors Journal compilation C 2012 Biochemical Society ... and promote the expression of various genes involved in cell survival.... surgical removal of the ovarian tumour and resolution of ascites in patient was found to be directly associated with decrease in serum levels of IL-1β [33].................. thus suggesting that IL-8 secretion could be a key factor involved in proliferation... IL-1α ..... survival....... 18 % to infections and 7 % to radiation and environmental pollutants [10]......... including NF-κ B and AP-1.. inflammatory markers were measured at baseline in 52 patients with stage IV colorectal cancer. glioblastoma [25] and neuroblastoma [26]... evasion from apoptosis... SCC (squamous cell carcinoma)............ lung cancer... Constitutive expression of IL-8 mRNA and secreted IL-8 protein has been observed in various tumour cell lines and animal models..... the cervical epithelial cancer [24]....... IL-6 modulates the expression of genes involved in proliferation.. novel strategies that neutralize systemic TNFα may be useful in cancer treatment and prevention... Elevated levels of TNFα have also been detected in various cancer patients.... culminating in up-regulation of VEGF (vascular endothelial growth factor)................. ROLE OF IL (INTERLEUKIN) IN INFLAMMATION AND CANCER Several ILs have been linked with inflammation and subsequent cancer development.... TNFα level was significantly higher as compared with the healthy con- ..35]...... invasion...... Chronic inflammation acts as a key regulator of tumour promotion and progression by several mechanisms including accelerated cell proliferation......... oncogenes. angiogenesis and metastasis of cancer cells [42]...... indicated by increased plasma CRP (C-reactive protein) levels... including cellular transformation.......... myeloma-cell proliferation and poor prognosis [39].... has also been found in 37 % of multiple myeloma patients at diagnosis and is associated with disease aggressiveness.. In another study.. proliferation and angiogenesis [30].22].....12]...... IL-8 and IL17. ROS (reactive oxygen species)......... and significantly elevated levels of IL-6 and gp130 were observed in these patients and inflammatory markers paralleled clinical outcome [41].... colorectal cancer.. proliferation.............. AP-1 and NF-κ B were found to be responsible for this ROLE OF TNF (TUMOUR NECROSIS FACTOR) IN INFLAMMATION-DRIVEN CANCERS TNFα was first isolated as an anticancer cytokine more than two decades ago.. which is expressed in both normal tissue and several tumour cells.... In a genetic model of liver cancer... Moreover......... chemokines.. angiogenesis and metastasis [15.. The molecular mechanism(s) by which these risk factors induce cancer are becoming increasingly evident and one major process that seems to be common between all these risk factors is inflammation. These ILs include IL-1..... trol population and it also acted as a predictor of patient survival [29]....

.. they found that IL-8.......... Several studies have reported the involvement of chemokines and chemokine receptors in cell proliferation.. ROLE OF ONCOGENES IN INFLAMMATION-DRIVEN CANCER Oncogenes are altered versions of normal cellular genes... tumourderived IL-8 has been shown to induce the differentiation and activation of osteoclasts...... Huang et al.. Furthermore... and therefore strategies to inhibit IL-8 signalling may sensitize hypoxic tumour cells to conventional treatments......... suggesting the potential utility of anti-IL-8 as a modality to treat melanoma and other solid tumours either alone or in combination with conventional chemotherapy or other antitumour agents. migration.......... Ancrile et al.... CXCL8 and IL-11 in human ovarian cells [64]....... mediates the release of VEGF-A from mast cells and onset of tumour angiogenesis [68].......... Recent reports indicate that Myc oncogene can also orchestrate a complex inflammatory program [67]... Thus.. covering approx.............................. Recently. IL-17........ has also been found to act as a growth factor in cutaneous T-cell lymphoma and a key regulator of angiogenesis [47].... it has become increasingly evident that pleiotropic effects of oncogenes also include the induction of a protumour microenvironment.... In another report.org / Volume 32 (1) / Pages 1–15 3 .... [64] have shown that HRAS.... [44] have further found that the neutralizing antibodies to IL-8 can inhibit angiogenesis. hypochlorous acid..... determining the metastatic destination of tumour cells...52]... malignant breast tumours and metastasis [56].. including IL-1α ....... are derivatives of molecular oxygen such as superoxide. another important cytokine... neutralizing the interactions of CXCL12/CXCR4 significantly impairs metastasis of breast cancer cells to regional lymph nodes and lung [59].......... Mast cell activation is required not only for angiogenesis during outgrowth of Myc-dependent islet tumours but also for tumour maintenance and the inhibitors of mast cell function trigger hypoxia and cell death of tumour and endothelial cells [69].. These results indicate that IL-8 signalling confers a survival advantage to hypoxic prostate cancer cells... CXCR1 (CXC chemokine receptor 1) and CXCR2 mRNA expression in prostate cancer PC3 cells was up-regulated in response to hypoxia in a time-dependent manner... underpinning the characteristic osteolytic metastasis of breast cancer cells that have disseminated to the bone [45]....... H2 O2 .. [66] have demonstrated that IL-6 acts downstream of Ras in a paracrine fashion to promote angiogenesis... transcription factor NF-κ B is activated in Ras-transformed ovarian epithelial cells and this activation is responsible for the increased expression of CXCL8 [65]...... tumour growth and metastasis of human melanoma..... Furthermore.. Moreover.. Thus chemokines and their receptors have a critical role in ROLE OF OXIDATIVE STRESS IN CHRONIC INFLAMMATION AND CANCER Reactive oxygen intermediates... [46] determined whether hypoxia can increase IL-8 and IL-8 receptor expression in prostate cancer cells and whether this contributes to a survival advantage in hypoxic cells. www...51. In breast cancer cells..... signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation and subsequently induces chemotactic and invasive responses [56]....... singlet oxygen and the hydroxyl radical [71–73]..... Maxwell et al.............. IL-17-overexpressing human cervical cancer [48]... four mutually exclusive genetic lesions have been identified in papillary thyroid carcinoma......... The chemokine receptors CXCR4 and CCR7 (CC chemokine receptor 7) are highly expressed in human breast cancer cells....... CC....... The ........ CXC and CX3C [8. the socalled proto-oncogenes. IL-1β ......... Chronic inflammation is often accompanied by increased production of tissue reactive oxygen intermediates [74].......... involved in the regulation of cell growth [60............... ROS can alter signal transduction cascades as well as induce changes in transcription factors such as NF-κ B... and invasion and metastasis of different types of tumours [53–55]... several oncogene-driven inflammatory pathways are activated in various human cancers and are likely to play a key role in various stages of carcinogenesis................. Myc activation in β -cells rapidly induces the expression and release of the pro-inflammatory cytokine IL-1β that.76]..... It has been reported that CXCR4 and SDF-1 (stromal-cell-derived factor 1) induces proliferation in ovarian cancer cells... For example.. in turn.... NF-E2/rf2 or Nrf2 (nuclear factor erythroid 2/related factor 2) and AP-1 that mediate immediate cellular stress responses [75.... ROLE OF CHEMOKINES IN INFLAMMATION AND CANCER Chemokines are soluble chemotactic cytokines that are grouped into four classes based on the positions of key cysteine residues: C... In vivo..................... The functional chemokine receptor CCR3 has been shown to be upregulated in human RCC [57].Multifaceted link between cancer and inflammation process [43]...... and this correlated with EGFR [EGF (epidermal growth factor) receptor] transactivation.. Indeed..... IL-6.....bioscirep.. CXCL14 (CXC chemokine ligand 14) [BRAK (breast and kidney chemokine)] RNA expression has been observed in normal and tumour prostate epithelium and focally in stromal cells adjacent to cancer [58]..... fibrosarcoma [49] and human NSCLC (non-small cell lung cancer) preferentially exhibit higher oncogenic growth in vivo [50].... 80 % of the cases: rearrangements of Ret or Trk genes and activating mutation of Ras or Braf genes [70].......... through the persistent promotion of an inflammatory milieu [61–63].... Liu et al..... also generically referred to as oxidants.61].. They also found that the inhibition of IL-8 signalling potentiated etoposide-induced cell death in hypoxic PC3 cells [46]...and KRAS-G12V induce the expression of various cytokines....... Moreover........ A list of various ILs and chemokines associated with cancer initiation and promotion is briefly summarized in Table 1...

