Biochem. J. (2008) 410, 225–235 (Printed in Great Britain)

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REVIEW ARTICLE

Genetic aspects of inflammation and cancer Georgina L. HOLD and Emad M. EL-OMAR1 Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, U.K.

Chronic inflammation is involved in the pathogenesis of most common cancers. The aetiology of the inflammation is varied and includes microbial, chemical and physical agents. The chronically inflamed milieu is awash with pro-inflammatory cytokines and is characterized by the activation of signalling pathways that cross-talk between inflammation and carcinogenesis. Many of the factors involved in chronic inflammation play a dual role in the process, promoting neoplastic progression but also facilitating cancer prevention. A comprehensive understanding of

the molecular and cellular inflammatory mechanisms involved is vital for developing preventive and therapeutic strategies against cancer. The purpose of the present review is to evaluate the mechanistic pathways that underlie chronic inflammation and cancer with particular emphasis on the role of host genetic factors that increase the risk of carcinogenesis.

INTRODUCTION

matory cell involvement. Mast cells especially play an important role in releasing preformed stored inflammatory mediators that attract migratory inflammatory cells to the site. Next, monocytes migrate to the area, differentiate into macrophages and become activated in response to local chemokine and cytokine interactions. Macrophages in turn secrete a number of potent bioactive inflammatory mediators which promote tissue healing at the site of injury. When considering the inflammatory environment within a neoplastic site, TAMs (tumour-associated macrophages) make up the largest proportion of the inflammatory cell infiltrate and their presence has a profound impact on the local micro-environment [4,5]. However, the downside is that persistent macrophage activation can result in continued tissue damage through the stimulation of local tissue remodelling, cellular proliferation and angiogenesis, which helps to potentiate neoplastic progression [6].

There is a significant body of epidemiological evidence showing a clear association between chronic inflammatory diseases and subsequent malignant transformation. Microbially induced inflammation is estimated to be associated with approx. 15 % of the global cancer burden [1]. Moreover, strong evidence is also available to support long-term use of non-steroidal antiinflammatory drugs as a means of reducing risk of several cancers [2]. Attempts aimed at defining the role of inflammation in carcinogenesis initially identified that inflammation can activate and induce a variety of oxidant-generating enzymes including NADPH oxidase and iNOS (inducible nitric oxide synthase), which can cause DNA damage and ultimately result in tumour initiation. More recently, however, it has been recognized that cancer development on the back of inflammation may be driven by inflammatory cells and a variety of mediators which together establish an inflammatory micro-environment. ACUTE OR CHRONIC INFLAMMATION WITHIN THE TUMOUR ENVIRONMENT

Chronic inflammation may progress from acute inflammation if the injurious agent persists, but more often than not, the inflammatory response is chronic from the outset. The most compelling examples of chronic-inflammation-induced carcinogenesis are seen within the gastrointestinal tract including inflammatorybowel-disease-induced colon carcinogenesis and also Helicobacter-pylori-induced gastric cancer [3]. However, there are numerous other examples throughout the body (Table 1). In contrast with the largely vascular changes of acute inflammation, chronic inflammation is characterized by infiltration of damaged tissue by leucocytes. Initially neutrophils and tissue mast cells are recruited as part of a multifactorial mechanism which co-ordinates inflam-

Key words: cancer, chronic infection, genetic polymorphism, inflammation.

ROS (REACTIVE OXYGEN SPECIES)

It is well-established that free-radical-mediated DNA damage occurs in cancer tissue, with overexpression of iNOS, an enzyme catalysing nitric oxide production, found in several cancers with known inflammatory involvement [7–11]. Leucocytes including neutrophils, dendritic cells, mast cells and lymphocytes are all capable of producing a variety of ROS including nitric oxide, superoxide anions and hydrogen peroxide. In addition to ROS, RNS (reactive nitrogen species), such as peroxynitrites and nitrogen oxides, are also formed and can react to generate mutagenic adducts [12–15]. To date, more than 100 products have been identified which cause oxidation of DNA. Nitric oxide and its products may exert oncogenic effects via several mechanisms including direct DNA (single- or double-stranded DNA breaks, deoxynucleotide or deoxyribose modifications and DNA crosslinks) and also protein damage. This can result in altered

