review

Inflammatory networks underlying

colorectal cancer
Audrey Lasry1,2, Adar Zinger1,2 & Yinon Ben-Neriah1

Inflammation is emerging as one of the hallmarks of cancer, yet its role in most tumors remains unclear. Whereas a minority
of solid tumors are associated with overt inflammation, long-term treatment with non-steroidal anti-inflammatory drugs is
remarkably effective in reducing cancer rate and death. This indicates that inflammation might have many as-yet-unrecognized
© 2016 Nature America, Inc. All rights reserved.

facets, among which an indolent course might be far more prevalent than previously appreciated. In this Review, we explore the
various inflammatory processes underlying the development and progression of colorectal cancer and discuss anti-inflammatory
means for its prevention and treatment.

Chronic inflammation is one of the hallmarks of cancer1, and many
tumors arise following prolonged inflammation or display character-
istics of chronic inflammation throughout their progression2,3 (Fig. 1).
Colorectal cancer (CRC) has long been known as one of the best examples
of a tumor tightly associated with chronic inflammation, which can be
present from the earliest stages of tumor onset. CRC, the third most com-
mon form of cancer-related death in the USA, is most often sporadic (with
no clear hereditary basis), usually caused by a somatic mutation in a gene
encoding a component of the Wnt signaling pathway4, or is sometimes
caused by an hereditary mutation, as in patients with Lynch syndrome4
or familial adenomatous polyposis (FAP)5. Much less often, it arises
following prolonged inflammation in the intestine, as in patients with
inflammatory bowel disease (IBD), such as Crohn’s disease or ulcera-
tive colitis6. Strikingly, while the hereditary cases are rarely preceded by
npg
and its surroundings, which include billions of microorganisms, as
well as numerous organic and inorganic substances, that are poten-
tially harmful. In the gastrointestinal tract, intestinal epithelial cells
(IECs) acquire a series of properties that enable them to function as a
selective barrier, orchestrate the complex interaction between the host
and its environment, and maintain tissue homeostasis. Along with
other mucosal and sub-mucosal cells, including cells of the immune
system, and the overlying mucus layer, the IECs constitute a pro-
tective shield that stands between the host and the hazardous
intestinal lumen9,10. Damage to this barrier results in pathological
interactions among epithelial cells, microflora and the immune system.
This might lead to a disruption of homeostasis, pathological inflam-
matory responses and tumorigenesis. Barrier dysfunction has been
linked to various pathological conditions11, including complications

overt chronic inflammation, they can be prevented or delayed by treat-
ment with anti-inflammatory drugs7,8, which suggests the involvement
of inflammatory processes in the tumor onset. Inflammatory reactions
are often linked to microbial responses, and the intestinal tract is popu-
lated by myriad bacterial strains, which commonly live in harmony with
their host, yet any substantial shift in the bacterial population can have a
considerable effect on inflammatory responses and contribute to tumor
development. In this Review, we explore the various inflammatory proc-
esses underlying the development and progression of CRC and discuss
anti-inflammatory means for the prevention and treatment of CRC.
Gut epithelial immunity in CRC
Epithelial structures, including the skin, respiratory mucosa and
intestinal mucosal epithelium, constitute a barrier between the host
1The Lautenberg Center for Immunology and Cancer Research, Institute
for Medical Research Israel-Canada, Hebrew University–Hadassah Medical
School, Jerusalem, Israel. 2These authors contributed equally to this work.
Correspondence should be addressed to Y.B.-N. (yinonb@ekmd.huji.ac.il).
Received 19 October 2015; accepted 17 December 2015; published online
16 February 2016; doi:10.1038/ni.3384
of liver cirrhosis12, IBD13,14 and CRC15. Here we will discuss the
epithelial immunological networks underlying barrier function in
health and disease.
Epithelial innate immune responses activated by various exoge-
nous and endogenous danger signals fulfill a critical role in mucosal
immunity16,17, well beyond classical inflammation, and their impor-
tance in both the maintenance of homeostasis and tumorigenesis is
increasingly recognized. Pattern-recognition receptors and sensors
of cytoplasmic nucleic acids are key mediators of innate immunity18.
After being activated, those receptors and sensors induce signaling
via type I interferons, the main anti-viral effector arm of the immune
system, as well as signaling via the adaptor MyD88 (refs. 19,20). Type I
interferons and MyD88 can be activated not only by exogenous patho-
gens and microbe-associated molecular patterns but also in response
to intrinsic cellular stressors, such as danger-associated molecular
patterns (DAMPs)21. An example of a DAMP is the nucleic acid frag-
ments produced as part of the DNA-repair process after damage to
DNA. Damage caused by ultraviolet irradiation, for example, results in
the release of a 30–base pair nucleotide-excision product that includes
the damage site22. Such fragments, protected by association with a
repair protein, could ignite various signaling pathways, including

230 VOLUME 17  NUMBER 3  MARCH 2016  nature immunology

 review

Figure 1  The inflammatory spectrum a Chronic inflammation

Inflammatory cytokines
underlying the development of CRC. (a) Chronic IL-6, TNF, IL-1β, IL-17
inflammation, such as IBD, can be caused Invading bacteria DNA
damage
by barrier dysfunction, Paneth cell defects or
defective innate immune responses, which lead IBD Inflamed epithelial
to enhanced susceptibility to bacterial invasion. cells and
breached barrier
The inflamed environment acts as a fertile
ground for the accumulation of mutations, Normal epithelial tissue
and intact barrier
which can result in tumor development. (b) The
formation of ectopic lymphoid structures (ELSs)
by cells of the immune system in the intestine
b Focal inflammation and ELSs

acts as a tumor-suppressor mechanism for the

eliminatation of transformed cells. In the liver,
however, such structures act as a niche for
Immune Cytotoxic activity
tumor progenitor cells until they mature, acquire of ELSs
cells
self-sufficiency and egress to form tumors.
(c) DNA damage in the intestinal epithelium

Marina Corral Spence/Nature Publishing Group

can activate reactions of the innate immune
system via sensors of double-stranded Tumor
cells ELSs as a niche
DNA. Prolonged DNA damage can result in
for tumor cells
parainflammation, which renders the cells
more sensitive to transformation after
mutation of the gene encoding p53 (TP53).
© 2016 Nature America, Inc. All rights reserved.

signaling by the innate immune system via c Parainflammation

sensors of nucleic acids (Fig. 2). STING is
a receptor for cytoplasmic nucleotides and
serves as a mediator of signaling by other
Normal epithelial tissue
innate sensors23. In a mouse model of defi-
ciency in the DNA-damage sensor ATM
(‘ataxia-telangiectasia mutated’), loss of ATM leads to inactivation
of DNA-repair pathways and constitutive DNA damage, followed
by release of DNA to the cytoplasm, which results in a type I inter-
feron response via activation of the STING pathway24. When treated
with the carcinogen AOM, followed by induction of intestinal inflam-
mation by dextran sulfate sodium (DSS), STING-deficient mice
display more phosphorylation of the transcription factor STAT3 and
activation of the transcription factor NF-κB, followed by a greater tumor
load, than that of their wild-type counterparts; this suggests an anti-
tumorigenic role for STING in colitis-associated CRC (CAC)25.
Indeed, cytoplasmic sensors are dysregulated in cancerous lesions26,27
and have been recognized as important participants in tumorigenesis,
npg
TP53
Chronic DNA damage mutation
Parainflamed epithelial tissue Tumor
partly as mediators between intracellular processes and the tumor
microenvironment (Box 1).
Inflammasomes are cytoplasmic protein complexes that sense
diverse inflammatory stimuli, many of which are DAMPs, and serve
as intracellular signaling platforms downstream of those stimuli28–30.
The inflammasome components include, among others, the sensor
NAIP, the scaffold proteins NLRC4, NLRP3, NLRP6 and AIM2,
and the adaptor ASC31. Once the complex is assembled, it activates
caspase-1, which in turn leads to the cleavage of precursors and
release of the proinflammatory cytokines interleukin 1β (IL-1β)
and IL-18. Whereas macrophages are considered the main source of
IL-1β32, both IL-1β and IL-18 are also produced by IECs and regulate

Figure 2  DNA damage and the innate immune

Bacteria UV
response. Cytoplasmic nucleic acid fragments (A)
act as danger signals that modulate various
inflammatory and tumorigenic pathways. ROS Oligonucleotide-repair
Bacterial toxin protein complex (A)
These can be from an exogenous source (A),
such as microbial nucleic acids, bacterial Innate sensors
toxins, ultraviolet irradiation (UV) or ROS, or (B)
endogenous signals (B), a result of continuous STING AIM2
Inflammasome
DNA damage due to impaired mismatch-repair
Mismatch-
mechanisms, as in Lynch syndrome. It has repair defect
Marina Corral Spence/Nature Publishing Group

been suggested that oligonucleotides that

Type I interferon Parainflammation
are excised from the genome in the process
of repairing damage caused by ultraviolet IL-18 IL-1β
irradiation might remain in a cytoplasmic
complex with repair proteins and act as a
signaling factor. These danger signals induce
inflammasome activation, type I interferon
responses and parainflammation. The Intestinal barrier
inflammasome-processed cytokine IL-1β causes
barrier dysfunction, dysbiosis and recruitment
of inflammatory cells, whereas the other Inflammatory
inflammasome-derived cytokine, IL-18, acts to cells
reinforce the intestinal barrier.