.......and highgrade astrocytomas indicated a correlation between the percentage of COX-2 expression and patient survival [90]...... is known to mediate tumorigenesis [11. angiogenesis Growth Metastasis Metastasis Invasion and growth Higher risk Cell invasion Proliferation Inhibits tumour growth Reference [193] [194] [195] [196] [197] [198] [32] [199] [200] [37] [201] [202] [203] [204] [56] [56] [43] [57] [205] [206] [58] pro-neoplastic activity of ROS is mainly due to their ability to cause DNA damage [77]... COX-2 has also been implicated in the progression of human lung adenocarcinoma..... has been implicated in the growth and progression of a variety of human cancers..........................83]........... CXCR4/CXCL12 CCR3 MIP-3α and CCR6 CXCR4 and SDF1 CXCL14 Mechanism(s) Transformation Proliferation Increased risk Metastasis Metastasis Angiogenesis Angiogenesis Tumour growth Angiogenesis Autocrine growth Chemoresistance Disease progression Growth.. Sethi and others Table 1 Role of ILs and chemokines in cancer MIP-3α ... Steady-state levels of COX-2 mRNA were high in well-differentiated adenocarcinoma samples but low in poorly differentiated adenocarcinoma. the inducible isoform of prostaglandin H synthase....... oncogenes and other factors....... This forms the basis for the theory that dietary antioxidants can inhibit the development or progression of cancer [80–82]... Agents that either scavenge reactive oxygen intermediates or prevent their formation inhibit the induction of DNA damage................ Overexpression of COX-2 is also associated with a poor prognosis in patients with SCC of the uterine cervix treated with radiation and concurrent chemotherapy [91]... 4 C The Authors Journal compilation C 2012 Biochemical Society ......... COX-2 has been shown to regulate colorectal cancer-induced angiogenesis by two mechanisms: COX-2 can modulate the production of angiogenic factors by colon cancer cells... Levels of COX-2 expression were also found to be a significant prognostic factor for patients with multiple myeloma [92]........ Oxidative damage to DNA has also been linked to aflatoxin B-induced p53 and Ras gene mutations in hepatocarcinogenesis [78] and in UV-induced mouse and human skin cancers [79].... an inducible enzyme regulated by NF-κ B... IL-1β has been reported to up-regulate COX-2 in human colorectal cancer cells via multiple signalling pathways [87]........................... mutagenesis and transformation by inflammatory phagocytes.... COX-2 expression was observed to be strong in the SCCs and weak in oesophageal ADCs (adenocarcinomas) [89]...... cytokines......86].. macrophage inflammatory protein-3α .......... a murine model of human adenomatous polyposis....... COX-2 overexpression enhanced the in vitro expression of both CXC ligand CXCL8 and CXCL5...... OVEREXPRESSION OF COX CAN MEDIATE INFLAMMATIONASSOCIATED CANCERS COX-2... It has been found that COX-2 and mPGES (membrane-associated prostaglandin E synthase) were induced in the COX-1-expressing fibroblasts in human familial adenomatous polyposis polyps [84]. For example..........................G.. NSCLC angiogenic peptides in the NSCLC cell lines [88]. Overall survival of those patients ............... COX-2 expression levels in tumour specimens from patients with low........................... thereby indicating the correlation between the abnormal up-regulation of COX-2 and tumorigenesis.................. COX-2.............. reduced the number and the size of intestinal polyps [85. Cancer type Bladder cancer Multiple myeloma Colorectal cancer Melanoma Pancreatic carcinoma Prostate cancer Lung carcinoma Melanoma Glioblastoma RCC Pancreatic carcinoma Ovarian tumours Tumour Lung carcinoma Breast cancer Melanoma Ovarian carcinoma RCC Pancreatic carcinoma Ovarian carcinoma Prostate carcinoma Inflammatory mediator IL-6 IL-6 poly IL-6 IL-18 IL-1α IL-8 poly IL-1α IL-8 IL-8 IL-6 IL-1β IL-8 IL-8 IL-1β CXCR4 and CCR7 CXCR4 and CCR7.............. COX-2 expression in human tumours can be induced by growth factors.......................... SCC and small cell lung cancer......................... Administration of the COX2-selective inhibitor rofecoxib or the functional inactivation of the COX-2 in adenomatous polyposis coli knockout mice.. while COX-1 regulates angiogenesis in endothelial cells................................