Abbreviations used: CI, confidence interval; COX, cyclo-oxygenase; ECM, extracellular matrix; HCV, hepatitis C virus; HIF-1, hypoxia-inducible factor-1; IFN, interferon; IκB, inhibitor of nuclear factor κB; IL, interleukin; iNOS, inducible nitric oxide synthase; LPS, lipopolysaccharide; MCP, macrophage chemotactic protein; MIF, migration inhibitory factor; MMP, matrix metalloproteinase; NF-κB, nuclear factor κB; OR, odds ratio; PGE2 , prostaglandin E2 ; PPAR, peroxisome-proliferator-activated receptor; PRR, pattern-recognition receptor; ROS, reactive oxygen species; SNP, single nucleotide polymorphism; Th-1, T helper-1; TLR, Toll-like receptor; TNF-α, tumour necrosis factor α; VEGF, vascular endothelial growth factor. 1 To whom correspondence should be addressed (email [email protected]).
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Table 1

Cancers associated with infectious organisms

Infectious organism Associations with identified organisms Viral Hepatitis B (HBV) Hepatitis C (HCV) Epstein–Barr virus (EBV) Human herpes 8 (HH8)

Human immunodeficiency virus (HIV)

Human T-cell leukaemia virus type-1 (HTLV-1) Human papillomavirus (HPV)

Cytomegalovirus (CMV) Bacterial Helicobacter pylori Chlamydia trachomatis Parasitic Chinese liver fluke infestation Schistosomiasis Liver fluke (Opisthorchis viverrini ) Associations with unidentified infectious organisms

Inflammation/cancer link

Hepatitis/hepatocellular carcinoma Hepatitis/hepatocellular carcinoma Nasopharyngeal carcinoma Malignant lymphoma Kaposi’s sarcoma Squamous cell carcinoma Non-Hodgkin’s lymphoma Kaposi’s sarcoma Squamous cell carcinoma Non-Hodgkin’s lymphoma T-cell lymphoma Leukaemia Penile carcinoma Anogenital carcinoma Cervical carcinoma Ovarian carcinoma Gastric carcinoma Gastritis/gastric carcinoma Cervical carcinoma Cholangiocarcinoma Chronic cystitis/bladder carcinoma Cholangiosarcoma/colon carcinoma Inflammatory bowel disease/colorectal carcinoma Chronic cholecystitis/gall bladder carcinoma Osteomyelitis/skin carcinoma in draining sinuses

transcription or signal transduction induction, genomic instability and also replication errors [16,17]. Other mechanisms include inhibition of apoptosis, mutation of DNA and cellular repair functions such as p53 and also via promotion of angiogenesis [9,11]. There is also evidence of mitochondrial oxidative DNA damage within the carcinogenic process, with mutations and altered expression in mitochondrial genes encoding complexes I, III, IV and V having been identified in several human cancers [17a]. Most of the DNA-damaging effects of ROS are non-specific; however, studies have revealed that, in addition to inducing these actions, ROS can specifically activate certain intracellular signalling cascades and thus contribute to tumour development and metastasis through the regulation of cellular functions such as proliferation, death and motility. Growing evidence suggests that ROS production is tightly regulated and their downstream targets are quite specific [18]. It is also known that different cellular responses are affected by specific ROS. ROS are divided into free oxygen radicals and non-radical ROS. Free radicals contain one or more unpaired electrons and include superoxide and nitric oxide. Non-radical ROS include hydrogen peroxide. Hydrogen peroxide, which is generated by numerous intracellular reactions, exerts most of its mutagenic effects via hydroxyl ions which can activate oncogenes including K-ras [19]. In contrast, nitric oxide production is more specifically involved with tumour-cell killing and activation of the proto-oncogene p21 and the tumoursuppressor gene p53. These effects are thought to be caused as a consequence of overproduction of nitric oxide [20]. Nitric oxide is also associated with the generation of carcinogenic p53 mutations which have been shown to occur in approx. 50 % of cancers [21– 26].
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ROS, tumour survival and metastasis

It has been suggested that when subjected to oxidative stress such as the effects of ROS, certain cancer cells exhibit decreased attachment to the basal lamina meaning that they are more likely to detach and possibly metastasize. ROS can regulate cellular adhesion by modulating integrin expression, they have also been shown to suppress anoikis [apoptosis which is induced by anchorage-dependent cells detaching from their surrounding ECM (extracellular matrix)]. The degradation of the ECM involves MMPs (matrix metalloproteinases), with ROS including hydrogen peroxide, nitric oxide and iNOS implicated in the increased expression of several MMPs and also inactivation of tissue inhibitors of metalloproteinases [27–30]. It is possible that this effect on MMP expression may be due to activation of Ras, or direct action by MAPK (mitogen-activated protein kinase) family members including ERK1/2 (extracellular-signalregulated kinase 1/2), p38 or JNK (c-Jun N-terminal kinase). In vitro experiments have shown that induction of various MMPs occurs in response to expression of the Ras oncogene [31]. Ras can be activated by ROS via oxidative modification, which leads to the inhibition of GDP/GTP exchange [32]. Other redox-sensitive transcription factors such as NF-κB (nuclear factor κB) have also been implicated in MMP gene regulation [27]. HIF-1 (HYPOXIA-INDUCIBLE FACTOR-1)