nature immunology  VOLUME 17  NUMBER 3  MARCH 2016 231

 review

Box 1  Atypical inflammatory responses in CRC

In addition to the well-established role of chronic inflammation in the initiation of CRC, there is also accumulating evidence for the
involvement of atypical inflammatory responses, which might have a substantial effect on tumor development and progression.
  Ectopic lymphoid structures are often found in inflamed or cancerous tissues and exhibit all of the characteristics of lymph nodes
associated with activation of the adaptive immune response161,162. In CRC, these structures have been identified as a positive
prognostic marker163. The mechanism for their formation in tumors has yet to be elucidated; they differ in size and composition in
different patients161, which suggests that their role might also vary. Interestingly, they have a tumor-promoting role in hepatocellular
carcinoma, in which they can act as a niche for the developing tumor cells164 (Fig. 1).
  Another atypical inflammatory role can be attributed to the activation of innate nucleotide sensors in hereditary CRC syndromes.
The two most common familial syndromes are FAP and hereditary non-polyposis CRC (HNPCC; Lynch syndrome). FAP is characterized
by mutation of the gene encoding APC, a negative regulator of Wnt signaling that also regulates cell polarity and chromosome segrega-
tion during mitosis165. Patients with FAP have a truncated APC protein, which leads to the activation of Wnt and chromosomal instability
and as a result, they develop thousands of polyps in the intestine. HNPCC is caused by specific mutations in genes encoding factors
involved in DNA-mismatch repair, which leads to microsatellite instability and eventually results in mutation of the gene encoding
APC166. Whereas both FAP and HNPCC are tightly linked to specific mutations in genes encoding products in signaling pathways
related to DNA repair, they are generally not associated with inflammatory syndromes. However, several studies have indicated that
the treatment of patients with FAP or HNPCC with anti-inflammatory drugs has a beneficial effect and can delay tumor onset7,8, which
suggests that inflammation contributes to tumor formation in these patients. Innate DNA sensors might thus provide the link between
chronic DNA damage and inflammation; several sensors of DNA damage have also been linked to the sensing of cytosolic DNA and the
activation of an immune response via the adaptor STING167,168. It is possible that in patients with impaired DNA-repair pathways,
© 2016 Nature America, Inc. All rights reserved.

the sensors are constantly engaged, which would generate a state of chronic inflammation. Constant activation of DNA sensors by
persistent DNA damage might also be linked to parainflammation. High rates of mutation might also favor loss of functional p53,
which, when combined with parainflammation, creates a potent tumor-promoting mechanism73 (Fig. 3).

the epithelial barrier function32–34 and activity of effector and
regulatory CD4+ T cells in intestinal mucosa35 (Fig. 2). Accumulating
evidence has shown substantial expression of inflammasome pro-
teins in IECs, which highlights their role in mucosal immunity and
the maintenance of gut homeostasis36. In the AOM-DSS model,
caspase-1 has a protective effect against tumorigenesis, probably when
activated downstream of the NLRC4 inflammasome. This effect is
not achieved through a reduction in colonic inflammation but is
instead a consequence of direct regulation of the proliferation and
apoptosis of IECs37.
AIM2 is a sensor of double-stranded DNA that serves as one of the
mediators of inflammasome assembly. The contribution of AIM2 to
tumorigenesis has gained interest over the past few years. Analysis of tis-
npg
in colonic myofibroblasts within the epithelial stem cell niche, with
an important role in the regulation of epithelial proliferation and
wound healing42.
IBD and CRC
Patients with IBD, most commonly Crohn’s disease or ulcerative
colitis, are at a higher risk of developing CRC, and CAC is responsible
for approximately 15% of deaths due to IBD6. IBD is characterized
by a prolonged inflammatory response to luminal bacteria or to
sustained mucosal danger signals (DAMPs), yet the genetic factors
underlying IBD have only just begun to be delineated, with approxi-
mately 100 different risk loci for IBD identified via genome-wide
association studies, 30 of which are common to Crohn’s disease

sues from 414 patients with CRC revealed that 67% of them had reduced
expression of AIM2 in tumor tissue compared with that of adjacent
normal tissue. Lower expression of AIM2 was linked to higher
mortality rate26. For characterization of the role of AIM2 in colonic
tumorigenesis, the AOM-DSS CRC protocol was applied to AIM2-
deficient mice. AIM2-deficient mice developed a significantly greater
tumor load, both in number and size, than that of their wild-type
counterparts. This effect was inflammasome independent and was
attributed to the inhibitory effect of AIM2 on the tumor-initiating
intestinal stem cells with high Wnt activity38,39.
NLRP6, a member of the NLR family of receptors, takes part in
inflammasome signaling and has a critical role in host defense against
infection. Several studies have shown that NLRP6 is an important par-
ticipant in the maintenance of mucosal homeostasis. It is expressed in
IECs, especially in goblet cells, in which it regulates mucus secretion
and barrier integrity via control of the autophagy pathway40. Defects
in the NLRP6 inflammasome result in mucosal hyperplasia, spontane-
ous colitis and exacerbation of the inflammatory response after treat-
ment with DSS. The protective effect of NLRP6 has been attributed
to inflammasome-mediated release of IL-18 and modulation of the
intestinal microbiome41, possibly via the secretion of anti-microbial
peptides34. Notably, one study has shown high expression of NLRP6
and ulcerative colitis43.
Genome-wide association studies have enabled the identification of
common pathways affected by mutations in IBD-risk genes, including
intestinal barrier function44,45, defense against microbes46, regulation
of innate immunity, generation of reactive oxygen species (ROS) 47,
autophagy48–50, endoplasmic reticulum stress51 and adaptive immu-
nity. In some cases, a mutation in a relevant gene is enough to cause
the disease, while in other cases the mutation by itself will not lead to
disease development, unless it occurs in combination with an as-yet-
unknown environmental effect52. Patients with IBD, as well as mouse
models mimicking the human disease, often show defects in intes-
tinal barrier function that result from several causes. These include
defects in the mucus layer lining the intestine, as well as changes
in intestinal microbiota, which culminate in an increase in muco-
lytic bacteria. Impaired innate immune responses can occur due to
mutations in genes encoding major regulators of the innate immune
system that affect the function of dendritic cells, macrophages and
neutrophils, as well as mutations in genes encoding such factors that
regulate IECs. An example of the latter is the NLRP3 inflamma-
some, in which single-nucleotide polymorphisms in related genes
are associated with enhanced susceptibility for Crohn’s disease53.
Mice with deficiency in the NLRP3 inflammasome display defects in

232 VOLUME 17  NUMBER 3  MARCH 2016  nature immunology


Figure 3  Inflammatory basis of sporadic CRC a Sporadic CRC
or of CAC. (a) In sporadic CRC, an early event Normal tissue
is mutation in the Wnt pathway, usually in the
gene encoding APC, accompanied by loss of
cell polarity and tight junctions, which enables
the invasion of bacteria and production of the
pro-inflammatory cytokines IL-23 and IL-17.
Mutations in the gene encoding APC are
usually followed by mutations in the oncogene Intestinal crypts
KRAS and the gene encoding p53 (TP53),
which enable the progression from adenoma to Activation of innate dsDNA sensors, loss of
cell polarity, tumor-suppressive parainflammation
carcinoma. dsDNA, double-stranded DNA.
(b) In CAC, inflammatory cytokines are constantly
present in the intestinal tissue. Mutation of
the gene encoding p53, an early event in CAC,
b CAC
Inflamed tissue
results in prolonged activation of NF-κB and
IL-6, TNF
enhanced inflammation. Additionally, barrier
dysfunction promotes the invasion of bacteria,
which further enhances the inflammatory
response. The inflammatory environment
generates ROS, which can drive DNA damage, ROS
finally resulting in mutation of the gene encoding
APC and the development of carcinomas. STAT3 activation, NF-κB activation, barrier dysfunction
© 2016 Nature America, Inc. All rights reserved.
the activation of both macrophages and epithelial cells of the colon
and are thus more susceptible to DSS-induced colitis 54,55. Finally,
mutations that affect the function of Paneth cells have also been linked
to IBD51,56–58. Paneth cells reside in the bottom of intestinal crypts
and protect against pathogenic bacteria59, and they create a niche for
the neighboring intestinal stem cells60. The breakdown of defense
mechanisms activated by Paneth cells can lead to prolonged inflam-
mation and can contribute to a noxious environment for stem cell
proliferation, which might account, at least in part, for the increased
risk for CAC development.
CAC is the most serious complication of IBD, and thus considerable
effort has been invested in understanding the molecular events that gov-
ern the transition from inflammation to malignancy (Fig. 3). NF-κB,
one of the key transcription factors that regulates immunological and
inflammatory responses61, has been identified as one of the main
participants in this transition. In mouse models, epithelial insertion
of a constitutively active IκB kinase (IKKβ), which phosphorylates
IκB (the inhibitor of NF-κB)62 and enables constitutive activation
npg
of NF-κB, lead to the accelerated development of colorectal tumors
caused by enhanced DNA damage, with no overt signs of inflamma-
tion63. Accordingly, epithelial deletion of IKKβ, which prevents the
activation of NF-κB, leads to a significant reduction in tumor inci-
dence due to increased apoptosis of epithelial cells during the early
stages of tumorigenesis, and myeloid deletion of this kinase results
in reduced tumor size64. That last result is due to reduced production
of pro-inflammatory cytokines, which also promote tumor growth; a
comprehensive review of cytokines in CRC has been published else-
where65. One of the main cytokines induced by NF-κB is IL-6 (ref. 64),
which has a crucial role in the initiation and progression of CAC. IL-6
originates from cells of the immune system in the lamina propria
and can enhance the proliferation of epithelial cells as well as protect
them from apoptosis. Deletion of IL-6 reduces tumorigenesis in the
AOM-DSS mouse model. IL-6 signals from the lamina propria activate
STAT3 in IECs, which can then promote tumorigenesis via facilitating
their proliferation, inhibition of apoptosis, and other pro-tumorigenic
pathways66,67. The IL-6–STAT3 signaling axis can also repress the
tumor-suppressor microRNA miR-34a and thereby enhance epithelial-
to-mesenchymal transition and promote tumor-cell invasion68.
Another major arm of NF-κB signaling is the activation of TNF,
a proinflammatory cytokine involved in various diseases, such as
nature immunology  VOLUME 17  NUMBER 3  MARCH 2016 233
review
Early adenoma Late adenoma Carcinoma
IL-17, IL-23
Bacteria
APC KRAS TP53
Marina Corral Spence/Nature Publishing Group
Modulated inflammatory environment,
tumor-promoting parainflammation
Low-grade dysplasia High-grade dysplasia Carcinoma
TP53 APC
rheumatoid arthritis69, psoriasis70 and type 2 diabetes71. In CAC
mouse models, constitutive activation of Wnt induces TNF, which
leads to enhanced activation of NF-κB, with de-differentiation of
IECs and facilitated tumor initiation72. Similar de-differentiation
processes are observed in patients with ulcerative colitis72, which
suggests that de-differentiation might be a part of the wound-healing
response that is activated following bouts of intestinal inflammation
and facilitates tumor initiation. However, other models of constitutive
activation of Wnt have not provided evidence of NF-κB activation73;
hence, the overall effect of the inflammatory basis for epithelial
de-differentiation in CAC remains to be established. Constitutive
activation of NF-κB can induce DNA damage by activation of ROS74,
which provides an additional link between chronic inflammation
and tumor initiation. Therefore, in addition to promoting cell pro­
liferation, the inflammatory environment creates a noxious envi-
ronment for cell proliferation and thus increases the risk for the
occurrence of tumor-initiating cells.
NF-κB is also activated following loss of the tumor suppressor p53
in IECs in a mouse model of CAC75,76. Mutation of the gene encoding
p53 is one of the most common events in sporadic CRC, occurring
in approximately 50% of human colorectal tumors77, and is usually
thought to be the final stage in the transition from benign adenoma to
invasive carcinoma (Fig. 3). However, in CAC arising after prolonged
intestinal inflammation, mutation of the gene encoding p53 is an early
event in tumor development78, which suggests that its role in that is
different from its role in sporadic CRC. Loss of p53 in AOM-DSS–
treated mice is reported to cause activation of NF-κB in epithelial cells
as well as surrounding stromal cells75 and to enhance the recruitment
of inflammatory myeloid cells and invasion. This is mediated by loss
of barrier function following ablation of p53, which permits the inva-
sion of bacteria into tumors and leads to the activation of NF-κB.
Along the same lines, mutations in the gene encoding p53 have been
found to be associated with activation of NF-κB in an experimental
mouse model of colitis and in samples from patients with CAC76, but
without defects in epithelial barrier function, and the mechanism by
which mutant p53 leads to the activation of NF-κB remains unknown.
Interestingly, loss of p53 can also modulate the inflammatory response
caused by senescence in a mouse model of sporadic CRC73, which
suggests that the loss of p53 at a late stage of CRC influences the
inflammatory environment. Overall, much remains to be elucidated
 review

