Cellular Signalling 25 (2013) 403416

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Cellular Signalling
journal homepage: www.elsevier.com/locate/cellsig

Review

Signaling pathways bridging microbial-triggered inammation and cancer

Maulilio John Kipanyula a, Paul Faustin Seke Etet b, Lorella Vecchio c, Mohammed Farahna b,
Elias Nchiwan Nukenine d, Armel Herv Nwabo Kamdje d, e,
a
Department of Veterinary Anatomy, Sokoine University of Agriculture, P.O. Box 3016, Chuo Kikuu, Morogoro, Tanzania
b
Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, 51452 Al-Qaseem, Saudi Arabia
c
Laboratory of Cytometry, Institute of Molecular Genetics, CNR, University of Pavia, 27100 Pavia, Italy
d
Department of Biomedical Sciences, University of Ngaoundr, P.O. Box 454, Ngaoundr, Cameroon
e
Biomedical Research Center, University of British Columbia, 2222 Health Science Mall, Vancouver BC, Canada, V6T 1Z3

a r t i c l e i n f o a b s t r a c t

Article history: Microbial-triggered inammation protects against pathogens and yet can paradoxically cause considerable sec-
Received 7 October 2012 ondary damage to host tissues that can result in tissue brosis and carcinogenesis, if persistent. In addition to
Accepted 26 October 2012 classical pathogens, gut microbiota bacteria, i.e. a group of mutualistic microorganisms permanently inhabiting
Available online 30 October 2012
the gastrointestinal tract and which plays a key role in digestion, immunity, and cancer prevention, can induce
inammation-associated cancer following the alterations of their microenvironment. Emerging experimental
Keywords:
Signaling pathways
evidence indicates that microbiota members like Escherichia coli and several other genotoxic and mutagenic
Microbe pathogens can cause DNA damage in various cell types. In addition, the inammatory response induced by
Infection chronic infections with pathogens like the microbiota members Helicobacter spp., which have been associated
Inammation with liver, colorectal, cervical cancers and lymphoma, for instance, can also trigger carcinogenic processes. A mi-
Carcinogenesis croenvironment including active immune cells releasing high amounts of inammatory signaling molecules can
Cancer favor the carcinogenic transformation of host cells. Pivotal molecules released during immune response such as
the macrophage migration inhibitory factor (MMIF) and the reactive oxygen and nitrogen species' products
superoxide and peroxynitrite, can further damage DNA and cause the accumulation of oncogenic mutations,
whereas pro-inammatory cytokines, adhesion molecules, and growth factors may create a microenvironment
promoting neoplastic cell survival and proliferation. Recent ndings on the implication of inammatory
signaling pathways in microbial-triggered carcinogenesis as well as the possible role of microbiota modulation
in cancer prevention are herein summarized and discussed.
2012 Elsevier Inc. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404
2. Pathogens and cancer: protective effects of inammation and mutagenic potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404
2.1. Microbiota and susceptibility to infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404
2.2. Outcome of immune defense against pathogens: mutagenic responses and cancer . . . . . . . . . . . . . . . . . . . . . . . . . 406
3. Pattern-recognition receptors: example of Toll-like receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
3.1. TLRs, pathogen-triggered inammation, and cancer: lessons from microbiota . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
3.2. TLR signaling and inammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
4. NF-B, pathogen-triggered inammation, and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
4.1. NF-B, infection, and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
4.2. NF-B signaling and carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
5. Pro-inammatory cytokines and COX-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409
5.1. IL-1 and TNF- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409
5.2. IL-32 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410
5.3. IL-8 and IL-29 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410
5.4. COX-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410

Corresponding author at: Department of Biomedical Sciences, University of Ngaoundr, P.O. Box 454, Ngaoundr, Cameroon/Biomedical Research Center, University of British
Columbia, 2222 Health Science Mall, Vancouver BC, Canada, V6T 1Z3. Tel.: +1 604 822 0441(ofce); fax: +1 604 822 7815.
E-mail address: armel.nwabo@gmail.com (A.H. Nwabo Kamdje).