Aside from elevated ROS, the reduction in physiological tissue oxygen tension (hypoxia), which occurs during tumour initiation, can also regulate cancer cell proliferation. Since angiogenesis within a tumour can be both erratic and also sub-optimal once established, tumours often become hypoxic. HIF-1, a heterodimeric transcription factor comprising HIF-1α and HIF1β, is a mediator of oxygen homoeostasis which, under hypoxic conditions, binds to the promoter of hypoxia-regulated genes and activates a range of hypoxia-responsive molecules including iNOS and VEGF (vascular endothelial growth factor), a potent angiogenic factor that is important in tumour growth and metastasis [14,33,34]. As such it is considered that the presence of HIF-1α plays an important role, in particular in early tumorigenesis in endocrine cancers [35]. Hypoxia-induced NFκB activation is dependent on the presence of HIF-1α, the oxygensensitive component of the HIF-1 molecule [36,37]. HIF-1α is also activated by pro-inflammatory cytokines, including TNF-α (tumour necrosis factor α) and IL (interleukin)-1β, in an NFκB dependent manner [38,39]. COX-2 (cyclo-oxygenase-2) also mediates IL-1β-induced HIF-1α expression through production of PGE2 (prostaglandin E2 ) [38]. Cancer cells have adapted these pathways effectively, allowing tumours to survive and even grow under adverse hypoxic conditions. This adaptation of tumour cells to hypoxia contributes to the malignant phenotype and to aggressive tumour progression, with the presence of tumour hypoxia resulting in poorer prognosis at diagnosis [40,41]. COX-2

Another inducible enzyme with carcinogenic properties that is active within inflamed and malignant tissues is COX-2. COX-2 is overexpressed in various cancers and, as COX-2 protein accumulates, it catalyses the formation of prostaglandins (most notably PGE2 within the tumour environment) and reactive byproducts which in turn accelerate neoplastic progression [42]. This includes inhibition of apoptosis, modulation of cellular adhesion and motility, promotion of angiogenesis and metastasis, and immunosuppression [43–47]. Other by-products of the COX-2 pathway, such as malondialdehyde production, are known

Genetic aspects of inflammation and cancer Table 2

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Human TLRs, their specific ligands and cell expression patterns

DC, dendritic cell; gp96, heat-shock protein gp96; Hsp, heat-shock protein; HMGB1, high mobility group box protein-1; NK, natural killer; PMN, polymorphonuclear; RSV, respiratory syncytial virus; –, currently unknown. Endogenous ligands present during tissue injury including chronic inflammation are shown in bold-type. Receptor

Exogenous ligand

Endogenous ligand

Cell type

TLR1 TLR2 TLR3 TLR4

Triacylated lipoprotein Peptidoglycans, triacylated/diacylated lipoprotein Double-stranded RNA Bacterial LPS, viral fusion protein (RSV), envelope protein, paclitaxel, mannan

Ubiquitous PMN leucocytes, DCs and monocytes DCs and NK cells Variety of cell types including monocytes, macrophages, endothelial cells and DCs

TLR5

Flagellin

– Hsp60, Hsp70, Gp96, HMGB1 mRNA Hsp60, Hsp70, Gp96, fibrinogen, fibronectin, heparan sulfate, soluble hyaluronan, β-defensin 2, HMGB1 –

TLR6 TLR7 TLR8 TLR9

Diacylated lipoprotein Viral single-stranded RNA Viral single-stranded RNA DNA with non-methylated CpG islands