Box 2  The intestinal microbiome, inflammation and cancer

Advances in sequencing techniques have allowed considerable progress in elucidating the intestinal microbiome, previously considered
a ‘black box’. Particularly interesting is the integration of the microbiome into the signaling networks that underlie mucosal immunity
and its contribution to intestinal tumorigenesis. CRC is often associated with dysbiosis, a broad change in intestinal microbes and
enrichment for certain microbial strains86,87. While some strains are probably passive bystanders whose overgrowth is a result of the
changing microenvironment, others might have an active role in tumorigenesis. It is well known that microbes produce molecular patterns
that activate innate immunity, yet it appears that commensal bacteria can also modify DNA-repair pathways and induce DAMPs that
trigger epithelial innate immunity. ETBF, via its toxin, upregulates expression of the catabolic enzyme spermin oxydase and induces ROS
formation and thus DNA damage169. Shigella flexneri deregulates expression of the activation of p53 and impairs p53-dependant repair
of DNA170. E. coli strains of the phylogenic group B2 contain a preserved gene cluster (the ‘pks island’) that encodes the genotoxin
colibactin. These E. coli strains induce histone variant γ-H2AX foci in mouse colon as evidence of DNA damage. In vitro studies of
mammalian cell lines have shown that pks+ E. coli strains induce DNA damage, chromosomal aberrations and aneuploidy171.
  In other cases, the microbiota does not have a direct carcinogenic effect in the epithelial cells but serves as a mediator in the
crosstalk between cells of the immune system and the tumor. One example of this is IL-23- and IL-17-dependent tumor growth: the
pro-tumorigenic IL-17 response is triggered by IL-23 secreted from tumor-associated myeloid cells, whose activation is mediated by
tumor-infiltrating microbes88,89. Another example is the inhibitory effect of F. nucleatum on natural killer cells, which allow the tumor
to evade immunosurveillance172.

about the involvement of the loss of p53 or mutation of its gene in the can be eliminated by prolonged antibiotic treatment, which empha-
© 2016 Nature America, Inc. All rights reserved.

development of CAC and of inflammation in CRC.
Microbiota, inflammation and cancer
The association between bacteria and cancer was first described
decades ago, yet a causal relationship between the two has remained
debatable. However, accumulating evidence suggests a ‘driver’ role
for bacteria in tumorigenesis, rather than a solely passive ‘passenger’
role79. A striking, well-known example of this relationship is gas-
tric infection with Helicobacter pylori. Chronic gastritis caused by
H. pylori is a strong risk factor for gastric adenocarcinoma80,81.
Mucosa-associated lymphoid tissue lymphoma is another malignant
disease attributed to H. pylori infection82. Strikingly, at an early stage,
this lymphoma can be cured by eradication of H. pylori alone83 and
thus constitutes an example of a malignancy that can be eliminated
solely by antibiotic treatment.
The bacterial population that constitutes the gut microbiome
exceeds the number of human cells in the body by approximately
tenfold84, and the microbiota is sometimes referred to as the ‘forgotten
npg
sizes the importance of microbiota in this model.
Innate lymphoid cells are a heterogeneous group of hematopoietic cells.
They express various effector cytokines that resemble those expressed by
helper T cell populations, but they lack antigen-specific rearranged recep-
tors, which distinguishes them from classic lymphocytes of the adaptive
immune system. Innate lymphoid cells are increasingly recognized as
important participants in mucosal immunity, microbe-induced inflam-
matory responses, IBD and tumorigenesis90. These cells can promote
bacteria-driven colon cancer via IL-23-dependent secretion of IL-22 by
inducing phosphorylation of STAT3 and tumor progression91.
Studies have suggested the existence of ‘outside-in’ and ‘inside-out’
reciprocal interactions between cell-intrinsic processes and the
microbiome86. As noted above, AIM2 is a sensor of double-stranded
DNA and an inflammasome protein whose downregulation facilitates
tumorigenic processes and hyper-proliferation of cancer stem cells 38.
Sequencing analysis of 16S rRNA from mouse stools has revealed
a markedly distinct microbial population in Aim2-deficient mice
relative to that of wild-type mice. This, in turn, modifies the AIM2

organ’ due to its increasingly recognized importance in various
processes in health and disease85. However, it is not only pathogenic
bacterial infections that cause overt chronic inflammation that have
a role in tumorigenesis, as altered interactions between the host and
commensal bacteria can also contribute to malignant transformation86.
We are tempted to speculate that the much greater prevalence of colon
tumors than of small intestinal tumors in humans is related to the
greater bacterial load in the former.
The development of CRC is associated with a broad change in the
intestinal microbe population: dysbiosis87. In various CRC mouse
models involving genetic manipulations and exposure to carcinogens,
tumor development can be modulated by growth of the mice in a germ-
free environment, provision of antibiotic treatment, or co-housing
with wild-type counterparts. This highlights the possibility of a
role for the microbiome in intestinal tumorigenesis, either as a direct
carcinogen or as a mediator in the crosstalk between tumor cells and
their microenvironment, including the immune system. Indeed,
tumor-infiltrating microbes induce IL-23 production by tumor-
associated myeloid cells, which in turn upregulates the expression
of pro-tumorigenic cytokines, including IL-17 (ref. 88) (Fig. 3).
IL-17 signals via its receptor IL-17A in transformed IECs and pro-
motes their growth and survival89. IL-23-dependent tumor growth
pro-tumorigenic phenotype. Strikingly, when Aim2-deficient mice
are co-housed with wild-type mice, their tumor load after treatment
with AOM-DSS is significantly smaller than that of their mutant
counterparts housed separately, a result that might be attributable to
the transferable intestinal bacterial population38.
Autophagy is an important intracellular process known to be essen-
tial for cell survival, especially under stress conditions. Its regulation
is important in tumor development92–94. Inhibition of autophagy by
ablation of the autophagy-related protein ATG7 results in a signifi-
cant decrease in intestinal tumor load in mice heterozygous for the
gene encoding the Wnt negative regulator APC. The inhibition of
autophagy causes barrier dysfunction, with bacterial invasion of the
crypts and changes in microbiome composition90. Different from
other models in which dysbiosis is a pro-tumorigenic driver39,41,88,
inhibition of autophagy results in increased infiltration of CD8+
T cells, the TH1 subset of helper T cells, and regulatory T cells, which
facilitates an anti-tumorigenic immune response. This protective
response is abolished by antibiotic treatment, a result possibly attrib-
utable to the overgrowth of specific antibiotic-resistant bacterial
strains. These contradicting effects of dysbiosis on tumor develop-
ment highlight the complexity of microbiome-tumor interactions.
Unless a microbiotic effect is resolved at single-species level, the effect

234 VOLUME 17  NUMBER 3  MARCH 2016  nature immunology

 review

Figure 4  Therapeutic modulation of a Cytokines b

the inflammatory environment in CRC. Bacteria
Activated
The inflammatory environment of CRC tumors Barrier
Tumor immune cells
can be modulated by several therapeutic cells
strategies. (a) Treatment with NSAIDs
can attenuate the production of prostaglandin
E2 (PGE2), an inflammatory mediator that PGE2
Antibiotics
enhances tumor growth. Inhibition of NSAIDs
COX-2 by NSAIDs can prevent evasion of Immune Parainflamed
the immune system. In addition, NSAIDs cells tumor cells
target parainflammatory cells and thus delay
tumor formation or induce tumor regression.
(b) CRC tumors are often invaded by specific
pathogenic bacteria, which can promote

