Inflammation and colorectal cancer.

Abstract

Patients with long-standing inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer (CRC). However, the underlying mechanisms are not entirely clear. A genetic basis for the increased risk of CRC in IBD patients is only a partial explanation. It is possible that high levels of inflammatory mediators that are produced in this setting may contribute to the development and progression of CRC. Growing evidence supports a role for various cytokines, released by epithelial and immune cells, in the pathogenesis of IBD-associated neoplasia. Two key genes in the inflammatory process, cyclooxygenase-2 (COX-2) and nuclear factor kappaB (NF-kappaB), provide a mechanistic link between inflammation and cancer while other factors such as, TNF-alpha and IL-6-induced signaling have been recently shown to promote tumor growth in experimental models of colitis-associated cancer. This article reviews the pathogenesis of IBD-related CRC and summarizes the molecular mechanisms underlying the development of intestinal neoplasia in the setting of chronic inflammation.

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Inflammation and colorectal cancer
Sarah Kraus1and Nadir Arber1,2
Patients with long-standing inflammatory bowel disease (IBD)
have an increased risk of developing colorectal cancer (CRC).
However, the underlying mechanisms are not entirely clear. A
genetic basis for the increased risk of CRC in IBD patients is
only a partial explanation. It is possible that high levels of
inflammatory mediators that are produced in this setting may
contribute to the development and progression of CRC.
Growing evidence supports a role for various cytokines,
released by epithelial and immune cells, in the pathogenesis of
IBD-associated neoplasia. Two key genes in the inflammatory
process, cyclooxygenase-2 (COX-2) and nuclear factor
kappaB (NF-kB), provide a mechanistic link between
inflammation and cancer while other factors such as, TNF-a
and IL-6-induced signaling have been recently shown to
promote tumor growth in experimental models of colitis-
associated cancer. This article reviews the pathogenesis of
IBD-related CRC and summarizes the molecular mechanisms
underlyingthedevelopmentofintestinalneoplasiainthesetting
of chronic inflammation.
Addresses
1Integrated Cancer Prevention Center, Tel Aviv Souraski Medical
Center, 6 Weizmann Street, Tel Aviv 64239, Israel
2Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Corresponding author: Arber, Nadir (nadir@tasmc.health.gov.il)
Current Opinion in Pharmacology 2009, 9:1–6
This review comes from a themed issue on
Cancer
Edited by Bharat B Aggarwal
1471-4892/$ – see front matter
Published by Elsevier Ltd.
DOI 10.1016/j.coph.2009.06.006
Introduction
The functional relationship between inflammation and
cancer has long been recognized and was already estab-
lished two centuries ago. This link was made on the basis
of several observations (reviewed in [1??]):
1. Tumors arise at sites of chronic inflammation.
2. Inflammatory cells, chemokines and cytokines are
present in tumors.
3. Overexpression of cytokines and chemokines can
induce cancer.
4. The same molecular targets and similar pathways are
activated or shut down in inflammation, as well as in
the carcinogenesis process.
5. Epidemiological studies have shown that chronic
inflammatory states increase the risk of numerous
cancers.
6. Non-steroidalanti-inflammatory
reduce the incidence and the mortality of several
cancers.
drugs (NSAIDs)
The role of the immune system during cancer develop-
ment is complex, involving extensive reciprocal inter-
actions between genetically altered cells, adaptive and
innate immune cells, their soluble mediators and struc-
tural components present in the tumor microenvironment
[2].
In this review we discuss the model of colorectal cancer
(CRC) and inflammation as the proof of concept linking
between these two processes.
CRC remains a major health concern in the Western
world. There is a body of literature suggesting a link
between chronic inflammation and CRC, in which gastro-
intestinal (GI) inflammation may contribute to the pro-
motionofCRC development.
treatment is known to reduce GI neoplasia, while CRC
incidence is increased in inflammatory bowel disease
(IBD) [3?].
Anti-inflammatory
Human CRC can be classified by etiology as: (1) inher-
ited, including hereditary non-polyposis colorectal cancer
(Lynch Syndrome/HNPCC) due to genetic instability,
and familial adenomatous polyposis coli (FAP) due to a
mutation in the adenomatous polyposis coli gene, APC;
(2) inflammatory, including Crohn’s disease (CD) and
ulcerative colitis (UC); or (3) sporadic, accounting for
?80% of CRCs but with poorly defined etiology.