..... the inactive NFκ B/Iκ Bα complex is activated by phosphorylation on two conserved serine residues within the N-terminal domain of the Iκ B proteins..... Such expression was accompanied by an up-regulation of MMP2 and VEGF.....220] [221] [103] [104] OVEREXPRESSION OF 5-LOX LINKS INFLAMMATION AND CANCER 5-LOX is a key enzyme in the metabolism of arachidonic acid to leukotrienes [93].....208] [90] [209] [210.. Generally... In unstimulated cells...... a hallmark of cancer progression to metastasis [102]...... MMPs are now also implicated in the EMT (epithelial to mesenchymal transition).......... and survival in cancer of the lung [107].......................217] [218] [84....... patient survival... 5-LOX..... A role of COX-2........................ Studies also indicate that the exposure to the mainstream smoke of unfiltered cigarettes enhanced the 5-LOX protein expression in the inflammation-associated colonic adenomas [97].... The 5-LOX transcript is expressed in human brain tumours and the 5-LOX gene product may play a role in human tumour-induced brain oedema [96].... Tumour Breast cancer Glioma Prostate cancer Melanoma Oesophageal adenocarcinoma Oesophageal SCC and AC Urinary bladder Pancreatic cancer Head and neck SCC Lung carcinoma Gastric carcinoma Colorectal cancer Brain tumours Colorectal cancer Pancreatic cancer Skin cancer Enzyme COX-2 COX-2 COX-2 COX-2 COX-2 COX-2 COX-2 COX-2 COX-2 COX-2 COX-2 COX-2 5-LOX COX-2 and 5-LOX MMP-9 MMP-9 References [207............ first discovered by David Baltimore in 1986... adenocarcinoma.....219] [96......... aggressiveness .. RelB.. gene overexpression and RNAi (RNA interference) validation data showed that MMP-1 is the second most important gene in a 95-gene expression profile in determining the metastatic potential of breast cancer to produce lung metastases [106]... Abundance of the mRNA for arachidonate 5-LOX..... the increased expression of 5-LOX has been linked with the progression and development of cancer of the pancreas [98]..........bioscirep... In addition..Multifaceted link between cancer and inflammation with negative or weak-to-moderate COX-2 expression was significantly better than that of patients with strong COX-2 immunoreactivity.... has been investigated in a series of human brain tumours [96]..... the NF-κ B family of transcription factors is composed of homodimers and heterodimers derived from five distinct subunits..... All family members share a highly conserved RHD (Rel homology domain............211] [212] [89] [213] [214] [215] [216................ Several studies suggest that there is a link between 5-LOX and carcinogenesis in humans and animals [93– 95]............ stomach [108] and oesophagus [109]. the intracellular inhibitor of NF-κ B [111–113]..... In mammalian cells... Activation of ROLE OF MMP IN INFLAMMATION AND CANCER MMPs are a multigene family of zinc-dependent endopeptidases that share a similar structure and which collectively have the capacity to degrade ECM (extracellular matrix) [101]. is present in the nucleus and binds the promoter of immunoglobulin κ chain in B-cells........... ∼300 amino acids) responsible for DNA binding.... www...... In another study............... p50 (NF-κ B1) and p52 (NF-κ B2)... RCC and in NHL (non-Hodgkin’s lymphoma) [110]..... Phosphorylation of these conserved serine residues in response to stimulation leads to the immediate polyubiquitination of Iκ B proteins by the SCF-β -TrCP (transducin repeatcontaining protein-β -transducin repeat-containing protein) complex.... ROLE OF TRANSCRIPTION FACTOR NF...................... and MMPs in cancer is briefly summarized in Table 2.... RelA (p65).. two of the 70 genes identified were found to be MMP-1 and MMP-9 [105].... 5-LOX and MMP-9) in cancer AC......... Table 2 Role of inflammatory enzymes (COX2.. dimerization domain and interaction with Iκ Bs (inhibitory κ Bs)......... These findings indicate that high COX-2 expression in tumour cells is associated with clinically more aggressive tumours and is a strong predictor of poor survival....... MMP-9 is up-regulated in angiogenic dysplasias and invasive cancers of the epidermis in a mouse model of multi-stage tumorigenesis elicited by HPV16 (human papillomavirus 16) oncogenes [104]...................... In gene expression profiles associated with poor outcome of patients with breast tumours......... the majority of NF-κ B complexes are predominantly cytoplasmic and in an inactive form due to their binding to the Iκ B family of proteins that prevent DNA binding and as a consequence prevent nuclear accumulation [114]....... the key angiogenic factors for tumorigenesis and 5-LOX inhibitors were found to decrease the incidence of colonic adenoma formation and reduced angiogenesis. This modification subsequently targets Iκ B proteins for rapid degradation by the 26S proteasome [115]..... c-Rel.. which is the rate-limiting enzyme in leukotriene synthesis.......κ B IN CHRONIC INFLAMMATION AND CANCER The transcription factor NF-κ B............org / Volume 32 (1) / Pages 1–15 5 . breast [99] and kidney [100].... Expression of MMP-9 has also been correlated with prognosis......... MMP-2 activity and VEGF protein expression [97]. It has been observed that MMP-9 is a potent regulator of the angiogenic switch in a pancreatic tumour model [103].