Marina Corral Spence/Nature Publishing Group

Immunological
checkpoint blockers: Anti-IL-6, JAK-STAT
tumorigenesis by evading the immune system
(for example, Fusobacterium nucleatum), c M1
anti-PD-1,
anti-CTLA-4
inhibitors, anti-IL-1β

inducing DNA damage (Escherichia coli, macrophage

ETBF and Enterococcus fecalis) or enhancing d
pro-tumorigenic signaling pathways.
Antibiotics can target those bacteria,
whose elimination might result in tumor
regression. (c) The blockade of immunological
checkpoints such as PD-1 or CTLA-4 can
enhance the recruitment and activation
© 2016 Nature America, Inc. All rights reserved.

of cells of the immune system and

anti-tumorigenic inflammatory cells,
such as anti-tumorigenic M1 macrophages, to
the tumor microenvironment, where they help to eliminate tumor cells. (d) Treatment with cytokine antagonists, such as inhibitors of IL-6 or IL-1β, or
blockade of their downstream signaling pathways, such as with inhibitors of JAK and STAT, can result in the attenuation of inflammatory signaling
and delay of tumor formation. In addition, inhibition of IL-1β can enhance barrier formation.

of a particular mutation of a gene involved in innate immunity on
dysbiosis and tumorigenesis cannot be predicted with certainty.
Nutrition is an important factor in determining the risk for CRC.
Specifically, consumption of red meat has been linked to an increased
incidence of CRC. Heme, which is present in high levels in red meat,
induces epithelial hyperproliferation, which leads to hyperplasia. This
protumorigenic effect is microbiota dependent and can be eliminated
by antibiotic treatment. Bacterial mucolysis by hydrogen sulfide dam-
ages the protective mucus layer and exposes the epithelium to the
toxic luminal environment, induced by consumption of heme95.
Although dysbiosis constitutes a broad change in microbial popu-
lation, studies from the past decade have identified certain bacterial
npg
chronic inflammation and basal homeostasis 100 characterized by
activation of various genes encoding products involved in innate
immunity, with a remarkable paucity of secreted factors, particularly
chemokines, and thus little recruitment of cells of the immune
system to the inflamed tissue. Parainflammation was first described
for a mouse model of Wnt activation in the intestine, in studies of
mice deficient in CKIα73, a negative regulator of Wnt signaling101.
In these mice, CKIα is deleted from the intestinal epithelium,
which results in massive activation of Wnt, along with a prominent
DNA-damage response and activation of p53, with the result of
senescence102. Gut homeostasis is maintained, with no tumors, in
CKIα-deficient mice despite the hyperactivation of Wnt, probably

strains that have a primary role in tumor initiation and propagation
(Box 2 and Fig. 2). Streptococcus gallolyticus has long been associated
with colonic pathologies. Although a causal relationship to CRC is
not clear, increased production of inflammatory factors, including the
cyclooxygenase COX-2, IL-1 and IL-8, in S. gallolyticus–bearing tumor
tissue might indicate its possible contribution to tumor progression96.
Enterotoxinogenic Bacteroides fragillis (ETBF) induces cleavage of
E-cadherin97, increases Wnt signaling and triggers the activation
of NF-κB98. Together these processes contribute to increased epi-
thelial permeability and mucosal inflammation, which might sup-
port tumorigenesis. A protumorigenic role for ETBF has also been
demonstrated in mice heterozygous for the ‘min’ mutation (‘multiple
intestinal neoplasia’) of the gene encoding APC (Apcmin/+), in which
colonization by ETBF is associated with increased formation of colon
adenomas mediated at least in part by induction of a mucosal response
by the TH17 subset of helper T cells99. Antibiotic treatment target-
ing specific bacterial strains might thus help to prevent or suppress
colorectal tumorigenesis (Fig. 4).
Parainflammation and CRC
A novel type of inflammation with a considerable effect on CRC pro-
gression is parainflammation. This is an intermediate state between
due to the parallel activation of several tumor-suppressive pathways.
Parainflammation might contribute to the maintenance of home­
ostasis by acting together with the activation of p53 in tumor suppres-
sion. After loss of p53, parainflammation loses its tumor-suppressive
nature to become tumor promoting (Fig. 1). Remarkably, parainflam-
mation on a background of p53 deficiency can be attenuated by treat-
ment with non-steroidal anti-inflammatory drugs (NSAIDs), which
results in tumor regression73 (Fig. 4).
A buildup of parainflammation in early tumors might be one of
the mechanisms that account for the observation that adenomatous
polyps only rarely progress to invasive carcinomas. Activation of
wild-type p53, which is preserved in half of the human polyps, might
act in conjunction with parainflammation, similar to its role in the
CKIα-deficient mouse model, and halt tumor progression; only pol-
yps that subsequently undergo mutation of the gene encoding p53
would progress to full-blown tumors (Fig. 1). This indicates that
NSAID treatment might be beneficial only after such mutation,
whereas by reducing the tumor-suppressor effect of parainflamma-
tion, NSAID treatment in the absence of such mutation would prove
harmful. On the other hand, NSAID treatment might also suppress
pro-tumorigenic pathways, such as Wnt signaling103; thus, it remains
to be determined if the status of p53 in a tumor influences the efficacy

nature immunology  VOLUME 17  NUMBER 3  MARCH 2016 235

 review
Table 1  Therapeutic strategies for modulating the inflammatory environment in CRC
Drug Pathway targeted Target population
Aspirin COX-2 and/or Patients at medium or
parainflammation high risk of both
sporadic CRC and
familial CRC
Sulindac, Patients with FAP,
celecoxib Lynch syndrome or
mutations involving
the DNA-repair pathway
© 2016 Nature America, Inc. All rights reserved.
PD-1 inhibitors PD-1 Patients with mismatch
(nivolumab; repair defects in whom
pembrolizumab) a high rate of mutations
facilitates the generation
of novel epitopes
Antibody to CTLA-4 CTLA-4
(ipilimumab)
Tocilizumab and IL-6 Patients with IBD or CAC, in
siltuximab which IL-6 is known to have
a major role in tumorigen-
esis; combined therapy with
drugs that target TNF and
IL-6 might be beneficial for
patients with CAC
npg
Ruxolitinib and JAK-STAT
tofacitinib
Infliximab, etaner- TNF Patients with IBD or CAC, in
cept and adali- which IL-6 is known to have
mumab a major role in tumorigenesis;
combined therapy with drugs
that target TNF and IL-6
might be beneficial for
patients with CAC
IL-1β inhibitor IL-1β Patients with CRC and
anakinra CAC, including metastatic
disease; the precursor
of IL-1β is activated
by caspase-1 upon
inflammasome activation
in tumor cells, and IL-1β
induces various growth
factors and angiogenic
factors (such as VEGF)
and promotes tumor
growth and metastasis157
236 VOLUME 17  NUMBER 3  MARCH 2016  nature immunology
CRC mouse model
Apcmin/+ mice, in which Sulindac
has been shown to delay
tumorigenesis105; mice deficient
in both CKIα and p53, a model
of gut parainflammation in
which NSAIDs have been shown
to suppress parainflammation
and tumorigenesis73
Deletion of IL-6 or its receptor
in mouse models of CAC
leads to a reduction in tumor
burden66,67
STAT3 has been shown to have a
major role in CRC downstream
of IL-6 signaling66,67; inhibition
of the JAK-STAT pathway rather
than the IL-6 pathway can prevent
the activation of alternative
signaling pathways such as IL-11
In a mouse model of CAC, IL-1β
released from tumor-infiltrating
neutrophils has a critical role in
tumorigenesis158; mice with
single deficiency in the immu­
noglobulin IL-1 receptor–related
molecule SIGIRR show enhanced
Toll–IL-1 receptor signaling and
increased tumorigenesis induced
by DSS-AOM159
Status (as of December 2015)
Aspirin is used mainly for cardiovascular diseases
treatment and prevention. Multiple large-scale
observational retrospective studies have shown
that long-term aspirin use has a protective
effect of against CRC in patients of average
risk, with a modest effect on all-cause mortality.
In prospective studies of high-risk patients,
such as those with FAP or Lynch syndrome or
with a history of colon adenoma, aspirin
significantly reduces tumor frequency142,143.
Ongoing clinical studies of aspirin in CRC include
adjuvant therapy for advanced-stage CRC144 and
prevention of recurrence after polyp resection145.
NSAIDs and selective COX-2 inhibitors (‘coxibs’) are
used for analgesia and for the treatment of some
rheumatological diseases.
These agents result in a reduction in CRC in
high-risk populations146–148, but their long term
use is limited mainly by cardiovascular toxicity.
Ongoing studies include adjuvant therapy added
to standard chemotherapy in advanced CRC149,
a phase I/II study assessing the combination of
celecoxib and EPO 906 (a microtubule stabilizer)
in metastatic CRC150, and the combination of
celecoxib, sulindac and eflornithine (an inhibitor of
ornithine decarboxylase) in the prevention of primary
and secondary CRC151,152
A phase II clinical trial of pembrolizumab has
reported increased response and survival in patients
with mutations in the mismatch-repair pathway141;
clinical trials of nivolumab are now underway153.
Clinical trials to evaluate the efficacy of treatment
with ipilimumab alone or in combination with
nivolumab are underway153.
Antibodies to IL-6 or its receptor are in use in the
clinic for the treatment of inflammatory diseases
such as rheumatoid arthritis or Castleman’s disease.
A phase I/II clinical trial has failed to show
a substantial clinical effect of siltuximab,
a monoclonal antibody to IL-6, on patients with
advanced solid tumors, including CRC154.
JAK2 inhibitors are in use for myeloproliferative
disorders. The JAK1/3 inhibitor tofacitinib is used
for rheumatoid arthritis. Clinical trials for IBD are
underway155,156.
Antibody to TNF is in use in the clinic for the
treatment of patients with various rheumatological
diseases and IBD.
These agents are in use for the treatment of
autoimmune and autoinflammatory disease.
An ongoing phase II clinical trial is assessing
5-fluorouracil and bevacizumab (monoclonal
antibody to VEGF) in combination with anakinra
in the treatment of metastatic CRC160.