Patients with long-standing IBD have an increased risk of
developing CRC [4]. In fact, although patients with IBD
representonlyasmallfractionofCRCcases(1–2%),these
patients are among those at greatest risk of CRC in the
general population. Moreover, in patients with prolonged
(>30 years) and extensive colitis, the risk of CRC is much
higher (18%). Risk factors for CRC include extent and
duration of UC, primary sclerosing cholangitis, a family
history of sporadic CRC, severity of bowel inflammation
and early onset of the disease [3?].
Manyofthemolecularalterationsresponsibleforsporadic
CRC, namely chromosomal and microsatellite instability,
and hypermethylation also play a role in colitis-associated
CRC carcinogenesis. This article provides an overview on
the pathogenesis of IBD-related colorectal neoplasia and
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some of the molecular mechanisms underlying malignant
transformation in the mucosa of IBD patients.
Chronic inflammation and tumor development
Chronic inflammation is characterized by a continued
active inflammatory response and tissue destruction.
Many of the immune cells contributing to the pathology
of chronic inflammation (e.g. macrophages, neutrophils
and eosinophils) are involved directly or by producing
inflammatory cytokines that may influence the carcino-
genesis process [5?].
Chronic inflammation promotes carcinogenesis by indu-
cing gene mutations, inhibiting apoptosis, or stimulating
angiogenesis and cell proliferation [6]. Inflammation also
induces epigenetic alterations that are associated with
cancer development. Two key genes in the inflammatory
process, cyclooxygenase-2 (COX-2) and nuclear factor
kappaB (NF-kB), provide a mechanistic link between
inflammation and cancer and are targets for chemopre-
vention and particularly, in CRC [7].
NF-kB transcription factors have a key role in many
physiological processes and disease conditions. Given
its important role in mediating inflammatory signals, a
lotofattentionhasbeenfocusedontheroleofNF-kBand
its upstream activator, IkB kinase (IKK), and their invol-
vement in inflammation and cancer [8].
NF-kB is not a single gene but represents a family of
closely related transcription factors that includes five
genes NF-kB1 (p50/p105), NF-kB2 (p52/p100), RelA
(p65), c-Rel and RelB. NF-kB regulates the expression
of genes, many of which play important roles in the
regulation of inflammation and apoptosis. Although RelA,
RelB and NF-kB1 genetic alterations are rare in human
cancer, these proteins are constitutively activated in a
wide variety of human tumors and have been associated
with tumor progression [9]. Constitutive NF-kB acti-
vation has been recently evaluated in CRC [10?]. Thus,
constitutively active NF-kB was found in 40% of CRC
tissues and 67% of cell lines, and shown to promote tumor
growth.
Theupstream IkB kinasesarealso constitutively active in
some types of cancer. Defective IKKa was found in
several solid tumors such as breast, colon, ovarian, pan-
creatic, bladder, prostate carcinomas and melanoma [11].
A recent study has shown that IKKa is activated in
colorectal tumors and associates to the chromatin of
specific Notch targets, leading to the release of the co-
repressor SMRT (silencing mediator of retinoic acid and
thyroid hormone receptor) [12?]. The Notch pathway
plays an extensive role in the immune system and oper-
ates at various levels by acting in conjunction with
defined immunological signals such as cytokines, T cell
antigen receptor and co-stimulatory receptor-mediated
signaling. A role for Notch signaling in cancer has exten-
sively been reported (reviewed in [13]).
Many humancancersexhibitelevated prostaglandin(PG)
levels owing to upregulation of COX-2, a key enzyme in
eicosanoid biosynthesis. PGE(2) is a major downstream
mediator of COX-2 that promotes cellular proliferation
and angiogenesis, inhibits apoptosis, enhances invasive-
ness, and modulates immunosuppression. COX-2 is sig-
nificantly overexpressed in a variety of tumors, including
colorectal neoplasms, making it an attractive therapeutic
target [14]. Although COX-2 is regularly expressed at low
levels in colonic mucosa, its activity increases dramatic-
ally following mutation of the APC gene, suggesting that
the APC-b-catenin/TCF signaling activity may regulate
COX-2 gene expression.
Selective inhibitors of COX-2 (coxibs) have established
efficacy in the treatment of pain and inflammation com-
parabletothatofnon-selectiveNSAIDsbutwithsuperior
GI safety. Subsequently, additional pharmacologic activi-
ties have emerged outside of coxibs’ analgesic activity.
Celecoxib (Celebrex1, Pfizer, USA) is unique among the
coxibs and traditional NSAIDs, because this particular
drug displays the greatest potency to induce apoptotic
cell death and has clinically relevant anti-neoplastic
applications, arising from additional activities that may
exert anti-tumor functions independent of the COX-2
inhibitory activity [15].