– mRNA mRNA Autoimmune–IgG complex

TLR10

–

–

to form DNA adducts which result in mutations that also play a role in neoplastic initiation [47]. Upon binding to cellsurface receptors, PGE2 not only activates downstream G-coupled proteins but also indirectly activates other pathways which are becoming increasingly implicated in cancer progression, including the Wnt and PPAR (peroxisome-proliferator-activated receptor) signalling pathways [47–49]. In particular it has been demonstrated that PGE2 increases phosphorylation of glycogen synthase kinase-3β which prevents β-catenin degradation and results in increased β-catenin/T-cell-factor-mediated transcription which activates various Wnt target genes involved in early neoplasia including c-myc, c-jun, cyclin D1 and PPARδ [50]. There is strong epidemiological evidence implicating COX-2 in the pathogenesis of a number of epithelial malignancies. Inhibitors of the enzyme are associated with a reduction in risk of several cancers including gastric, cervical, lung, colon and prostate [51–53], with a reduction of up to 50 % in the morbidity and mortality of colorectal cancer [2,44,54–56]. Among the most potent inducers of COX-2 are the key pro-inflammatory cytokines IL-1α, IL-1β and TNF-α, as well as LPS (lipopolysaccharide), growth factors and oncogenes [57]. It has been reported that human gastric tumours with p53 missense mutations exhibit higher levels of COX-2 expression compared with tumours without p53 mutations suggesting that p53 mutations may downregulate COX-2 expression [58]. Until recently the role of COX in tumorigenesis has focused almost exclusively on the inducible form COX-2. However, there is now emerging evidence that COX-1, the constitutively expressed form of COX, is also important, with increased COX-1 expression shown in cancers of the female reproductive tract including ovarian and cervical cancers. Up-regulation of COX-1, but not COX-2, has been demonstrated in ovarian cancer, with COX-1-derived PGE2 promoting angiogenesis through production of VEGF [59,60]. INFECTION, INFLAMMATION AND CANCER: ROLE OF NF-κB

Chronic inflammation caused by persistent infection with a microorganism is a major driving force in tumour development. Classic examples among others include H.-pylori-associated gastritis and gastric cancer, inflammatory bowel disease-associated colorectal cancer, Epstein–Barr virus and nasopharyngeal carcinoma (Table 1). Unless micro-organisms carry their own oncogenes, toxins or growth factors, they affect the host and trigger

Monocytes, immature DCs, epithelial cells, NK cells and T-cells B-cells, monocytes and NK cells B-cells and plasmacytoid precursor DCs B-cells, monocytes and NK cells Plasmacytoid precursor DCs, B-cells, macrophages, NK cells and microglial cells B-cells and plasmacytoid precursor DCs

inflammation through activation of receptors that recognize PAMPs (pathogen-associated molecular patterns), which include LPS, peptidoglycan and also viruses and nucleic acids. The best described of these PRRs (pattern-recognition receptors) are TLRs (Toll-like receptors). TLRs play a key role in the inflammatory response against invading micro-organisms. TLRs are membrane-bound receptors that are expressed on a large number of cell types and recognize highly conserved components of bacteria, viruses and parasites (Table 2). TLRs also recognize various endogenous ligands, several of which are present within the inflammatory environment (Table 2). The engagement of PRRs activates numerous signal transduction pathways that target several transcription factors which regulate innate and adaptive immune responses [61,62]. These responses in turn activate other receptors that hone and amplify the inflammatory response, with the central role in this process being played by the NF- κB pathway (Figure 1). However, depending on the cell type in which it acts, NF-κB can either facilitate or inhibit cancer progression [63]. The NF-κB transcription factor family was discovered in 1986 by Baltimore and co-workers and has since been shown to be ubiquitously expressed in all human cell types [64,65]. NF-κB is a hetero- or homo-dimer consisting of five subunits of the Rel family of polypeptides comprising RelA (p65), CRel, RelB, p50/p105/NF-κB1 and p52/p100/NF-κB2; however, NF-κB mainly exists in the form of the heterodimer p65/p50. Prior to activation, most NF-κB molecules are retained in the cytoplasm, bound to one of the IκB (inhibitor of NF-κB) proteins. Upon stimulation, the IKK (IκB kinase) complex is activated which phosphorylates NF-κB-bound IκB and targets them for polyubiquitination and ultimately degradation. This allows NFκB to enter the nucleus and bind to κB-regulatory elements and co-ordinate the transcriptional activation of many immune response genes [66–68]. This is known as the classical NFκB signalling pathway and is triggered in response to proinflammatory cytokines and micro-organisms. Once activated, NF-κB regulates expression of over 200 genes, including genes encoding cell adhesion molecules and immune response genes including cytokines, and cell proliferation. NF-κB also regulates expression of NF-κB members and also the IκB proteins. There are other pathways of NF-κB activation which are less well described. These ‘alternative’ pathways are not directly activated as part of an innate immune response, and are triggered by only a limited number of stimuli. These other pathways are involved in generation of secondary lymphoid organs as well as
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Figure 1

G. L. Hold and E. M. El-Omar

Role of NF-κB in the inflammatory process

Ap-1, activator protein 1; ICAM-1, intercellular adhesion molecule 1; IKK, IκB kinase; IL-1R, IL-1 receptor; MAPK, mitogen-activated protein kinase; NIK, Nck-interacting kinase; TNFR, TNF receptor; TRAF, TNFR-associated factor.