of NSAID treatment. Given the role of mutation of the gene encoding
p53 in enhancing NF-κB activation in CAC76, such mutations might
also possibly enhance parainflammation, which again might explain
the switch in its nature from tumor suppressor to tumor promoter.
Anti-inflammatory therapeutic strategies for CRC
Due to its deep inflammatory roots, CRC might be a candidate for
treatment or prevention by anti-inflammatory agents (Fig. 4 and
Table 1). Most striking is the role of NSAIDs in CRC prevention, first
noticed when preliminary studies of small groups of patients with FAP
demonstrated that after 1 year of treatment with the NSAID sulin-
dac, patients tend to develop less polyps104. Those studies have also
been recapitulated in a mouse model of FAP (Apcmin/+) with similar
results105. In 1991, a large-population observational study reported
that NSAID use reduces the risk for fatal CRC106. Subsequently, ret-
rospective studies demonstrated that NSAID treatment is associated
with a reduced risk for colorectal polyps and tumor recurrence107,
with an overall reduction of 40–50% in the risk of CRC for patients
who reported long-term use (more than 5 years) of low-dose aspirin.
NSAID treatment also has a positive effect in patients with advanced
CRC, in whom long-term use reduces tumor recurrence108.
© 2016 Nature America, Inc. All rights reserved.
Following studies demonstrating a protective effect of NSAIDs in
CRC, additional studies have demonstrated a similar effect in several
other cancer types109–111. However, there is controversy about the
exact mechanism for the function of NSAIDs in tumor prevention.
It is conceivable that the anti-carcinogenic effect of NSAIDs stems
at least in part from their anti-inflammatory properties. NSAIDs are
non-selective inhibitors of COX-2 (ref. 112), and indeed, expression of
COX-2 is elevated in many tumors, including colorectal113, breast114,
pancreas115, stomach116, bladder117 and lung118. COX-2 catalyzes the
production of prostaglandins involved in myriad tumor-promoting
pathways119–121. COX-2 also has a documented role in modulating the
immunological environment and can mediate evasion of the immune
system in a mouse model of melanoma122. Thus, it is not surprising
that inhibition of COX-2 by NSAIDs has an anti-tumorigenic effect
in cancers that arise following prolonged chronic inflammation, in
which COX-2 is indeed active. However, NSAIDs are also effective
in the prevention of tumors not preceded by inflammation, such as
in patients with FAP or hereditary Lynch syndrome 7,8. Through the
npg
years, many conflicting mechanisms have been proposed to explain
the anti-tumorigenic effects of NSAIDs. One such mechanism sug-
gests that cytokines released during inflammation have a role in
reprogramming adult stem cells to become malignant cells123. NSAID
use can block this reprogramming and thus prevent tumor develop-
ment. Another proposed mechanism is related to activation of the
Wnt pathway by prostaglandins124. This pathway is activated in many
different tumors, most notably in CRC, in which NSAID efficacy was
originally detected. NSAIDs have been reported to have a significant
advantage in patients with CRC who have a mutation in the gene
encoding the lipid kinase PI(3)K125, yet a subsequent study reported
no beneficial effects of NSAID use in patients with this mutation126.
We note that most studies of NSAIDs in cancer therapy are obser-
vational and do not point out a clear mechanism of action. It is thus
possible that NSAIDs act by both alleviating overt inflammation, as
seen in patients with CAC, and suppressing covert inflammation, such
as parainflammation, which might account for the tumor-suppressive
effects in patients with hereditary CRC and in sporadic CRC.
Given the major role of IL-6 in CAC, inhibition of the IL-6 pathway
might constitute another therapeutic strategy for CRC (Fig. 4). In
mouse models of CAC, inhibition or ablation of IL-6 or its receptor
reduces tumor burden66,67. Inhibitors of IL-6 or its receptor are clinically
nature immunology  VOLUME 17  NUMBER 3  MARCH 2016 237
review
available for the treatment of rheumatoid arthritis or Castelman’s
disease127,128, and it is possible that these inhibitors, when adminis-
tered alone or together with conventional chemotherapy, might also
have a beneficial effect in the treatment of CAC. Furthermore, inhibi-
tion of IL-6 in patients with IBD might prevent or delay the onset of
CAC. Another possibility is that inhibition of the downstream effec-
tors of IL-6 signaling, JAK-STAT129, would prevent the activation of
alternative pathways following the inhibition of IL-6, such as that of
the IL-6 family member IL-11, also shown to have a major role in
tumors of the gastrointestinal tract67,130. Patients with IBD are often
treated with inhibitors of the cytokine TNF131, which is also a major
participant in the development of CAC. It is possible that the combina-
tion of treatment with IL-6 inhibitors plus TNF inhibitors might have
enhanced or synergistic effects in the prevention of CAC (Table 1).
However, the benefit of such preventive strategies must be weighed
against the treatment hazards. NSAID treatment is associated with
an increased risk of bleeding, particularly in the gastrointestinal
tract, even at low doses132. Certain patients with fragile blood vessels
(for example, those with amyloid angiopathy) might be at particular
risk of bleeding after treatment with aspirin 133, a condition that is
difficult to diagnose for the exclusion of patients from such treatment.
Treatment with antibody to TNF is associated with an increased risk
of certain infectious diseases, such as tuberculosis134 or infection with
Clostridium difficile135, as well as increased risk of fungal infections136
and skin cancer137, and blockade with antibody to IL-6 might lead to
upper respiratory tract infections138.
Inhibitors of immunological checkpoints, which serve to reactivate
the adaptive immune system in tumors, are an emerging therapeutic
strategy in many cancer types. The adaptive immune system has a
major role in battling CRC, and the tumor ‘immunoscore’, which quan-
tifies the presence of infiltrating cells of the immune system in tumors,
is a better predictor of survival than is tumor stage 139. In particular,
in CRC, polarization to the TH1 subset of helper T cells and the pres-
ence of T cells in tumors are beneficial and are positively correlated
with patient survival140. In this context, using inhibitors of immuno-
logical checkpoints might be a particularly effective strategy for the
treatment of patients with CRC who have a low ‘immunoscore’ and
might possibly alter it to an efficacious high ‘immunoscore’ (Fig. 4).
Indeed, treatment of patients with CRC with an inhibitor of the cos-
timulatory molecule PD-1 has a beneficial effect in patients with
advanced CRC and mismatch-repair deficiency141, in whom the high
rate of mutation might generate new epitopes that are recognized upon
activation of the immune system. Likewise, COX-2 inhibitors and PD-
1 inhibitors act synergistically in a mouse model of melanoma122, and
given the major role of COX-2 in CRC, it is possible that a similar
synergistic effect might be apparent also in CRC.
Conclusion
Whereas researchers estimate that approximately 15% of CRC occurs
in patients with IBD, epidemiological studies have demonstrated a
much greater incidence of beneficial effects of anti-inflammatory
treatment in patients with CRC, particularly prolonged treatment
with NSAIDs, mostly more than 5 years. Although there is only cur-
sory understanding of the mechanisms underpinning the beneficial
effects of NSAIDs, the reported studies suggest that the inflamma-
tory basis of common sporadic CRC is much wider than previously
estimated and perhaps underlies most CRC cases. Confirming that
conjecture has important clinical value, as it might tilt the balance of
benefit versus hazard in the preventive use of NSAID or new means
of anti-inflammatory therapy, depending on CRC risk factors, or
even universally, only after a patient has aged. Moreover, aspirin, the
 review
most commonly used NSAID, provides cancer-protective benefits
after years of treatment. The mechanism of action of NSAIDs must
be understood for the improvement of preventive therapy and
possibly for the combination of anti-inflammatory therapy with
immunotherapy, chemotherapy and targeted cancer therapies in
progressive cancer (Fig. 4). Part of this might be achieved by eluci-
dation of the diversity of inflammatory responses and their possible
documentation in cancer-susceptible people, especially by non-
invasive procedures. Mechanistic studies that explain the origin of
various inflammatory responses and their progression might also
result in more-effective, possibly less-hazardous means of inter­
vention than those currently available.
Acknowledgments
Supported by Israeli Science Foundation Centers of Excellence, the European