0898-6568/$ see front matter 2012 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cellsig.2012.10.014
404 M.J. Kipanyula et al. / Cellular Signalling 25 (2013) 403416

6. Oxygen/nitrogen species and microbial-triggered cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410

6.1. Oxidative and nitrative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410
6.2. Hypoxia-inducible factor 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
7. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
Disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412

1. Introduction In this review, we summarize and discuss the recent ndings on

In the presence of pathogens or irritants and associated molecules,
the body mounts a strong immune response termed as inamma-
tion aimed at preventing tissue injury and combating infection.
Mononuclear phagocytes residing in tissues are the rst to be activat-
ed during innate immune response. They recognize pathogens and
molecules associated with tissue damage through intracellular or
surface-expressed pattern recognition receptors (PRRs) that have in-
herent capacity to directly or indirectly detect pathogen-associated
molecular patterns (PAMPs) such as microbial nucleic acids, bacterial
cell wall lipopolysaccharide (LPS) and proteoglycans, and fungal cell
wall components like -mannan and -glucan; and danger/damage
associated molecular patterns (DAMPs), including molecules released
by injured cells such as: nucleic acids, uric acid, ATP, amyloid and
cytoplasmic proteins of the S100 family [1,2], for instance.
PRR signaling is an important partner of the immune system
whose pivotal role is to promote the release of factors triggering the
activation and recruitment of circulating immune cells like mono-
cytes and neutrophils, and even adaptive immune cells like lympho-
cytes, to the infection/damage site in case of persistent challenge
[25]: The rst transient changes in vascular wall are caused by se-
creted factors like prostaglandins, and nitric oxide that act on vascular
smooth muscle to cause vasodilation thus increase blood ow and
transport more circulating leukocytes. Secondly, vascular permeabili-
ty is further increased by inammatory mediators such as histamine
and leukotrienes that act on endothelial cells to allow plasma proteins
and leukocytes to exit the circulation. Finally pro-inammatory cyto-
kines such as interleukin 1 (IL-1) and tumor necrosis factor alpha
(TNF-) promote immune cell inltration to the affected tissue,
whereas the chemoattractant factors direct them to the inamed
site. The immune cells recruited ght against invading bacteria, virus-
es, or parasites at the infection site, while swelling (i.e. the buildup of
uids in the interstitium) and immune cell phagocytic activity
aimed at eliminating DAMPS protect injured areas from further
harm [6,7].
Inammatory reactions are ceased following the elimination of
pathogens, but can persist in case of chronic infection or following
chronic exposure to DAMPs [4,8,9], resulting in tissue brosis and car-
cinogenesis. The link between inammation and the risk of develop-
ing cancer was reported as early as 1863, when Virchow observed
that carcinogenesis tends to occur at chronic inammation sites
[10]. Subsequently, epidemiologic data have strongly indicated that
chronic inammation is associated with increased risk of cancer
[11,12]. It is estimated that about two million cancer cases are caused
by infectious agents each year [13]. Agents like human papillomavi-
ruses, hepatitis B and C viruses, and the Gram-positive bacterium
Helicobacter pylori, which is a gut microbiota member, are responsible
for about a third of all cancers attributable to infections [13,14], which
mainly include gastric, liver, colorectal, and cervix uteri cancers
[15,16]. In addition, both non-mutualistic microorganisms and gut
microbiota, i.e. mutualistic microorganisms permanently inhabiting
the gastrointestinal tract and which play a key role in digestion,
immunity, and cancer prevention [15,17], may trigger aggravating
inammatory responses in various cancer types, including blood
cancers such as leukemia [1820] and lymphoma [2123].
signaling pathways bridging pathogen-triggered inammation and
cancer initiation and progression. The possible role of gut microbiota
modulation for cancer prevention is also considered.
2. Pathogens and cancer: protective effects of inammation and
mutagenic potential
2.1. Microbiota and susceptibility to infection
Although the body is continuously exposed to microorganisms,
only a small fraction is pathogenic or can escape/resist immune re-
sponse whereas many live in a mutualistic relationship with the
body, such as the gut microbiota that is a group of microorganisms
permanently inhabiting the gastrointestinal tract [5]. As already men-
tioned, the commensal microorganisms that inhabit the mammalian
body surfaces and the gut play a critical role in many key functions
of the organism, including immune response, energy metabolism,
and cancer prevention [15,17]. However, in circumstances that dis-
turb their microenvironment they can breach the skin barrier or the
intestinal mucosa layer and enter bloodstream, resulting in chronic
inammation, and subsequently causing tissue brosis and carcino-
genesis [24]. Certain commensal bacteria can invade colonic epithelial
cells, activating early intracellular signaling systems to trigger host in-
ammatory reactions. Such bacteria include Fusobacterium varium,
Bacteroides vulgatus, Escherichia coli and Clostridium clostridioforme,
for instance, which are commonly isolated from the mucosa of in-
ammatory bowel disease patients [25]. An in vitro study conducted
by Ohkusa and collaborators [25] have reported that these commen-
sal bacteria, but not probiotics, adhere to colonic epithelial cells and
invade their cytoplasm, resulting in the expression of mRNAs of
IL-8, IL-6, TNF-, and CCL2 (CC motif ligand 2, chemokine), and in
the release of signicant amounts of IL-8 and TNF- by invaded
host cells. Furthermore, these authors observed an increased expres-
sion of IL-8, TNF-, and phosphorylated NF-B (nuclear factor B)
p65 in inamed epithelia with cryptitis or crypt abscess in ulcerative
colitis patients, in further clinical studies. In addition, H. pylori that
has been reported protective effects against pathogenic bacteria and
esophageal cancer [15], can also play crucial roles in the progression
from inammation to cancer in the stomach [26]. Recent studies in
a mouse colitis-associated adenocarcinoma model have indicated
that H. hepaticus promotes tumorigenesis [16]. Similarly, E. coli that
induces homeostatic mucosal immune responses can also cause
inappropriate immune activation in genetically susceptible hosts,
resulting in colitis-associated colorectal cancer [17]. Murine isolate
of E. coli chronic intestinal inammation causes functional alterations
in gene expression in commensal gut bacteria [27]. Further investiga-
tion of the mechanisms accounting for these effects might identify
therapeutic targets for patients with inammatory bowel diseases
and colitis-associated colorectal cancer. Various microbiota bacteria
causing inammation-mediated carcinogenesis are presented in Table 1.
Besides, following microenvironment changes, the microbiota mem-
ber E. coli can alter the microbial composition in the intestinal gut in
order to induce the expansion of microorganisms with genotoxic
capabilities, including itself [13,17,26] (Fig. 1A). This alteration may
also result in an increase in epithelial cell susceptibility of hijacking
 M.J. Kipanyula et al. / Cellular Signalling 25 (2013) 403416 405