B-cell maturation and survival and are thought to be important in B-cell lymphoma and skin carcinogenesis [69–71]. Evidence supporting the role of NF-κB in the initiation and promotion of malignancy comes from the fact that constitutive expression of NF-κB has been identified in a number of malignancies including hepatocellular carcinoma and breast and colorectal cancer [72–85]. NF-κB activation in at least two cell types is crucial for cancer development and progression. First, cells that are recruited to the tumour environment and produce cytokines, growth factors and proteases which support cancer development and progression. Production of several pro-inflammatory cytokines, including TNF-α, IL-1 and IL-6, chemokines such as IL-8, growth factors including VEGF and GRO-α (growth-related oncogene α), MMPs, adhesion molecules and also anti-apoptotic proteins including c-FLIP [cellular FLICE (Fas-associated death domain-like IL-1β-converting enzyme) inhibitory protein], Bcl-2 and p53, by these recruited cells are known to be dependent on NF-κB activation via the classical pathway [57,86,87]. However, once activated, these cells can also promote ROS production which induces DNA damage in a second cell type, cells that are programmed to undergo malignant transformation [88]. NF-κB also activates COX-2 expression, which is responsible for the induction of HIF-1α, which ultimately controls VEGF gene expression [57,89,90]. The up-regulated expression of cytokines and growth factors promotes cancer cell proliferation both directly and indirectly by increasing NF-κBmediated angiogenesis, tumour invasion and metastasis, with antiapoptotic proteins protecting against apoptosis and immune attack [91]. NF-κB activation also leads to a suppression of autophagy which is an alternative cell death pathway that is called in to play when apoptosis is inactivated. The role of autophagy in cancer will be discussed below. Furthermore, NF-κB contributes to drug resistance through multi-drug resistance-1 expression in cancer
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cells which is the basis for resistance to anti-cancer chemotherapy [92]. AUTOPHAGY AND CANCER

Defects in apoptosis which promote tumour growth and treatment resistance are common during tumorigenesis and have been well defined over the years. However, the importance of other forms of cell death such as autophagy and necrosis has been less well-understood and has only recently been linked with the carcinogenic process. Various cancers including breast, ovarian and prostate cancers have all been shown to display allelic loss of an essential autophagy gene beclin 1, which suggests that autophagy may well play a role in tumour suppression [93–95]. Autophagy, or type II programmed cell death is a highly regulated catabolic process in which organelles and cytoplasm are engulfed and targeted to lysosomes for degradation [96,97]. This is in contrast with apoptosis, which is termed type I programmed cell death. Autophagy is an adaptive response to nutrient deprivation, allowing cells to persist for prolonged periods under suboptimal nutrient conditions including during carcinogenesis where tumour growth frequently outstrips nutrient and oxygen supply, with autophagy known to localize to hypoxic tumour regions [97,98]. However, there is also evidence that autophagy, when allowed to proceed to completion, is a means of achieving cell death [98,99]. Autophagy also plays a crucial role in removal of damaged or surplus organelles. This removal limits exposure of cellular DNA to free radical damage which ultimately decreases basal DNA mutation rates, inflammation and suppresses oncogenesis [100,101]. These two mechanisms of the role of autophagy in carcinogenic development would appear to be paradoxical. However, it is thought that during carcinogenesis,

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Figure 2

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Role of cell death pathways in tumorigenesis

where normal apoptotic function is decreased, abrogation of autophagy creates reduced metabolic stress tolerance and cell viability which ultimately activates necrotic cell death and increases the inflammatory load of the tumour [96] (Figure 2). Moreover several oncoproteins including c-Myc, PI3K (phosphoinositide 3-kinase) and Ras are potent inhibitors of autophagy, whereas certain tumour suppressors including p53 actually activate autophagy [102–105]. Consistent with the observation that autophagy is reduced in tumour progression; it has been clearly demonstrated to be induced by several anti-cancer drugs and is therefore a target for cancer therapy. The growing evidence identifying the role of autophagy within carcinogenic progression cannot now be ignored; however, several important questions remain to be answered. These include defining what benefits a tumour derives from suppressing autophagy and also identifying the mechanisms by which cancer treatments induce autophagy. CYTOKINES