Colitis-associated colorectal cancer
The association of IBD with CRC was first described by
Burrill Crohn in 1925 [16]. More than two decades
elapsed before the first description of a cancer of the
colon complicating ‘regional enteritis’ [17]. Later on,
additional case reports were published describing CRC
in patients with CD [18]. However, no statistically sig-
nificant increase in cancer risk among these patients was
found, mainly because the absolute numbers of CD-
associated cancer cases were usually small. Therefore,
CRC in CD has been less well studied and most of our
knowledge on the pathobiology of CRC is based on
studies of patients with UC.
In the early 1980s, a first attempt to calculate direct
comparisons between cancer incidences in CD and UC
was described. Studies conducted at The Mount Sinai
Hospital noted a parity of similar extent between the
relative risks of colon cancer in CD and in left sided
UC. Thus, it was suggested that ‘when cases of ulcera-
tive and Crohn’s colitis of similar anatomic extent are
followed for similar durations of time, the two diseases
may ultimately prove to have similar increases in risk
for CRC [19]. Generally, both diseases are characterized
by chronic, relapsing inflammation of the intestines. It
is assumed that chronic inflammation is what causes
cancer.
2
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The neoplastic transformation in IBD is thought to be
similar to the adenoma–carcinoma sequence in sporadic
CRC (reviewed in [20?]). However, unlike sporadic CRC
where dysplastic lesions arise in one or two focal areas of
the colon, in colitic mucosa, the dysplasia is usually
multifocal, reflecting a broader ‘field effect’.
The transition from normal epithelium to adenoma to
carcinoma is associated with acquired molecular events
involving mutations in oncogenes and tumor suppressor
genes, abnormal gene expression and genetic defects in a
variety of genes. This tumor progression model was
deduced by Fearon and Vogelstein from comparison of
genetic alterations seen in normal colon epithelium,
adenomas of progressively larger size, and malignancies
[21]. Among the earliest events in CRC carcinogenesis is
loss of the APC gene, which appears to be consistent with
itsimportantrole inpredisposingcarriersofgermlineAPC
mutations to colorectal tumors. These studies showed
that the molecular steps that occur after the activation of
the APC/b-catenin/TCF pathway involve a non-linear
accumulation of specific genetic changes, which include
detectable losses at the molecular level of portions of
chromosome 5q, chromosome 18q, and chromosome 17p,
changes in methylation patterns and mutation of the K-
ras oncogene. The important genes involved in these
chromosome lossesare
MADH4(18q), and p53(17p).
APC(5q), DCC/MADH2/
Many ofthemolecularalterationsresponsibleforsporadic
CRC development also play a role in colitis-associated
colon carcinogenesis. However, there are several differ-
ences in the sequence of molecular events leading from
dysplasia to invasive adenocarcinoma inIBDas compared
with sporadic CRC. For example, APC loss of function,
considered to be a common early event in sporadic CRC,
ismuch lessfrequent and usually occurslate inthe colitis-
associated dysplasia–carcinoma sequence. On the con-
trary, p53 mutations in sporadic neoplasia usually occur
late in the adenoma–carcinoma sequence, whereas in
patients with colitis, p53 mutations occur early and are
often detected in non-dysplastic mucosa [20?].
Microsatellite instability and hypermethylation
Chromosomal instability, microsatellite instability (MSI),
and hypermethylation are assuming increasing import-
ance as mechanisms contributing to the genetic altera-
tions in IBD. MSI due to mismatch repair deficiency has
been reported to occur at variable frequencies in IBD-
associated intestinal neoplasias [22?]. Moreover, the
mutational events in target genes for instability in these
cancers are similar to those in sporadic and hereditary
colorectal cancers, indicating a colon-related repertoire of
target gene alterations.
About 12–15% of sporadic CRCs display defective DNA
mismatch repair, manifested as high levels of MSI. In this
group of cancers, promoter hypermethylation of the mis-
match repair gene hMLH1 is strongly associated with
MSI. Silencing the hMLH1 gene expression by its pro-
moter methylation stops the formation of MLH1 protein,
and prevents the normal activation of the DNA repair
gene. This is an important cause for microsatellite
instability and cell proliferation to the point of colorectal
cancer formation [23]. In IBD neoplasia, hMLH1 pro-
moter hypermethylation is a frequent event. Further-
more, hMLH1 hypermethylation and MSI are strongly
associated with reduced hMLH1 protein expression in
IBD-related neoplasia, suggesting that its hypermethyla-
tion causes defective DNA mismatch repair in at least a
subset of IBD cancers [24].