Research Council Framework Programme 7 (294390 PICHO), The Dr. Miriam and
Sheldon G. Adelson Medical Research Foundation, the I-CORE program of the
Israel Science Foundation (41/11) and the Israel Cancer Research Fund (Y.B.-N.).
COMPETING FINANCIAL INTERESTS
The authors declare no competing financial interests.
© 2016 Nature America, Inc. All rights reserved.
Reprints and permissions information is available online at http://www.nature.com/
reprints/index.html.
1. Hanahan, D. & Weinberg, R.A. Hallmarks of cancer: the next generation.
Cell 144, 646–674 (2011).
2. Aggarwal, B.B., Vijayalekshmi, R.V. & Sung, B. Targeting inflammatory pathways
for prevention and therapy of cancer: short-term friend, long-term foe. Clin. Cancer
Res. 15, 425–430 (2009).
3. Balkwill, F.R. & Mantovani, A. Cancer-related inflammation: common themes and
therapeutic opportunities. Semin. Cancer Biol. 22, 33–40 (2012).
4. Rowan, A.J. et al. APC mutations in sporadic colorectal tumors: A mutational
“hotspot” and interdependence of the “two hits”. Proc. Natl. Acad. Sci. USA 97,
3352–3357 (2000).
5. Groden, J. et al. Identification and characterization of the familial adenomatous
polyposis coli gene. Cell 66, 589–600 (1991).
6. Jess, T., Frisch, M. & Simonsen, J. Trends in overall and cause-specific mortality
among patients with inflammatory bowel disease from 1982 to 2010.
Clin. Gastroenterol. Hepatol. 11, 43–48 (2013).
7. Labayle, D. et al. Sulindac causes regression of rectal polyps in familial
adenomatous polyposis. Gastroenterology 101, 635–639 (1991).
8. Burn, J. et al. Long-term effect of aspirin on cancer risk in carriers of hereditary
colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet
378, 2081–2087 (2011).
9. Turner, J.R. Intestinal mucosal barrier function in health and disease. Nat. Rev.
Immunol. 9, 799–809 (2009).
npg
10. Zhang, K., Hornef, M.W. & Dupont, A. The intestinal epithelium as guardian of
gut barrier integrity. Cell. Microbiol. 17, 1561–1569 (2015).
11. Tlaskalová-Hogenová, H. et al. The role of gut microbiota (commensal bacteria)
and the mucosal barrier in the pathogenesis of inflammatory and autoimmune
diseases and cancer: contribution of germ-free and gnotobiotic animal models of
human diseases. Cell. Mol. Immunol. 8, 110–120 (2011).
12. Tsiaoussis, G.I., Assimakopoulos, S.F., Tsamandas, A.C., Triantos, C.K. &
Thomopoulos, K.C. Intestinal barrier dysfunction in cirrhosis: Current concepts in
pathophysiology and clinical implications. World J Hepatol 7, 2058–2068 (2015).
13. Kiesslich, R. et al. Local barrier dysfunction identified by confocal laser
endomicroscopy predicts relapse in inflammatory bowel disease. Gut 61,
1146–1153 (2012).
14. Salim, S.Y. & Soderholm, J.D. Importance of disrupted intestinal barrier in
inflammatory bowel diseases. Inflamm. Bowel Dis. 17, 362–381 (2011).
15. Velcich, A. et al. Colorectal cancer in mice genetically deficient in the mucin
Muc2. Science 295, 1726–1729 (2002).
16. Dunn, G.P., Koebel, C.M. & Schreiber, R.D. Interferons, immunity and cancer
immunoediting. Nat. Rev. Immunol. 6, 836–848 (2006).
17. Saleh, M. & Trinchieri, G. Innate immune mechanisms of colitis and colitis-
associated colorectal cancer. Nat. Rev. Immunol. 11, 9–20 (2011).
18. Lin, W.W. & Karin, M. A cytokine-mediated link between innate immunity,
inflammation, and cancer. J. Clin. Invest. 117, 1175–1183 (2007).
19. Siegal, F.P. et al. The nature of the principal type 1 interferon-producing cells in
human blood. Science 284, 1835–1837 (1999).
20. Schoggins, J.W. et al. A diverse range of gene products are effectors of the type
I interferon antiviral response. Nature 472, 481–485 (2011).
21. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation.
Cell 140, 805–820 (2010).
22. Kemp, M.G. & Sancar, A. DNA excision repair: where do all the dimers go?
Cell Cycle 11, 2997–3002 (2012).
238 VOLUME 17  NUMBER 3  MARCH 2016  nature immunology
23. Sharma, S., Fitzgerald, K.A., Cancro, M.P. & Marshak-Rothstein, A. Nucleic acid-
sensing receptors: rheostats of autoimmunity and autoinflammation. J. Immunol.
195, 3507–3512 (2015).
24. Härtlova, A. et al. DNA damage primes the type I interferon system via the
cytosolic DNA sensor STING to promote anti-microbial innate immunity. Immunity
42, 332–343 (2015).
25. Zhu, Q. et al. Cutting edge: STING mediates protection against colorectal
tumorigenesis by governing the magnitude of intestinal inflammation. J. Immunol.
193, 4779–4782 (2014).
26. Dihlmann, S. et al. Lack of Absent in Melanoma 2 (AIM2) expression in tumor
cells is closely associated with poor survival in colorectal cancer patients.
Int. J. Cancer 135, 2387–2396 (2014).
27. Hou, J. et al. Hepatic RIG-I predicts survival and interferon-α therapeutic response
in hepatocellular carcinoma. Cancer Cell 25, 49–63 (2014).
28. Strowig, T., Henao-Mejia, J., Elinav, E. & Flavell, R. Inflammasomes in health
and disease. Nature 481, 278–286 (2012).
29. Hoque, R. et al. TLR9 and the NLRP3 inflammasome link acinar cell death with
inflammation in acute pancreatitis. Gastroenterology 141, 358–369 (2011).
30. Pétrilli, V., Dostert, C., Muruve, D.A. & Tschopp, J. The inflammasome: a danger
sensing complex triggering innate immunity. Curr. Opin. Immunol. 19, 615–622
(2007).
31. Vanaja, S.K., Rathinam, V.A. & Fitzgerald, K.A. Mechanisms of inflammasome
activation: recent advances and novel insights. Trends Cell Biol. 25, 308–315
(2015).
32. Kanarek, N. et al. Critical role for IL-1β in DNA damage-induced mucositis.
Proc. Natl. Acad. Sci. USA 111, E702–E711 (2014).
33. Nowarski, R. et al. Epithelial IL-18 equilibrium controls barrier function in colitis.
Cell 163, 1444–1456 (2015).
34. Levy, M. et al. Microbiota-modulated metabolites shape the intestinal
microenvironment by regulating NLRP6 inflammasome signaling. Cell 163,
1428–1443 (2015).
35. Harrison, O.J. et al. Epithelial-derived IL-18 regulates Th17 cell differentiation
and Foxp3+ Treg cell function in the intestine. Mucosal Immunol. 8, 1226–1236
(2015).
36. Sellin, M.E., Maslowski, K.M., Maloy, K.J. & Hardt, W.D. Inflammasomes of the
intestinal epithelium. Trends Immunol. 36, 442–450 (2015).
37. Hu, B. et al. Inflammation-induced tumorigenesis in the colon is regulated by
caspase-1 and NLRC4. Proc. Natl. Acad. Sci. USA 107, 21635–21640
(2010).
38. Man, S.M. et al. Critical role for the DNA sensor AIM2 in stem cell proliferation
and cancer. Cell 162, 45–58 (2015).
39. Rommereim, L.M. & Subramanian, N. AIMing 2 Curtail Cancer. Cell 162, 18–20
(2015).
40. Wlodarska, M. et al. NLRP6 inflammasome orchestrates the colonic host-microbial
interface by regulating goblet cell mucus secretion. Cell 156, 1045–1059
(2014).
41. Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and
risk for colitis. Cell 145, 745–757 (2011).
42. Normand, S. et al. Nod-like receptor pyrin domain-containing protein 6 (NLRP6)
controls epithelial self-renewal and colorectal carcinogenesis upon injury.
Proc. Natl. Acad. Sci. USA 108, 9601–9606 (2011).
43. Khor, B., Gardet, A. & Xavier, R.J. Genetics and pathogenesis of inflammatory
bowel disease. Nature 474, 307–317 (2011).
44. Muise, A.M. et al. Polymorphisms in E-cadherin (CDH1) result in a mis-localised
cytoplasmic protein that is associated with Crohn’s disease. Gut 58, 1121–1127
(2009).
45. Sabath, E. et al. Galpha12 regulates protein interactions within the MDCK cell
tight junction and inhibits tight-junction assembly. J. Cell Sci. 121, 814–824
(2008).
46. Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture
of inflammatory bowel disease. Nature 491, 119–124 (2012).
47. Keshavarzian, A. et al. Excessive production of reactive oxygen metabolites by
inflamed colon: analysis by chemiluminescence probe. Gastroenterology 103,
177–185 (1992).
48. Rioux, J.D. et al. Genome-wide association study identifies new susceptibility loci
for Crohn disease and implicates autophagy in disease pathogenesis. Nat. Genet.
39, 596–604 (2007).
49. Hampe, J. et al. A genome-wide association scan of nonsynonymous SNPs
identifies a susceptibility variant for Crohn disease in ATG16L1. Nat. Genet. 39,
207–211 (2007).
50. McCarroll, S.A. et al. Deletion polymorphism upstream of IRGM associated with
altered IRGM expression and Crohn’s disease. Nat. Genet. 40, 1107–1112
(2008).
51. Kaser, A. et al. XBP1 links ER stress to intestinal inflammation and confers genetic
risk for human inflammatory bowel disease. Cell 134, 743–756 (2008).
52. Cattin, A.L. et al. Hepatocyte nuclear factor 4alpha, a key factor for homeostasis,
cell architecture, and barrier function of the adult intestinal epithelium.
Mol. Cell. Biol. 29, 6294–6308 (2009).
53. Villani, A.C. et al. Common variants in the NLRP3 region contribute to Crohn’s
disease susceptibility. Nat. Genet. 41, 71–76 (2009).
54. Allen, I.C. et al. The NLRP3 inflammasome functions as a negative regulator of
tumorigenesis during colitis-associated cancer. J. Exp. Med. 207, 1045–1056
(2010).