It is known that cancer cells are capable of attracting different cell types into the tumour micro-environment through secretion of extracellular proteases, pro-angiogenic factors and cytokines. Cytokines are small molecules that can either inhibit or propagate inflammation and activate or deactivate cancer genes and their pathways. Several examples exist to show how important cytokines are in the inflammatory neoplastic environment, with various animal knockout models showing predisposition of knockout animals to cancer development and also a growing body of evidence showing that numerous cytokine polymorphisms are associated with increased risk of inflammatory diseases and cancer [106–110]. Production of cytokines is induced via the classical NF-κB pathway; with many cytokines directly affecting

signalling pathways including induction of iNOS and also COX-2. Cytokines also induce pro-cancerous pathways and directly influence tumour-suppressor function and oncogene induction. Therefore cytokine signalling is thought to contribute to the tumour environment via two mechanisms: first, stimulation of cell growth and differentiation, and, secondly, inhibition of apoptosis of damaged cells [111]. Key pro-inflammatory cytokines include IL-1, -6, -12 and -18, TNF-α and macrophage MIF (migration inhibitory factor) [23]. Anti-inflammatory cytokines include IL-4 and -10, IFN (interferon)-α and -β. MIF and IL-6 are both known to ameliorate p53 function which favours cell survival. IL-6 also induces other anti-apoptotic genes including Bcl-2 and Bcl-XL , with the role of IL-6 becoming increasingly apparent within colon carcinoma progression [112–115]. Cytokines also affect cell death and cell cycle pathways, with IL-2 and TNF-α able to induce apoptosis in colon cancer cells [116]. IL-10 is secreted by tumour cells as well as macrophages, and among other effects, it inhibits cytotoxic T-cells and thus aids in suppressing the immune response against the tumour [5]. Quite often it is the profile of cytokines existing at an inflammatory site which is pivotal to defining outcome. For example, TNF-α, which is produced mainly by macrophages but also by tumour cells, is associated with tissue destruction and plays a role in destroying tumour blood supply. However, when chronically produced, it can act as a tumour promoter by contributing to tissue remodelling and stromal development [4,117]. Chemokines, which comprise the largest family of cytokines, are characterized by their ability to induce migration and activation of leucocytes to specific sites. This includes tumour stroma and the CC chemokine MCP (macrophage chemotactic protein)-1, which has been shown to be a major determinant of monocyte/macrophage infiltration in tumours. Tumour epithelial areas have also been found to express MCP-1, whereas additional
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chemokines such as MIP (macrophage inflammatory protein)1β and RANTES (regulated upon activation, normal T-cell expressed and secreted) may be detected in the stroma and regulate the infiltrate of other inflammatory cells including T-cells. Furthermore, chemokines may stimulate cells to release proteolytic enzymes, aiding the digestion of the ECM and providing a path for further inflammatory cell migration, tumour growth and metastasis. However, it is important to appreciate that in many preneoplastic conditions an inflammatory cell infiltrate is already well-established and drives pro-tumour effects. THE ABILITY OF HOST GENETICS TO MODIFY CANCER RISK

Genetic polymorphisms have emerged in recent years as important determinants of disease susceptibility and severity [118]. The completion of the human genome project has opened up the opportunity to dissect complex human diseases including cancers and to identify and understand the role of genetic polymorphisms. Although linkage analysis studies are suitable for pursuing rare high-risk alleles in conditions that have a hereditary basis, population-based association studies are much more useful for examining genes with a role in more common multifactorial diseases that have a strong environmental component [119]. These association studies often estimate the risk of developing a certain disease in carriers and non-carriers of a particular genetic polymorphism. The overwhelming majority of polymorphisms studied are SNPs (single nucleotide polymorphisms) that occur with a frequency of >1 % in the normal population (in contrast with mutations that occur with a frequency of A (rs1800629) polymorphism is known to be involved in a number of inflammatory conditions. Carriage of the pro-inflammatory A allele increased the OR for non-cardia gastric cancer to 2.2 [95 % CI (confidence intervals), 1.4–3.7]. The role of the TNF-A − 308 G>A polymorphism in gastric cancer was independently confirmed by a study from Machado et al. [124], with its role in other cancers also now confirmed [135,136]. IL-10 is an anti-inflammatory cytokine that downregulates IL-1β, TNF-α, IFN-γ and other pro-inflammatory