.... Production of tumour-promoting cytokines by immune/inflammatory cells that activate NF-κ B... inhibition of TNFα production by non-parenchymal cells (Kupffer and endothelial cells) prevented NF-κ B activation in hepatocytes and in early tumours and reduced tumour multiplicity [27].......... tumour cell proliferation.... TNF-receptor-associated factor... metastasis. mutation of Iκ Bα such that it cannot bind to NF-κ B......... lymphotoxin β receptor... and regulates transcription of over 400 genes involved in inflammation...... HTLV-1... intracellular adhesion molecule 1........ human herpes virus 8... urokinase plasminogen activator.... transforming protein isolated from diffuse B-cell lymphoma.. Kaposi’s sarcoma-associated herpes virus. invasion.... GM-CSF (granulocyte/macrophage colony-stimulating factor) and KC (keratinocyte chemoattractant) [2.......... along with other transcription factors such as AP-1 and STAT3 in premalignant cells to induce genes that stimulate cell proliferation and survival. latent membrane protein 1.. HDAC. VCAM-1. 6 C The Authors Journal compilation C 2012 Biochemical Society . telomere maintenance-Janus kinase 2. EBV... What causes the constitutive activation of NF-κ B in various tumour cells is not fully understood... platelet-derived growth factor receptor........... ELAM-1. IRF2.. interferon regulatory factor 2... It has also been shown that Iκ B proteins do not bind and export NF-κ B that is phosphorylated at p65........125].... Sethi and others Figure 1 Mechanisms of constitutive activation of NF-κ B Abbreviations: BAFF. due to DNA binding [116–119].... XIAP . vFLIP ........... HCV. the NF-κ B signalling cascade is a consequence of degradation of Iκ B proteins.. designated as κ B elements..... X-linked inhibitor of apoptosis.. uPA.......... endothelial cell leucocyte adhesion molecule 1. immunoregulation... allowing nuclear accumulation of NF-κ B....... histone deacetylase. hepatitis B virus. viral proteins........125].... HER2.. IL1).... BAFFR....... ICAM-1......... TRAF.128].. growth arrest and DNA-damage inducible... including pro-inflammatory cytokines (e....... For instance.. B-cell activating factor belonging to the TNF family...... B-cell activating factor belonging to the TNF family receptor.......... HHV-8......and B-cell mitogens......g..... HBV.. Dbl/Dbs.................... LPS (lipopolysaccharide).. NF-κ B is activated by many divergent stimuli......... KSHV...... erythroblastic leukaemia viral oncogene.. MUC1.127....... human T-cell leukaemia virus type 1.. constitutive activation of Ras protein.. [126] reported that deleting IKKβ (Iκ B kinase β ) in myeloid cells caused suppression of NF-κ B. IL1α ....... GADD........... PDGFR. is a major tumourpromoting mechanism [2. Numerous studies have indicated that tumour cells exhibit constitutive production of the pro-inflammatory cytokines TNFα ......... TNFα .. hepatitis C virus..... mucin 1... Flt3.. bacteria........G. viruses. Epstein Bar virus..... chemoresistance and radioresistance [120–124]... caspase recruitment domain family 11........ GSK3β . Indeed phosphatases of p65 such as WIP1 (wild-type p53-induced phosphatase) have recently been identified with removed phosphates . thus leading to a significant decrease in tumour size. Greten et al......... Activated NF-κ B binds to specific DNA sequences in target genes......... fms-related tyrosine kinase 3..... The host environment promotes the constitutive activation of NF-κ B and pro-inflammatory cytokine expression during metastatic tumour progression of various cancers [113... and autocrine secretion of inflammatory cytokines (Figure 1)......... angiogenesis....... vascular cell adhesion molecule 1.. activation and diminished expression of inflammatory cytokines... including overexpression of growth factor receptors. viral FADD-like interleukin-1β -converting enzyme (FLICE)/caspase-8-inhibitory protein.... LT-β R..... TEL-Jak2.. Many different mechanism(s) have been described............. IL-6. glycogen synthase kinase 3β . CARD11.. high proteolytic activity directed to Iκ Bα ....... T... LMP1.. double-stranded RNA and physical and chemical stresses......