Table 1 instance. Various non-microbiota pathogens causing inammation-

Various microbiota bacteria causing inammation-associated carcinogenesis. mediated carcinogenesis or aggravating cancer aggressiveness are
Bacteria Types of cancer presented in Table 2.
The question why/how microbiota members can become pathogenic
Bacillus spp. Bladder cancer [66]
Bacteroides spp. Colorectal cancer [74,155,156] and start or favor the establishment of microbial chronic inammatory
Enterobacter spp. Solid [136,157,158] and blood cancers [34,35] diseases eventually resulting in cancer has been puzzling the scientic
Enterococcus spp. Solid cancers [137,138,157] community for decades. It has been hypothesized that the relatively
Escherichia coli Breast [159], bladder [66], and colorectal [17,160] cancers,
low burden of microbes in urban environment may have a profound in-
renal cell carcinoma [33], acute myeloid leukemia [18]
Helicobacter spp. Gastric, liver, cervical [13,26], esophageal [15], uence on the immune function and eventually on inammation-
and colon [16] cancers, lymphoma [21,105] mediated carcinogenesis [37]. A recent systematic review of the litera-
Klebsiella spp. Solid cancers [157,161] ture [37] revealed that up to date, only few studies have addressed the
Pseudomonas spp. Solid [64,157,160,161] and blood cancers [162165] effect of exposure to the environmental microbiota on the risk of cancer
development. Interestingly, from immunological studies it appears that
inammatory cytokines, and more frequently IL-23 released by
by various pathogenic non-microbiota bacteria (e.g. Neisseria spp. T-helper 17 (Th17) cells, are closely linked with tumor-associated in-
[28]), viruses (e.g. Hepatitis C virus [29]), fungi (e.g. Candida albicans ammation; however, the precise mechanisms accounting for the rela-
[30]), and parasites (e.g. Giardia intestinalis [31]), promoting malig- tionship between Th17/IL-23 axis and carcinogenesis are not well
nant transformation of various cell types, including epithelial cells understood. Moreover, a growing body of evidence indicates that Th17
in melanoma [32] and carcinoma [16,33], lymphocytes in several cells are associated with inammation and aberrant angiogenesis in
lymphoma and other blood cancers [22,23,3436] (Fig. 1B,C), for various cancer types, including leukemia [38], for instance. Considering