Genetic aspects of inflammation and cancer

cytokines. Relative deficiency of IL-10 may result in a Th1 (T helper-1)-driven hyperinflammatory response to H. pylori with greater damage to the gastric mucosa. We have reported that homozygosity for the low-IL-10 ATA haplotype [based on three promoter polymorphisms at positions − 592 (rs1800872), − 819 (rs1800871) and − 1082 (rs1800896)] increased the risk of non-cardia gastric cancer with an OR of 2.5 (95 % CI, 1.1– 5.7), with the importance of the IL-10 haplotype confirmed now in other cancers ([137] and extensively reviewed in [138]). We have studied the effect of having an increasing number of pro-inflammatory genotypes (IL-1B − 511*T, IL-1RN*2*2, TNF-A − 308*A and IL-10 ATA/ATA) on the risk of non-cardia gastric cancer [109]. The risk increased progressively so that by the time three or four of these polymorphisms were present, the OR for gastric cancer was increased to 27-fold [109]. The fact that H. pylori is a pre-requisite for the association of these polymorphisms with malignancy demonstrates that in this situation, inflammation is indeed driving carcinogenesis. Another important cytokine that is key in the pathogenesis of H.-pylori-induced diseases is IL-8. This chemokine belongs to the CXC family and is a potent chemoattractant for neutrophils and lymphocytes. It also has effects on cell proliferation, migration and tumour angiogenesis. The gene has a wellestablished promoter polymorphism at position − 251 [IL-8 − 251 A>T (rs4073)]. The A allele is associated with increased production of IL-8 in H.-pylori-infected gastric mucosa [139]. It was also found to increase the risk of severe inflammation and precancerous gastric abnormalities in Caucasian and Asian populations [140]. However, the same polymorphism was found to increase risk of gastric cancer only in some Asian populations [141–143] with no apparent effect in Caucasians. It is probable that other pro-inflammatory cytokine gene polymorphisms will be relevant to cancer initiation and progression. This exciting field has expanded greatly over the last few years and the search is now on for the full complement of risk genotypes that dictate the likelihood of an individual developing cancer. ROLE OF POLYMORPHISMS IN INNATE IMMUNE RESPONSE GENES

Genetic polymorphisms of cytokines of the adaptive immune response clearly play an important role in the risk of microbially induced carcinomas. However, micro-organisms are initially handled by the innate immune response and it is conceivable that functionally relevant polymorphisms in genes of this arm of the immune system could affect the magnitude and subsequent direction of the response of the host against the infection. In the case of H.-pylori-induced gastric carcinoma, the majority of H. pylori cells do not invade the gastric mucosa but the inflammatory response against it is triggered through attachment of H. pylori to the gastric epithelia, with TLR4 playing an important role in recognition [144]. Arbour et al. [145] described a functional polymorphism in the TLR4 gene (rs4986790). This A>G transition results in replacement of a conserved aspartic acid residue with a glycine residue at amino acid 299 (D299G) and alteration in the extracellular domain of the TLR4 receptor. This renders carriers hyporesponsive to LPS challenge by either disrupting transport of TLR4 to the cell membrane or by impairing ligand binding or protein interactions [145]. The mutation has been associated with a variety of inflammatory and infectious conditions including atherosclerosis, myocardial infarction, inflammatory bowel disease and septic shock [146–149]. Recent work demonstrates that defective signalling through the TLR4 receptor ultimately leads to an exaggerated inflammatory response with severe tissue destruction, even though the initial immune response may be blunted [150].