55. Zaki, M.H. et al. The NLRP3 inflammasome protects against loss of epithelial integrity
and mortality during experimental colitis. Immunity 32, 379–391 (2010).
56. Adolph, T.E. et al. Paneth cells as a site of origin for intestinal inflammation.
Nature 503, 272–276 (2013).
57. Cadwell, K. et al. A key role for autophagy and the autophagy gene Atg16l1 in
mouse and human intestinal Paneth cells. Nature 456, 259–263 (2008).
58. Biswas, A. et al. Induction and rescue of Nod2-dependent Th1-driven
granulomatous inflammation of the ileum. Proc. Natl. Acad. Sci. USA 107,
14739–14744 (2010).
59. Porter, E.M., Bevins, C.L., Ghosh, D. & Ganz, T. The multifaceted Paneth cell.
Cellular and molecular life sciences. Cell. Mol. Life Sci. 59, 156–170 (2002).
60. Sato, T. et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal
crypts. Nature 469, 415–418 (2011).
61. Ben-Neriah, Y. & Karin, M. Inflammation meets cancer, with NF-κB as the
matchmaker. Nat. Immunol. 12, 715–723 (2011).
62. Karin, M. & Ben-Neriah, Y. Phosphorylation meets ubiquitination: the control of
NF-κB activity. Annu. Rev. Immunol. 18, 621–663 (2000).
63. Shaked, H. et al. Chronic epithelial NF-κB activation accelerates APC loss and
intestinal tumor initiation through iNOS up-regulation. Proc. Natl. Acad. Sci. USA
109, 14007–14012 (2012).
64. Greten, F.R. et al. IKKβ links inflammation and tumorigenesis in a mouse model
of colitis-associated cancer. Cell 118, 285–296 (2004).
65. West, N.R., McCuaig, S., Franchini, F. & Powrie, F. Emerging cytokine networks
in colorectal cancer. Nat. Rev. Immunol. 15, 615–629 (2015).
66. Grivennikov, S. et al. IL-6 and Stat3 are required for survival of intestinal
epithelial cells and development of colitis-associated cancer. Cancer Cell 15,
103–113 (2009).
67. Bollrath, J. et al. gp130-mediated Stat3 activation in enterocytes regulates
© 2016 Nature America, Inc. All rights reserved.
cell survival and cell-cycle progression during colitis-associated tumorigenesis.
Cancer Cell 15, 91–102 (2009).
68. Rokavec, M. et al. IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated
colorectal cancer invasion and metastasis. J. Clin. Invest. 124, 1853–1867 (2014).
69. Feldmann, M. Development of anti-TNF therapy for rheumatoid arthritis.
Nat. Rev. Immunol. 2, 364–371 (2002).
70. Reich, K. et al. Infliximab induction and maintenance therapy for moderate-
to-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet 366,
1367–1374 (2005).
71. Moller, D.E. Potential role of TNF-α in the pathogenesis of insulin resistance and
type 2 diabetes. Trends Endocrinol. Metab. 11, 212–217 (2000).
72. Schwitalla, S. et al. Intestinal tumorigenesis initiated by dedifferentiation and
acquisition of stem-cell-like properties. Cell 152, 25–38 (2013).
73. Pribluda, A. et al. A senescence-inflammatory switch from cancer-inhibitory to
cancer-promoting mechanism. Cancer Cell 24, 242–256 (2013).
74. Tilstra, J.S. et al. NF-kappaB inhibition delays DNA damage-induced senescence
and aging in mice. J. Clin. Invest. 122, 2601–2612 (2012).
75. Schwitalla, S. et al. Loss of p53 in enterocytes generates an inflammatory
microenvironment enabling invasion and lymph node metastasis of carcinogen-
induced colorectal tumors. Cancer Cell 23, 93–106 (2013).
76. Cooks, T. et al. Mutant p53 prolongs NF-κB activation and promotes chronic
inflammation and inflammation-associated colorectal cancer. Cancer Cell 23,
634–646 (2013).
77. Rodrigues, N.R. et al. p53 mutations in colorectal cancer. Proc. Natl. Acad. Sci.
USA 87, 7555–7559 (1990).
npg
78. Brentnall, T.A. et al. Mutations in the p53 gene: an early marker of neoplastic
progression in ulcerative colitis. Gastroenterology 107, 369–378 (1994).
79. Tjalsma, H., Boleij, A., Marchesi, J.R. & Dutilh, B.E. A bacterial driver-passenger
model for colorectal cancer: beyond the usual suspects. Nat. Rev. Microbiol. 10,
575–582 (2012).
80. Parsonnet, J. et al. Helicobacter pylori infection and the risk of gastric carcinoma.
N. Engl. J. Med. 325, 1127–1131 (1991).
81. The EUROGAST Study Group. An international association between Helicobacter
pylori infection and gastric cancer. Lancet 341, 1359–1362 (1993).
82. Wotherspoon, A.C., Ortiz-Hidalgo, C., Falzon, M.R. & Isaacson, P.G. Helicobacter
pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet 338,
1175–1176 (1991).
83. Wotherspoon, A.C. et al. Regression of primary low-grade B-cell gastric lymphoma
of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori.
Lancet 342, 575–577 (1993).
84. Zhang, Y.J. et al. Impacts of gut bacteria on human health and diseases.
Int. J. Mol. Sci. 16, 7493–7519 (2015).
85. O’Hara, A.M. & Shanahan, F. The gut flora as a forgotten organ. EMBO Rep. 7,
688–693 (2006).
86. Elinav, E. et al. Inflammation-induced cancer: crosstalk between tumours, immune
cells and microorganisms. Nat. Rev. Cancer 13, 759–771 (2013).
87. Sears, C.L. & Garrett, W.S. Microbes, microbiota, and colon cancer. Cell Host
Microbe 15, 317–328 (2014).
88. Grivennikov, S.I. et al. Adenoma-linked barrier defects and microbial products
drive IL-23/IL-17-mediated tumour growth. Nature 491, 254–258 (2012).
89. Wang, K. et al. Interleukin-17 receptor a signaling in transformed enterocytes
promotes early colorectal tumorigenesis. Immunity 41, 1052–1063 (2014).
90. Lévy, J. et al. Intestinal inhibition of Atg7 prevents tumour initiation through a
microbiome-influenced immune response and suppresses tumour growth. Nat.
Cell Biol 17, 1062–1073 (2015).
nature immunology  VOLUME 17  NUMBER 3  MARCH 2016 239
review
91. Kirchberger, S. et al. Innate lymphoid cells sustain colon cancer through production
of interleukin-22 in a mouse model. J. Exp. Med. 210, 917–931 (2013).
92. Mathew, R., Karantza-Wadsworth, V. & White, E. Role of autophagy in cancer.
Nat. Rev. Cancer 7, 961–967 (2007).
93. Vitale, I., Manic, G., Dandrea, V. & De Maria, R. Role of autophagy in the
maintenance and function of cancer stem cells. Int. J. Dev. Biol. 59, 95–108
(2015).
94. Jiang, X., Overholtzer, M. & Thompson, C.B. Autophagy in cellular metabolism
and cancer. J. Clin. Invest. 125, 47–54 (2015).
95. Ijssennagger, N. et al. Gut microbiota facilitates dietary heme-induced epithelial
hyperproliferation by opening the mucus barrier in colon. Proc. Natl. Acad. Sci.
USA 112, 10038–10043 (2015).
96. Abdulamir, A.S., Hafidh, R.R. & Bakar, F.A. Molecular detection, quantification,
and isolation of Streptococcus gallolyticus bacteria colonizing colorectal tumors:
inflammation-driven potential of carcinogenesis via IL-1, COX-2, and IL-8. Mol.
Cancer 9, 249 (2010).
97. Wu, S., Lim, K.C., Huang, J., Saidi, R.F. & Sears, C.L. Bacteroides fragilis
enterotoxin cleaves the zonula adherens protein, E-cadherin. Proc. Natl. Acad.
Sci. USA 95, 14979–14984 (1998).
98. Housseau, F. & Sears, C.L. Enterotoxigenic Bacteroides fragilis (ETBF)-mediated
colitis in Min (Apc+/−) mice: a human commensal-based murine model of colon
carcinogenesis. Cell Cycle 9, 3–5 (2010).
99. Wu, S. et al. A human colonic commensal promotes colon tumorigenesis via activation
of T helper type 17 T cell responses. Nat. Med. 15, 1016–1022 (2009).
100. Bondar, T. & Medzhitov, R. The origins of tumor-promoting inflammation. Cancer
Cell 24, 143–144 (2013).
101. Amit, S. et al. Axin-mediated CKI phosphorylation of β-catenin at Ser 45: a
molecular switch for the Wnt pathway. Genes Dev. 16, 1066–1076 (2002).
102. Elyada, E. et al. CKIα ablation highlights a critical role for p53 in invasiveness
control. Nature 470, 409–413 (2011).
103. Bos, C.L. et al. Effect of aspirin on the Wnt/β-catenin pathway is mediated via
protein phosphatase 2A. Oncogene 25, 6447–6456 (2006).
104. Waddell, W.R., Ganser, G.F., Cerise, E.J. & Loughry, R.W. Sulindac for polyposis
of the colon. Am. J. Surg. 157, 175–179 (1989).
105. Beazer-Barclay, Y. et al. Sulindac suppresses tumorigenesis in the Min mouse.
Carcinogenesis 17, 1757–1760 (1996).
106. Thun, M.J., Namboodiri, M.M. & Heath, C.W. Jr. Aspirin use and reduced risk of
fatal colon cancer. N. Engl. J. Med. 325, 1593–1596 (1991).
107. Sandler, R.S. et al. A randomized trial of aspirin to prevent colorectal adenomas in
patients with previous colorectal cancer. N. Engl. J. Med. 348, 883–890 (2003).
108. Ng, K. et al. Aspirin and COX-2 inhibitor use in patients with stage III colon
cancer. J. Natl. Cancer Inst. 107, 345 (2015).
109. Rothwell, P.M. et al. Effect of daily aspirin on long-term risk of death due to
cancer: analysis of individual patient data from randomised trials. Lancet 377,
31–41 (2011).
110. Fraser, D.M., Sullivan, F.M., Thompson, A.M. & McCowan, C. Aspirin use and
survival after the diagnosis of breast cancer: a population-based cohort study.
Br. J. Cancer 111, 623–627 (2014).
111. Streicher, S.A., Yu, H., Lu, L., Kidd, M.S. & Risch, H.A. Case-control study of
aspirin use and risk of pancreatic cancer. Cancer Epidemiol. Biomarkers Prev.
23, 1254–1263 (2014).
112. Hawkey, C.J. COX-2 inhibitors. Lancet 353, 307–314 (1999).
113. Williams, C.S., Shattuck-Brandt, R.L. & DuBois, R.N. The role of COX-2 in
intestinal cancer. Expert Opin. Investig. Drugs 8, 1–12 (1999).