Fig. 1. Gut microbiota and carcinogenesis. Gut microbiota, a group of microorganisms permanently inhabiting the gastrointestinal tract and which plays a key role in digestion, im-
munity, and cancer prevention [15,17] can promote malignant transformation of various cell types following alterations of their microenvironment. In colorectal carcinoma genesis
(A), epithelial cells invaded by genotoxic bacteria start their transformation following DNA damage and produce inammatory factors favoring neoplastic cell survival. In
lymphomagenesis (B), the transformation of invaded lymphocytes starts following DNA damage induced by genotoxic bacteria that have entered the bloodstream. Affected
immune cells produce a large amount of pro-inammatory factors that favor neoplastic cell survival. Similarly, genotoxic bacteria can infect several other cell types that they
reach transported by the bloodstream, resulting eventually in breast, gastric, cervical, liver, and bladder cancers (C), for instance. MMIF: macrophage migration inhibitory factor.
ROS: reactive oxygen species. TLRs: Toll-like receptors.
406 M.J. Kipanyula et al. / Cellular Signalling 25 (2013) 403416

Table 2 factor- [51], prostaglandin E2 [52], and reactive oxygen and nitro-
Various non-microbiota pathogens causing inammation-associated carcinogenesis or gen species [53,54].
aggravating cancer aggressiveness.
Body failure to terminate inammatory response results in its
Types of cancer chronicity, with the establishment of deleterious inammatory cycles
Viruses Cytomegalovirus Glioblastoma [166], prostate cancer [167] [4,8,9]. The hallmarks of chronic inammation are inammatory foci
EBV Immunoblastic lymphoma [36,103], dominated by lymphocytes, plasma cells, and macrophages [55],
Kaposi's sarcoma [104] which produce a high amount of cytokines, chemokines, growth fac-
HBV, HCV Gastric, liver, cervical cancers [13,168]
tors, and reactive oxygen and nitrogen species that may cause contin-
Herpes viruses Kaposi's sarcoma [92,104], melanoma [32]
HIV Plasmablastic lymphoma [22,23,36], uous tissue damage [56]. Interestingly, reactive oxygen and nitrogen
Kaposi's sarcoma [104] species abundantly released in these pathological conditions may
HPV Gastric, liver, cervical [13,113,158], produce mutagenic agents, including peroxynitrite (ONOO ), for in-
prostate [167] cancers stance, which reacts with DNA and causes mutations and damages
Leukemia viruses T-cell leukemia [102], prostate cancer [167]
in proliferating cells [57,58]. The DNA alterations caused may predis-
Bacteria Acinetobacter spp. Solid [6466] and blood cancers [63]
Aeromonas spp. Solid [169] and blood cancers [170,171] pose to neoplasia [59]. In addition, the high concentrations of
Neisseria spp. Prostate [172] and cervical [31] cancers pro-inammatory cytokines and factors like TNF- and macrophage
Propionibacterium spp. Gastric [158], prostate [167,172,173] cancers migration inhibitory factor (MMIF) released by macrophages and
Staphylococcus aureus Solid cancers [64,66,160,161]
T-lymphocytes may exacerbate further DNA damage [60]. MMIF
Parasites Cryptosporidium spp. Colorectal Cancer [174,175]
Plasmodium spp. Burkitt's lymphoma [176,177] contributes to tumorigenesis by interfering with the crucial
Schistosoma spp. Bladder cancer, cholangiocarcinoma [175] cell-cycle signaling pathway cyclin/Rb/E2F [61], and also by impairing
Fungi Candida spp. Leukemia [19,20], other blood cancers [178] p53-dependent protective responses, thus causing the accumulation
Opportunistic yeast Solid and blood cancers [179] of oncogenic mutations [62]. Moreover, the inammatory microenvi-
EBV: Epstein-Barr virus. HBV: hepatitis B virus. HCV: hepatitis C virus. HIV: human im- ronment is favorable to the survival and proliferation of neoplastic
munodeciency virus. HPV: Human papillomavirus. cells [46,47], indicating that the modulation of factors fuelling chronic
inammation may have anticancer effects.
recent reports indicating that regulatory T cells have a counter- Intriguingly, a recent study has revealed that some commonly
regulatory effect on Th17 cells and even inhibiting their functions employed antineoplastic agents causing DNA damage-induced apopto-
[39,40], it can be hypothesized that continuous exposure to environmen- sis in more sensitive cells, such as transforming cells, have antibacterial
tal microbiota strengthens the inammatory cell regulatory network and activities against Acinetobacter spp. [63], non-microbiota pathogens as-
prevents the establishment of chronic inammation. Conversely, limited sociated with various solid [6466] and blood cancers [63]. These
constant exposure to environmental microbiota may favor the establish- agents include the alkaloid vincristine, the alkylating-like agent cisplat-