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This is due to inadequate production of IL-10-secreting type 1 regulatory cells [150]. We hypothesized that the TLR4+ 896A>G polymorphism would be associated with an exaggerated and destructive chronic inflammatory phenotype in H. pylori-infected subjects. This phenotype would be characterized by gastric atrophy and hypochlorhydria, the hallmarks of a subsequent increased risk of gastric cancer. We further hypothesized that the same polymorphism might increase the risk of gastric cancer itself. We proceeded to test the effect of this polymorphism on the H.-pylori-induced gastric phenotype and the risk of developing pre-malignant and malignant outcomes. We assessed associations with pre-malignant gastric changes in relatives of gastric cancer patients, including those with hypochlorhydria and gastric atrophy. We also genotyped two independent Caucasian population-based case-control studies of upper gastrointestinal tract cancer. TLR4+ 896G carriers had a 7.7-fold (95 % CI, 1.6–37.6) increased OR for hypochlorhydria; the polymorphism was not associated with gastric acid output in the absence of H. pylori infection. Carriers also had significantly more severe gastric atrophy and inflammation [151]. Also 16 % of gastric cancer patients in the initial study and 15 % of the non-cardia gastric cancer patients in the replication study had one or two TLR4 variant alleles compared with 8 % of both control populations (combined OR, 2.4; 95 % CI, 1.6–3.4) [151]. In contrast, the prevalence of TLR4+ 896G was not significantly increased in oesophageal squamous cell (2 %; OR, 0.4) or adenocarcinoma (9 %; OR, 0.8) or gastric cardia cancer (11 %; OR, 1.2). The association of the TLR4+ 896A>G polymorphism with both gastric cancer and its precursor lesions implies that it is relevant to the entire multistage process of gastric carcinogenesis, which starts with H. pylori colonization of the gastric mucosa. Subjects with this polymorphism have an increased risk of severe inflammation and, subsequently, development of hypochlorhydria and gastric atrophy, which are regarded as the most important precancerous abnormalities. This severe inflammation is initiated by H. pylori infection but it is entirely feasible that subsequent co-colonization of an achlorhydric stomach by a variety of other bacteria may sustain and enhance the microbial inflammatory stimulus and continue to drive the carcinogenic process. Evidence supporting this concept comes from the work of Sanduleanu et al. [152] who showed that pharmacological inhibition of acid secretion was associated with a higher prevalence of nonH. pylori bacteria. Furthermore, the simultaneous presence of H. pylori and non-H. pylori bacteria was associated with a markedly increased risk of atrophic gastritis, and with higher circulating levels of IL-1β and IL-8. Supporting evidence also comes from animal studies where hypochlorhydria was induced in mice either genetically (G− /G− gastrin-deficient mice) or pharmacologically (administration of omeprazole). Zavros et al. [153] found that genetic or chemical hypochlorhydria predisposes the stomach to bacterial overgrowth resulting in inflammation, which was not present in the wild-type mice or those not treated with an acid inhibitor. The potential mechanism by which the TLR4 polymorphism increases the risk of gastric cancer and its precursors is intriguing and may lie in the nature of the overall response of the host to the H. pylori LPS attack. Failure to handle the invasion by appropriately recognizing and activating the necessary pathways may lead to an imbalance of pro- and anti-inflammatory mediators. The findings emphasize, for the first time, the importance of innate immune response gene polymorphisms in outcome to neoplastic progression. This field of host genetic polymorphisms has expanded greatly over the last few years, and the search is now on for the full
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complement of risk genotypes that dictate the likelihood of an individual of developing cancer. This approach has now been adopted for many other cancers as described below. In Japanese patients with chronic HCV (hepatitis C virus) infection, the IL1B − 511 T/T genotype has been associated with an increased risk of progression to hepatocellular carcinoma [131]. Because the T/T pro-inflammatory genotype is related to greater IL-1 production, it is feasible that the risk of malignant transformation is higher. IL-1 leads to the production of PGE2 and hepatocyte growth factor and has angiogenic influence via iNOS and COX-2 expression. Furthermore, the degree of HCV-induced liver inflammation and fibrosis has been correlated with hepatic expression of Th-1 cytokines. At present, there is relatively little information on the relationship between other gastrointestinal malignancies and innate immune and cytokine polymorphisms. Some studies have addressed the influence of polymorphisms on cancer outcome. Barber et al. [154] found that possession of a genotype resulting in increased IL-1 production was associated with shortened survival in pancreatic cancer. Park et al. [155] investigated TNF-A and -B polymorphisms in 136 colorectal cancer patients and 325 healthy controls in an Asian population. Their results indicated that TNF-B*1/ TNF-B*1 genotypes showed an increased risk for colorectal cancer. De Jong et al. [156] performed pooled analyses on 30 polymorphisms in 20 low-penetrance genes and identified an additional three studies investigating TNF-A polymorphisms and colorectal cancer. Associations were detected for the a2, a5 and a13 TNF alleles and colorectal cancer. CONCLUDING REMARKS

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Received 1 October 2007/23 November 2007; accepted 30 November 2007 Published on the Internet 12 February 2008, doi:10.1042/BJ20071341


c The Authors Journal compilation
c 2008 Biochemical Society