Download Genetic aspects of inflammation and cancer

Biochem. J. (2008) 410, 225–235 (Printed in Great Britain)
225
doi:10.1042/BJ20071341
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]).
c The Authors Journal compilation c 2008 Biochemical Society
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G. L. Hold and E. M. El-Omar
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].
c The Authors Journal compilation c 2008 Biochemical Society
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
227
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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228
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
c The Authors Journal compilation c 2008 Biochemical Society
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,
Genetic aspects of inflammation and cancer
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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G. L. Hold and E. M. El-Omar
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 <1 %). It
is estimated that up to 10 million SNPs are probably present in
the human genome although not all have thus far been identified.
Naturally, most of these SNPs do not occur in coding sequences
and even those that do are not associated with any alteration
in the amino acid sequence and are therefore of no functional
consequence. A more useful definition of the variability of these
SNPs involves haplotype analysis. Haplotypes are a combination
of alleles at different markers along the same chromosome that
are inherited as a unit. The HapMap project was set up to
address this (http://www.hapmap.org) and is a valuable tool that
will facilitate the study of genetic polymorphisms relevant to
human health and disease. Other types of genetic variation include
deletion and insertion polymorphisms and microsatellite-repeat
polymorphisms.
Genetic polymorphisms directly influence inter-individual
variation in the magnitude of an inflammatory response, and
this clearly contributes to the ultimate clinical outcome of an
individual. An excellent example of this from our own work
[120] is the role of genetic polymorphisms in the pathogenesis
of H.-pylori-induced gastric cancer. H. pylori infection elicits
a powerful humoral and cell-mediated immune response that
causes inflammation in the gastric mucosa. The mediators of
this inflammatory response belong to the two main arms of the
immune system, namely adaptive and innate immunity. We
speculated that the most relevant candidate genes would be
ones whose products were involved in handling the H. pylori
attack and ones that mediated the resulting inflammation.
Because such a list of candidate genes would be prohibitively
extensive, our initial search focused on genes that were most
relevant to gastric physiology and, in particular, gastric acid
secretion. H.-pylori-induced gastritis is associated with three
main phenotypes that correlate closely with clinical outcome:
duodenal ulcer phenotype, benign phenotype and gastric cancer
phenotype [120]. Studies have shown that inhibition of gastric
acid pharmacologically can lead to a shift from an antrumpredominant pattern (duodenal ulcer phenotype) to a corpus-pre
c The Authors Journal compilation c 2008 Biochemical Society
dominant one with onset of gastric atrophy (gastric cancer
phenotype) [121]. Thus it was clear that an endogenous agent
that was up-regulated in the presence of H. pylori, has a profound
pro-inflammatory effect and was also an acid inhibitor would be
the most relevant host genetic factor to be studied. IL-1β fitted
this profile perfectly, for not only is it one of the earliest and most
important pro-inflammatory cytokines in the context of H. pylori
infection, but also it is the most powerful acid inhibitor known
[122]. We have shown that pro-inflammatory IL-1 gene cluster
polymorphisms (IL-1B encoding IL-1β and IL-1RN encoding
its naturally occurring receptor antagonist) increase the risk of
gastric cancer and its precursors in the presence of H. pylori
[108]. Individuals with the IL-1B − 31*C (rs1143627) or − 511*T
(rs16944) and IL-1RN*2/*2 genotypes are at increased risk of
developing hypochlorhydria and gastric atrophy in response to H.
pylori infection. This risk also extends to gastric cancer itself with
a 2–3-fold increased risk of malignancy compared with subjects
who have the less pro-inflammatory genotypes [108,109].
Furthermore, the pro-inflammatory IL-1 genotypes increased
the risk of both intestinal and diffuse types of gastric cancer
but the risk was restricted to the non-cardia subsite. Indeed,
the IL-1 markers had no effect on the risk of cardia gastric
adenocarcinoma, oesophageal adenocarcinoma or oesophageal
squamous cell carcinoma [109]. The latter findings are entirely
in keeping with the proposed mechanism for the effect of these
polymorphisms in gastric cancer, namely reduction of gastric acid
secretion. Thus a high IL-1β genotype increases the risk of noncardia gastric cancer, a disease characterized by hypochlorhydria,
whereas it has no effect on cancers associated with high acid
exposure such as oesophageal adenocarcinoma and some cardia
cancers.
The association between IL-1 gene cluster polymorphisms
and gastric cancer and its precursors has been confirmed
independently by other groups covering Caucasian, Asian and
Hispanic populations [123–129]. Machado et al. [125] were the
first to confirm the association between IL-1 markers and gastric
cancer in Caucasians and reported similar ORs (odds ratios)
to those reported by our group [108]. Furthermore, the same
group subsequently reported on the combined effects of proinflammatory IL-1 genotypes and H. pylori bacterial virulence
factors (cagA positive, VacA s1 and VacA m1) [123]. They showed
that for each combination of bacterial/host genotype, the odds of
having gastric carcinoma were greatest in those with both bacterial
and host high-risk genotypes. This highlights the important
interaction between host and bacterium in the pathogenesis of
gastric cancer. The role of IL-1 polymorphisms has also been
investigated in other cancers, with associations shown with
hepatitis-C-induced hepatocellular carcinoma, colorectal and also
breast cancer [130–133].
Soon after the IL-1 gene cluster polymorphisms were identified
as risk factors for gastric cancer, the pro-inflammatory genotypes
of TNF-A and IL-10 were reported as independent additional risk
factors for non-cardia gastric cancer [109]. TNF-α is another
powerful pro-inflammatory cytokine that is produced in the
gastric mucosa in response to H. pylori infection. Like IL-1β,
it has an acid inhibitory effect, albeit much weaker [134]. The
TNF-A − 308 G>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].
231
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
c The Authors Journal compilation c 2008 Biochemical Society
232
G. L. Hold and E. M. El-Omar
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
There is now substantial evidence that chronic inflammation and
malignant development are causally linked. However, further
studies are required to fully understand the complex relationship.
The situation is further complicated by the recent acceptance of
the role of chronic infection and also the contribution of host
genetic polymorphisms to the risk of an individual of developing
malignancy. Chronic inflammation, whether caused by microbes,
chemical or physical trauma, within a pre-malignant environment
favours neoplastic progression. However, once present, cancer
cells can ‘educate’ the immune infiltrate to produce the necessary
cytokine composition to facilitate tumour growth and metastasis
as well as acquiring immune tolerance. Understanding this
feedback loop is fundamental to resolving the complex interplay
between the causes of chronic inflammation and the genetic
disposition of the host to neoplastic progression, which will aid
the development of new and more effective anti-inflammatory
cancer prevention strategies in the future.
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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