ment of chronic inammation. Signaling pathways accounting for in, and the small molecule doxorubicin. The current ndings indicate
inammation-mediated carcinogenesis triggered by microbiota bacteria that Acinetobacter spp. become as sensible to DNA damage as
and other pathogens are considered in the following sections. transforming cells during inammation-mediated carcinogenesis, indi-
cating the complexity of the interactions between cancer-related
2.2. Outcome of immune defense against pathogens: mutagenic pathogens and transforming cells. Similarly, eradication of the Gram-
responses and cancer negative bacterium Campylobacter jejuni in immunoproliferative small
bowel disease suppresses the related inammation-mediated lympho-
Many pathogens can cause chronic inammations, including magenesis at its early stage [21]. Future studies addressing the relation-
the protozoan Trypanosoma brucei which causes inammation- ship between bacteria and transforming cells may provide new insights
associated functional alterations [41,42], fungi like Cryptococcus in bacteria-triggered inammation and in the subsequent carcinogenic
neoformans and Aspergillus fumigatus which take advantage of immu- processes.
nocompromised hosts to cause infection [43], and various bacteria
and viruses. As discussed earlier, emerging evidence indicates a 3. Pattern-recognition receptors: example of Toll-like receptors
strong link between cancer and microbiota (Table 1) or other patho-
gens establishing chronic inammation (Table 2). The mechanisms by 3.1. TLRs, pathogen-triggered inammation, and cancer: lessons from
which different microbial pathogens contribute to cancer develop- microbiota
ment are complex. A spate of recent investigations suggests that
these mechanisms involve interplay between chronic inammation, Toll-Like Receptors (TLRs), transmembrane proteins containing
direct microbial effects on host cell physiology and, ultimately, leucine-rich repeats, are involved in sensing endogenous danger sig-
changes in tissue homeostasis. nals and play a critical role in the early innate immune response to in-
The inammatory responses that successfully eliminate PAMPs vading pathogens by sensing PAMPs, predominantly through MyD88
and DAMPs are actively terminated and the healing process starts (myeloid differentiation primary response gene 88) adaptor protein
thereafter. Early studies revealed that the phagocytosis of apoptotic [1,2]. For instance, TLR/MyD88 signaling prevents the dissemination
cells enhances the production of anti-inammatory mediators, of bystander bacteria to deeper tissues during Clostridium difcile in-
promoting anti-inammatory response [44], and conversely, recent fection, by triggering neutrophil and monocyte recruitment to the
ndings indicate that impaired phagocytosis promotes inammation, lamina propria of the large intestine through mechanisms involving
to recruit more immune cells [45], suggesting a crosstalk between chemokine signaling pathways like CCL2/CCR2 (CC receptor type
inamed tissue and immune cells. Such crosstalk would be mediated 2)- and CXCL1 (CXC motif ligand 1)/CXCR2 (CXC motif receptor
by the anti- and pro-inammatory factors abundantly produced 2); mortality is markedly increased in MyD88-decient mice follow-
by both inltrating and resident cells [46,47]. Studies in a rat ing C. difcile infection [2]. Loss of function studies have shown that
carrageenin-sponge implant model have revealed a shift from genetic silencing of PRR signaling protects against chronic inamma-
antibacterial tissue damage to tissue repair involving factors with tory diseases [67], indicating that perturbations of microbiotaPRR
both pro-inammatory and anti-inammatory effects of which the interactions may promote inammation.
effects depend on the microenvironment at the inamed site Translocation of the microbiota from the gut into the systemic
[48,49]. Such factors have been observed in humans as well and in- milieu can cause bacterial sepsis [68,69]. Recent reports suggest that
clude, for instance, metalloproteinases [50], transforming growth small leucine-rich proteoglycans such as decorin and biglycan
 M.J. Kipanyula et al. / Cellular Signalling 25 (2013) 403416
orchestrate TLR crosstalk during inammation [70,71]. Septic inam-
mation evokes early responses which include activation of the gene
encoding decorin; decorin protein level is increased in the plasma of
septic patients and mouse models, and decorin increases the expres-
sion of pro-inammatory molecules in cancer cells [70]. Interestingly,
the ndings from recent studies aiming at unraveling the mecha-
nisms used by decorin signaling to control inammation and tumor
growth revealed two mechanisms [70]: i) rst, decorin may act as
an endogenous ligand of TLR2 and TLR4 to stimulate the production