114. Holmes, M.D. et al. COX-2 expression predicts worse breast cancer prognosis and
does not modify the association with aspirin. Breast Cancer Res. Treat. 130,
657–662 (2011).
115. Cascinu, S. et al. COX-2 and NF-κB overexpression is common in pancreatic
cancer but does not predict for COX-2 inhibitors activity in combination with
gemcitabine and oxaliplatin. Am. J. Clin. Oncol. 30, 526–530 (2007).
116. Han, S.L., Tang, H.J., Hua, Y.W., Ji, S.Q. & Lin, D.X. Expression of COX-2 in
stomach cancers and its relation to their biological features. Dig. Surg. 20,
107–114 (2003).
117. Kömhoff, M. et al. Enhanced expression of cyclooxygenase-2 in high grade human
transitional cell bladder carcinomas. Am. J. Pathol. 157, 29–35 (2000).
118. Achiwa, H. et al. Prognostic significance of elevated cyclooxygenase 2 expression
in primary, resected lung adenocarcinomas. Clin. Cancer Res. 5, 1001–1005
(1999).
119. Vane, J.R. Inhibition of prostaglandin synthesis as a mechanism of action for
aspirin-like drugs. Nat. New Biol. 231, 232–235 (1971).
120. Sheng, H., Shao, J., Washington, M.K. & DuBois, R.N. Prostaglandin E2 increases
growth and motility of colorectal carcinoma cells. J. Biol. Chem. 276,
18075–18081 (2001).
121. Williams, C.S., Mann, M. & DuBois, R.N. The role of cyclooxygenases in
inflammation, cancer, and development. Oncogene 18, 7908–7916 (1999).
122. Zelenay, S. et al. Cyclooxygenase-dependent tumor growth through evasion of
immunity. Cell 162, 1257–1270 (2015).
123. Herfs, M., Hubert, P. & Delvenne, P. Epithelial metaplasia: adult stem cell
reprogramming and (pre)neoplastic transformation mediated by inflammation?
Trends Mol. Med. 15, 245–253 (2009).
124. Liu, X.H. et al. Prostaglandin E2 modulates components of the Wnt signaling
system in bone and prostate cancer cells. Biochem. Biophys. Res. Commun. 394,
715–720 (2010).
 review
125. Liao, X. et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival.
N. Engl. J. Med. 367, 1596–1606 (2012).
126. Domingo, E. et al. Evaluation of PIK3CA mutation as a predictor of benefit from
nonsteroidal anti-inflammatory drug therapy in colorectal cancer. J. Clin. Oncol.
31, 4297–4305 (2013).
127. Deisseroth, A. et al. FDA approval: siltuximab for the treatment of patients with
multicentric Castleman disease. Clin. Cancer Res. 21, 950–954 (2015).
128. Karsdal, M.A. et al. IL-6 receptor inhibition positively modulates bone balance in
rheumatoid arthritis patients with an inadequate response to anti-tumor necrosis
factor therapy: biochemical marker analysis of bone metabolism in the tocilizumab
RADIATE study (NCT00106522). Semin. Arthritis Rheum. 42, 131–139 (2012).
129. Heinrich, P.C. et al. Principles of interleukin (IL)-6-type cytokine signalling and
its regulation. Biochem. J. 374, 1–20 (2003).
130. Putoczki, T.L. et al. Interleukin-11 is the dominant IL-6 family cytokine during
gastrointestinal tumorigenesis and can be targeted therapeutically. Cancer Cell
24, 257–271 (2013).
131. Peyrin-Biroulet, L. Anti-TNF therapy in inflammatory bowel diseases: a huge
review. Minerva Gastroenterol. Dietol. 56, 233–243 (2010).
132. Huang, E.S., Strate, L.L., Ho, W.W., Lee, S.S. & Chan, A.T. Long-term use of
aspirin and the risk of gastrointestinal bleeding. Am. J. Med. 124, 426–433
(2011).
133. Biffi, A. et al. Aspirin and recurrent intracerebral hemorrhage in cerebral amyloid
angiopathy. Neurology 75, 693–698 (2010).
134. Bruns, H. et al. Anti-TNF immunotherapy reduces CD8+ T cell-mediated
antimicrobial activity against Mycobacterium tuberculosis in humans. J. Clin.
Invest. 119, 1167–1177 (2009).
135. Ali, T. et al. Clinical use of anti-TNF therapy and increased risk of infections.
Drug Healthc. Patient Saf. 5, 79–99 (2013).
© 2016 Nature America, Inc. All rights reserved.
136. Ordonez, M.E., Farraye, F.A. & Di Palma, J.A. Endemic fungal infections in
inflammatory bowel disease associated with anti-TNF antibody therapy. Inflamm.
Bowel Dis. 19, 2490–2500 (2013).
137. Mercer, L.K. et al. The influence of anti-TNF therapy upon incidence of keratinocyte
skin cancer in patients with rheumatoid arthritis: longitudinal results from
the British Society for Rheumatology Biologics Register. Ann. Rheum. Dis. 71,
869–874 (2012).
138. Hoshi, D. et al. Incidence of serious respiratory infections in patients with
rheumatoid arthritis treated with tocilizumab. Mod. Rheum. 22, 122–127
(2012).
139. Galon, J. et al. Towards the introduction of the ‘Immunoscore’ in the classification
of malignant tumours. J. Pathol. 232, 199–209 (2014).
140. Tosolini, M. et al. Clinical impact of different classes of infiltrating T cytotoxic
and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer
Res. 71, 1263–1271 (2011).
141. Le, D.T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl.
J. Med. 372, 2509–2520 (2015).
142. Cole, B.F. et al. Aspirin for the chemoprevention of colorectal adenomas:
meta-analysis of the randomized trials. J. Natl. Cancer Inst. 101, 256–266
(2009).
143. Burn, J. et al. A randomized placebo-controlled prevention trial of aspirin and/or
resistant starch in young people with familial adenomatous polyposis. Cancer
Prev. Res. (Phila.) 4, 655–665 (2011).
144. https://clinicaltrials.gov/ct2/show/NCT00565708?term=NCT00565708&rank=1.
145. https://clinicaltrials.gov/ct2/show/NCT02301286?term=NCT02301286&rank=1.
npg
146. Ait Ouakrim, D. et al. Aspirin, ibuprofen, and the risk of colorectal cancer in
Lynch syndrome. J. Natl. Cancer Inst. 107, djv170 (2015).
240 VOLUME 17  NUMBER 3  MARCH 2016  nature immunology
147. Steinbach, G. et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in
familial adenomatous polyposis. N. Engl. J. Med. 342, 1946–1952 (2000).
148. Bertagnolli, M.M. et al. Five-year efficacy and safety analysis of the Adenoma
Prevention with Celecoxib Trial. Cancer Prev. Res. (Phila.) 2, 310–321 (2009).
149. https://clinicaltrials.gov/ct2/show/NCT01150045?term=NCT01150045&rank=1.
150. https://clinicaltrials.gov/ct2/show/NCT00159484?term=NCT00159484&rank=1.
151. https://clinicaltrials.gov/ct2/show/NCT00033371?term=NCT00033371&rank=1.
152. https://clinicaltrials.gov/ct2/show/NCT01483144?term=NCT01483144&rank=1.
153. https://clinicaltrials.gov/ct2/show/NCT02060188?term=NCT02060188&rank=1.
154. Angevin, E. et al. A phase I/II, multiple-dose, dose-escalation study of siltuximab,
an anti-interleukin-6 monoclonal antibody, in patients with advanced solid tumors.
Clin. Cancer Res. 20, 2192–2204 (2014).
155. https://clinicaltrials.gov/ct2/show/NCT01458574?term=NCT01458574&rank=1.
156. https://clinicaltrials.gov/ct2/show/NCT01470599?term=NCT01470599&rank=1.
157. Dinarello, C.A. Why not treat human cancer with interleukin-1 blockade? Cancer
Metastasis Rev. 29, 317–329 (2010).
158. Wang, Y. et al. Neutrophil infiltration favors colitis-associated tumorigenesis by
activating the interleukin-1 (IL-1)/IL-6 axis. Mucosal Immunol. 7, 1106–1115
(2014).
159. Xiao, H. et al. The Toll-interleukin-1 receptor member SIGIRR regulates colonic
epithelial homeostasis, inflammation, and tumorigenesis. Immunity 26, 461–475
(2007).
160. https://clinicaltrials.gov/ct2/show/NCT02090101?term=NCT02090101&rank=1.
161. Pitzalis, C., Jones, G.W., Bombardieri, M. & Jones, S.A. Ectopic lymphoid-like
structures in infection, cancer and autoimmunity. Nat. Rev. Immunol. 14,
447–462 (2014).
162. Dieu-Nosjean, M.C., Goc, J., Giraldo, N.A., Sautes-Fridman, C. & Fridman, W.H. Tertiary
lymphoid structures in cancer and beyond. Trends Immunol. 35, 571–580 (2014).
163. Coppola, D. et al. Unique ectopic lymph node-like structures present in human
primary colorectal carcinoma are identified by immune gene array profiling.
Am. J. Pathol. 179, 37–45 (2011).
164. Finkin, S. et al. Ectopic lymphoid structures function as microniches for tumor
progenitor cells in hepatocellular carcinoma. Nat. Immunol. 16, 1235–1244
(2015).
165. Kaplan, K.B. et al. A role for the Adenomatous Polyposis Coli protein in
chromosome segregation. Nat. Cell Biol. 3, 429–432 (2001).
166. Peltomäki, P. Deficient DNA mismatch repair: a common etiologic factor for colon
cancer. Hum. Mol. Genet. 10, 735–740 (2001).
167. Ferguson, B.J., Mansur, D.S., Peters, N.E., Ren, H. & Smith, G.L. DNA-PK is a
DNA sensor for IRF-3-dependent innate immunity. eLife 1, e00047 (2012).
168. Kondo, T. et al. DNA damage sensor MRE11 recognizes cytosolic double-stranded
DNA and induces type I interferon by regulating STING trafficking. Proc. Natl.
Acad. Sci. USA 110, 2969–2974 (2013).
169. Goodwin, A.C. et al. Polyamine catabolism contributes to enterotoxigenic
Bacteroides fragilis-induced colon tumorigenesis. Proc. Natl. Acad. Sci. USA 108,
15354–15359 (2011).
170. Bergounioux, J. et al. Calpain activation by the Shigella flexneri effector VirA
regulates key steps in the formation and life of the bacterium’s epithelial niche.
Cell Host Microbe 11, 240–252 (2012).
171. Cuevas-Ramos, G. et al. Escherichia coli induces DNA damage in vivo and
triggers genomic instability in mammalian cells. Proc. Natl. Acad. Sci. USA 107,
11537–11542 (2010).
172. Gur, C. et al. Binding of the Fap2 protein of Fusobacterium nucleatum to human
inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity 42,
344–355 (2015).