CpG island hypermethylation is a mechanism of gene
silencing that can be used by neoplastic cells to inactivate
undesirable genes. Methylation of CpG islands in several
genes seems to precede dysplasia and is more widespread
inUCpatients[25].Schulmannetal.havedeterminedthe
frequency of high-level MSI and the mutational and
methylation profile of IBD-related neoplasia, and found
that the profiles of coding microsatellite mutations (insta-
bilotypes) differ significantly between IBD cancers and
sporadic CRCs [26]. Specifically, TGFBR2 and ACVR2
mutations are significantly rarer in IBD. Furthermore,
HPP1 methylation occurs early, in non-dysplastic and
dysplastic mucosa, whereas RAB32 methylation occurs
at the transition to invasive growth, being rarer in dys-
plasias. Therefore, it is reasonable to assume that these
mutations evolve through different pathways, leading to
differentially expressed instabilotypes.
Tumor necrosis factor-alpha
Growing evidence supports a role for various cytokines,
released by epithelial and immune cells, in the patho-
genesis of colitis-associated cancer. Cytokines are essen-
tial mediators of the interactions between activated
immune cells and non-immune cells, including epithelial
and mesenchymal cells. Tumor necrosis factor-alpha
(TNF-a) is a potent pro-inflammatory cytokine thought
to be involved in the pathogenesis of IBD. Recent data
indicate that TNF-a promotes tumor development in
models of experimental colitis. Popivanova et al. have
recently shown that blockade of TNF-a reduces the
formation of colorectal tumors in mice lacking the
TNF receptor, p55 (TNF-Rp55 knockout) [27??]. Com-
bined treatment with azoxymethane and dextran sodium
sulfate (AOM/DSS), which causes severe colonic inflam-
mation and the subsequent development of multiple
tumors, induced the intracolonic expression of TNF-a,
which in turn regulated the trafficking of inflammatory
cells, a major source of COX-2. These findings are of
particular interest because they suggest that blocking
of TNF signaling can reverse tumorigenesis even
when CRC is already present, probably by reducing
the infiltration of inflammatory cells and, consequently,
Inflammation and colorectal cancer Kraus and Arber3
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the circulating levels of COX-2. Therefore, strategies
targeting TNF-a could potentially provide effective
anti-tumor therapies.
It should be noted that the regulation of TNF-a is partly
genetic. Single nucleotide polymorphisms (SNPs) in the
promoter of TNF-a were found associated with an
increased risk for IBD and may genetically predispose
towards developing colitis-associated CRC [28?].
Nuclear factor kappaB
Although the molecular mechanisms linking IBD with
CRC are not well understood, recent studies in pre-
clinical models point to NF-kB as a central player. NF-
kB regulates the expression of various cytokines and
modulates the inflammatory processes in IBD. On the
contrary, NF-kB stimulates the proliferation of tumor
cells and enhances their survival through the regulation
of anti-apoptotic genes.
Pro-inflammatory cytokines have been suggested to
regulate pre-neoplastic growth during colitis-associated
tumorigenesis. Interleukin 6 (IL-6) is a multifunctional
NF-kB-regulated cytokine that acts on epithelial and
immune cells. The importance of the IL-6 family of
pro-inflammatory cytokines and their downstream effec-
tor STAT3 in colitis-associated CRC has been recently
described (reviewed in [29]). Human patients with CRC
have been reported to have elevated levels of IL-6 and
increased levels of IL-6 have also been shown in murine
experimental models of colitis-associated cancer induced
by AOM/DSS [30].
STAT3, a nuclear transcription factor downstream of
gp130, is necessary for the growth of colitis-associated
CRC in mice [31??,32??]. It appears to function through
increased epithelial proliferation and protection against
AOM/DSS-induced epithelial cell apoptosis. Interest-
ingly, DSS-induced mucosal inflammation or colitis was
markedly increased in both IL-6-deficient mice and in
mice lacking STAT3 in intestinal epithelial cells, which
correlated with an increase in the expression of pro-
inflammatory cytokines within the colonic mucosa.
Oxidative stress
The exact mechanism by which chronic inflammation
results in carcinogenesis is still unclear. Persistent inflam-
mation is believed to result in increased cell proliferation
as well as oxidative stress, leading to the development of
dysplasia [33]. Oxidative stress develops particularly in
inflammatory reactions because the inflammatory cells,
activated neutrophils, and macrophages produce large
amounts of reactive oxygen and nitrogen species (RONs).