.. Inhibition of NF-κ B activation in TAMs has also been reported to correlate with impaired expression of NF-κ B-dependent inflammatory functions [141] and to exhibit the alternatively activated.... These observations appear to reveal that inflammatory cells can destroy tumour cells....... NF-κ B seems to function as a ‘rheostat’ whose function can be tuned to different levels... myeloidlineage-specific inactivation of the gene encoding IKKβ was found to inhibit cancer-related inflammation in the intestine........ phenotype [137]............ in certain tumours....... Constitutive activation of STAT3 has been observed in many kinds of solid tumours and haematological malignancies [4... For example...... Several infectious agents also exert their tumorigenic effects through STAT3 activation and depend on STAT3 for their oncogenic potential [149].............. ‘M2’...org / Volume 32 (1) / Pages 1–15 7 .......... predisposing individuals towards developing cancer. STAT3 can also act in close liaison with NF-κ B to mediate various steps involved in initiation... Thus STAT3 activation pathway also is an important contributor to inflammation-induced cancers. Defective NFκ B has also been reported in T-lymphocytes of patients with RCC [138]...........158].. which typically have an inflammatory milieu [139]. Studies in mice with GP130 mutations demonstrated that an increase in GP130 and STAT3 signalling led to inflammation-associated gastric tumorigenesis [155]..... Thus......147]. A critical role for STAT3 in inflammation-induced adenocarcinomas was also demonstrated using a transgenic mouse model with a constitutively active GP130 in epithelial cells [154].. NF-κ B and STAT3 control both distinct and overlapping groups of genes involved during tumorigenesis [149]... For instance............. Moreover..Multifaceted link between cancer and inflammation from p65 and make NF-κ B more submissive to Iκ B-mediated nuclear export [129].. Although several experimental and clinical results clearly indicate inflammation having a pro-tumour consequence.... metastasis and angiogenesis [151.... ROLE OF STAT3 IN INFLAMMATION AND CANCER STAT3 was originally identified as a DNA-binding protein that responds to stimulation by EGF and IL-6 and has an important role in their signalling [146.. Indeed agents that simultaneously target the p53 and NF-κ B pathway should be developed further in the treatment of cancers [134–136]. www.. JAK2.......... Also. JunB and JunD) and Fos (c-Fos. which encodes a subunit of the IL-6 receptor.. Global profiling of STAT3-dependent genes in mouse lung cells revealed a large number of genes whose expression is controlled by STAT3. Constitutive activation of NF-κ B also has been linked to chemoresistance and radioresistance in various tumour cell lines and in animal models [113..... the presence of inflammatory cells is associated with better prognosis [144]. activates STAT3 through its cytotoxin-associated gene A in host cells [156]..152].......... invasion.. a marked chronic inflammatory response is not associated with an increased risk of developing melanoma [143]................... and enables TAMs to maintain the inflammatory milieu [137]... providing evidence that inflammatory cells are involved in carcinogenesis [126]................ evidence indicates that NFκ B is an important determinant of the balance between the protumour and anti-tumour properties of macrophages [142.... TAMs (tumour-associated macrophages) have delayed and defective NF-κ B activation [140]....... Activation of IKKs in response to inflammatory stimuli has also been shown to deregulate cell cycle [133].... In addition..... some reports also demonstrate the inverse...... Taken together..149]........ Fra-1 and Fra-2) families.. Furthermore........ leading to nuclear translocation.. Evidence suggests that homodimers of the p50 subunit of NF-κ B (a negative regulator of the NF-κ B pathway) are responsible for this slow activation of NFκ B in TAMs and for the pro-tumour phenotype of these cells [142]..... among which a number of typical NF-κ B target genes are also present [160].... FosB.......... as well as colitis-associated cancer... in addition to normal tissue cells.. phosphorylation-induced homodimerization.........150] and this persistently active STAT3 is thought to contribute to oncogenesis by modulating the expression of a variety of genes involved in cell proliferation...... making it an attractive target for treating and/or preventing inflammation.. In established advanced tumours. it was demonstrated that obesity-promoted hepatocellular carcinoma development was dependent on enhanced production of the tumour-promoting cytokines IL-6 and TNFα ...........bioscirep. Chronic inflammatory conditions that drive carcinogenesis can also be attributed to genetic alterations that directly affect the STAT3 pathway [149].. On activation....... The phosphorylation is mediated through the activation of non-receptor protein tyrosine kinases called JAKs...... Thus the activation of NF-κ B represents the central event in linking the process of chronic inflammation to different aspects of tumorigenesis...... JAK1. a critical role of STAT3 activation in mediating UV-light-induced skin cancer in a transgenic mouse model and cigarette-smoke-associated cancer development has also been demonstrated [157. The importance of constitutively active mutations in GP130.......... It is also well known that it blocks the function of p53 tumour suppressor by causing its degradation [130–132]..145] and thus NF-κ B could be targeted to ‘re-educate’ tumour-promoting macrophages towards an anti-tumour role [145].....124].. STAT3 undergoes ROLE OF AP-1 IN INFLAMMATION AND CANCER The transcription factor AP-1 produced by 18 different dimeric combinations of proteins from the Jun (c-Jun....... DNA binding and subsequent gene transcription [148]................. JAK3 and TYK2 have been implicated in the activation of STAT3 [147... promotion and development of cancer [159]........ infection with Helicobacter pylori......... which cause hepatic inflammation and activation of the STAT3 [161].. has been demonstrated in human inflammatory HCC (haemofiltrate CC chemokine) [153]..... For example.... in a recent study... plays a critical role ....... which is associated with gastric cancer... An association between the development of cancer and inflammation is further strengthened by studies of the role of NF-κ B in tumour-infiltrating leucocytes [137].................

Some of the agents that have the potential to suppress these pro-inflammatory mediators and are being tested include TNFα blockers (such as thalidomide............. 8 C The Authors Journal compilation C 2012 Biochemical Society ........ TNFα and IL-1β were first shown to increase HIF-1α activity in the human hepatoma cell line HepG2 [184]. AP-1 has also been found to interact with pro-inflammatory transcription factor NF-κ B...... targeting the HIF-1α pathway provides an attractive strategy to treat various hypoxic and metastatic tumours..... bladder.. These include erythropoietin. ECM and is mediated predominantly through the MAPK (mitogen-activated protein kinase) [ERK (extracellularsignal-regulated kinase).......... ovarian.. and vasoactive peptides. CONCLUSION AND PERSPECTIVES There is growing evidence. hormones such as insulin or IGF-1 (insulin-like growth factor 1) and IGF-2... including inflammation..... whereas the β -subunit is permanently present in nuclei irrespective of the state of oxygenation [182].......... including growth factors..... as described above.... differentiation and apoptosis [162–164].. For example.... using mice overexpressing c-fos.......... Dominantnegative constructs of c-fos and c-jun can reverse the transformed phenotype induced by activated Ras and also inhibit the invasiveness and tumorigenesis of keratinocytes [171].. iNOS (inducible nitric oxide synthase)..... IL1 blockers (canakinumab and anakinra)... in contrast with benign tumours and normal tissues. Interestingly.... causing density.. autotaxin [175]... oncogenes and transcription factors play a pivotal role in mediating tumorigenesis... proliferation. Several AP-1 target genes are also implicated in the invasive phenotype. Another recent report indicates that inhibition of NF-κ B activation can accelerate hepatocellular carcinoma development and enhance proliferation of tumour-initiating cells [188]..177].. administration of TNFα blockers to patients ROLE OF HIF-1 α IN INFLAMMATION AND CANCER HIF-1 is a heterodimeric transcriptional complex composed of an α -subunit and a β -subunit [180.. in a skin cancer mouse model...186]..181]. [178] showed an intimate relationship between c-fos expression levels and chondrogenic tumour development.... renal.. glucose transporters and a number of glycolytic enzymes [185. VEGF and VEGF receptor........ Thus.... Sethi and others in variety of cellular processes... breast. is generally unstable and undergoes proteasomal degradation in normoxia.........and anchorage-independent growth in these cells [169............. Moreover. Moreover....... despite extensive inflammation........ the accumulation of HIF-1α in the absence of apparent hypoxic stimulation has been demonstrated in a number of different cancers.. HIF1α overexpression has also been found to correlate with increased angiogenesis and metastasis and thus can be used as a marker to predict outcome in patients with metastatic cancers [181]. immunohistochemical analyses of tissue sections have shown HIF-1α to be highly expressed in many tumour types including pancreatic......G. When activated.. The HIF-1α subunit ......... Recent studies have shown that a number of peptidic and non-peptidic mediators of inflammation can activate HIF-1α even under normoxic conditions [183]......... AP-1 is also overexpressed in a large number of tumours and transformed cell lines and targeted inhibition of its activity in these model systems suggest a pivotal role for AP-1 in oncogenic transformation and progression [163.... Wang et al..164].... the PKC (protein kinase C) substrate SSeCKS (Src-suppressed C-kinase substrate) [174] and the angiogenic factor..................... resveratrol and roscovitine) and COX-2 inhibitors (such as celecoxib).. For example..... brain..... Activation usually occurs both transcriptionally and post-translationally in response to a broad range of external stimuli.............. and the dominant-negative Jun has been reported to inhibit both AP-1 and NF-κ B activity in HPV-immortalized human keratinocytes [179]...... AP-1 recognizes and binds to the TRE (TPA response element) or cAMP response element within the promoter region of target genes [165].. the ECMassociated protein osteonectin/SPARC (secreted protein acidic and rich in cysteine) [173]... chemokines.. MMP-3 and MMP-9 [172].. Endogenous c-fos and c-jun are also oncogenes as indicated by their potential to morphologically transform murine fibroblasts............... COX-2.......... inhibition of Fos and Jun expression in murine fibroblasts and erythroleukaemia cells has indicated that AP-1 is required for cell proliferation and cell-cycle progression [164].. AP-1 is itself strongly oncogenic [168].... pro-inflammatory cytokines.. Moreover.. the existing literature also suggests that inhibition of pro-inflammatory pathways is not always beneficial... the pro-inflammatory transcription factor NF-κ B has been reported to inhibit tumour formation [187]....... including the MMPs MMP-1.... proliferation and progression........ colorectal and prostate [185].. bile duct tumours are rarely found.... head and neck....... Thus AP-1 acts as a master regulator of gene expression in response to oncogenic signal transduction cascades in a wide variety of tumour cell and animal models and can be considered as an important target for novel anti-cancer therapies.170].... NF-κ B inhibitors (such as curcumin.. JNK (c-Jun N-terminal kinase) and p38 MAPK] cascade [166.. in Mdr2-knockout mice.......... These include cytokines..... enzymes.... which is highly suggestive that chronic inflammation is a critical mediator of various aspects of development of cancer..... However.......167].... enbrel... such as angiotensin II [183]........ humira and remicade).... Among various cytokines.. Furthermore. NFκ B activation and abundant proliferation of bile ducts in portal spaces [27].............. Furthermore...... HIF-1α stimulates the expression of several genes encoding the proteins that promote inflammatory reactions.. In addition to being activated by oncogenic signal transduction cascades. And finally.. suppression of c-jun activity by using a dominant-negative c-jun in basal keratinocytes or conditional inactivation of c-jun in the liver resulted in the inhibition of the development of chemically induced papillomas and liver tumours respectively [176.... while most evidence discussed above indicates that pro-inflammatory cytokines......... It is becoming imminently clear that chronic inflammation contributes to carcinogenesis at all three stages: initiation.

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