DNA damage caused by oxidative stress in the charac-
teristic damage-regeneration cycle is a major contributor
to CRC development in UC patients. Thus, oxidative
stress-induced cellular damage may provide a mechan-
istic basis for many of the events thought to drive UC-
associated colon carcinogenesis in humans and animal
models, including specific gene alterations, genetic
instability and aberrant methylation. The available evi-
dence suggests that DNA damage caused by oxidative
stress in the characteristic damage-regeneration cycle is a
major contributor to CRC development in UC patients.
RONs produced by inflammatory cells can interact with
key genes involved in carcinogenic pathways such as p53,
DNA mismatch repair genes, and others. Factors such as
NF-kB and COX-2 may also contribute.
Studies in animal models of UC have provided support as
to the involvement of oxidative stress in inflammation-
drivenCRC.Seriletal.haverecentlyexaminedtheroleof
nitric oxide (NO) in UC-associated colorectal carcinogen-
esis using the DSS-induced and iron-enhanced model of
chronic UC in inducible nitric oxide synthase (iNOS)
knockout mice. These results showed that there is no
difference in UC-associated cancer development in
iNOS+/+and iNOS?/?mice, suggesting that in the
absence of iNOS, other factors, such as eNOS, may play
a role in nitrosative stress and UC-associated carcinogen-
esis in this model system [34].
Notably,
deficiency anemia owing to chronic disease and colonic
blood loss,and anemia is corrected in these individuals by
iron supplementation. It has been suggested that iron
over nutrition may contribute to the carcinogenesis pro-
cess by augmenting oxidative damage and inflammation-
caused epithelial proliferation. However, further clinical
studies are needed to clarify this issue [35].
UCpatients frequently experience iron
Transforming growth factor-beta and other factors
Despite a primary tumor suppressor role, there is increas-
ing evidence suggesting that transforming growth factor-
beta (TGF-b) can promote tumor growth, invasion and
metastasis in advanced stages of CRC. TGF-b has been
shown to attenuate an anti-tumor immune response
through the induction of regulatory T cells in spon-
taneous and inflammation-associated cancer. However,
IL-6 signaling promotes tumor growth in experimental
colitis-associated cancer, and this signaling has been
shown to be inhibited by TGF-b [36]. Therefore, the
role of TGF-b in this setting is not entirely clear.
Members of the IL-12 family, p35/p40 play an important
role in T helper (Th) cell polarization and Th1 T cell
differentiation. Recent findings have shown that both p35
and p40 can form other cytokines by heterodimerizing
with different proteins (IL-23: p19/p40; IL-35: p35/
EBI3). Furthermore, the cytokine IL-27 (EBI3/p28)
was recently identified as a member of the IL-12 family.
These cytokines have been implicated in the pathogen-
esis of colitis and IL-23, which plays a key role in the
induction and maintenance of gut inflammation during
4
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IBD, seems to be involved in inflammation-associated
carcinogenesis (reviewed in [37]).
While some cytokines promote tumor growth, others such
as IL-10, provide an anti-tumor effect. IL-10-deficient
mice develop colitis and colitis-associated cancer within
two to three weeks after birth. The IL-10 knockout
mouse model results in a disease similar to human IBD
and therefore, has been proven useful as an experimental
model for developing new and effective therapies for
active IBD and CD, in particular. However, a previous
report aiming to identify possible mutations of oncogenes
and tumor suppressor genes involved in colorectal tumor-
igenesis in these mice, showed no alterations in K-ras,
p53, APC and MSH genes, suggesting that other genes are
involved in the development of these tumors [38]. There-
fore,despitethehighsimilarities betweenthehistopatho-
logical pattern of CRCs in IL-10-deficient mice and IBD-
associatedcarcinomas, this model isapparentlynotappro-
priate for investigating IBD-associated carcinogenesis.
Since most of the above mentioned cytokines are
involved in both, inflammation and carcinogenesis, it is
difficulttoassesstheircontributiontotheindividualsteps
during pathogenesis of colitis-associated cancer.
Conclusion
Patients with IBD have an increased risk of developing
CRC. This risk appears to be closely associated to the
cumulative effect of chronic inflammation and is in
direct correlation with the severity of the inflammation
and the extent and duration of the disease. The exact
mechanism as to how chronic inflammation results in
carcinogenesis is not resolved, although it is becoming
clear that chronic inflammation and IBD in particular, is
an important driving mechanism that promotes the de-
velopment of cancer in the colon. Further studies are
needed in order to elucidate the pathogenesis of colitis-
associated CRC.
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