of pro-inammatory molecules, including programmed cell death
protein 4 (PDCD4), in macrophages; ii) second, decorin may prevent
translational repression of PDCD4 by decreasing the activity of
transforming growth factor (TGF)-1 and the expression of the key
regulator of oncogenic processes miR-21, which is also a translational
inhibitor of PDCD4. In addition, still in these studies, increases in
PDCD4 levels led to decreases in the expression of the anti-
inammatory cytokine IL-10, thereby making the cytokine prole
more pro-inammatory. Furthermore, increases in expression of
pro-inammatory molecules have been associated with tumor
growth promotion and poor patient outcomes in hepatocellular carci-
noma [72], for instance.
Experimental evidence suggests that TLRs are key players in
pathogen-triggered inammation-mediated carcinogenesis. Gut-derived
LPS has demonstrated the ability to promote hepatocellular carcinoma
development by activating TLR4 expression on myeloid-derived immune
cells in different types of liver injury models, including concanavalin
A-induced hepatitis model, which mimics human viral hepatitis [3], fur-
ther indicating that gut microbiota and TLR4 signaling modulation may
represent potential avenues for therapeutic intervention aimed at treat-
ment of hepatitis virus-induced hepatitis and prevention of hepatocellu-
lar carcinoma. Similarly, Ochi and collaborators [73] have found that
TLR4 signaling plays a key role in the cellular and molecular mechanisms
bridging chronic pancreatic broinammatory disease and pancreatic
carcinogenesis. These investigators observed that TLR4 signaling
triggered by LPS exacerbates pancreatic inammation and accelerates
tumorigenesis, whereas TLR4 inhibition or blockade of the MyD88-
independent Toll/IL-1 receptor domain-containing adapter-inducing
interferon- (TRIF) pathway have protective effects against pancreatic
cancer. Surprisingly, blockade of the MyD88-dependent pathway exacer-
bated pancreatic inammation and malignant progression, through den-
dritic cell (DC)-mediated induction of pancreatic antigen-restricted
Th2-deviated CD4 (+) T cells. Such pro-tumorigenic and bro-
inammatory effects of MyD88 inhibition indicate the complexity of
TLR signaling in carcinogenesis.
In addition, Uronis and collaborators [74] have demonstrated that
bacterial-induced inammation drives progression from adenoma to
invasive carcinoma in azoxymethane (AOM oncogene)-exposed
IL-10 knockout mice, a model of colitis-associated colorectal cancer.
These investigators have observed colon tumors in 62% of
AOM-IL-10(/) mice against only 20% in AOM-wild-type mice;
and tumor multiplicity directly correlated with the presence of
colitis. Interestingly, IL-10(/) mice mono-associated with the
mildly colitogenic bacterium B. vulgatus displayed signicantly re-
duced colitis and colorectal tumor multiplicity; and germ-free
AOM-treated IL-10(/) mice were devoid of tumors. In addition,
AOM-treated IL-10 (/) or MyD88 (/) mice displayed a re-
duced mRNA expression of TNF- and IL-12p40, a known component
of IL-12 and IL-23. These mice showed no signs of tumor develop-
ment, indicating that the TLR/MyD88 pathway is essential for
microbiota-induced development of colitis-associated colorectal can-
cer. These ndings also indicate that intestinal microbiota modulation
may decrease cancer risk in inammatory bowel disease. Accordingly,
it has been hypothesized that probiotics, i.e. live microorganisms con-
ferring a health benet on the host when administered in adequate
amounts, are capable of transient modulation of the microbiota, that
have been successfully used to manage inammatory bowel disease
407
may have an effect on the prevention of colorectal cancer by scaveng-
ing toxic compounds or preventing their generation in situ [75]. This
hypothesis should be investigated, considering the importance for co-
lorectal cancer prophylaxis.
Interestingly, other recent studies have shown that infections with
H. pylori activate oncogenic signaling pathways like Sonic Hedgehog
[26] and Wnt [76,77], which have been reported anti-apoptotic ef-
fects and the ability to confer stem-like properties to transforming
cells in various solid and blood cancers (for review see [78,79] and
[80,81]), respectively. In the APCMin/+ mouse, an animal model of
human colon cancer where a mutation in the murine homolog of
the Wnt inhibitor APC gene is induced, a recent report has indicated
that gut microbiota accelerate tumor growth in comparison with
wild type mice [82], suggesting a role for the Wnt signaling pathway
in that context. Rapid tumor growth occurred concomitantly with
systemic anemia, suggesting a role for intestinal barrier damage and
erythropoiesis-stimulating mitogens. The microbial cell wall compo-
nent LPS accounted for at least part of the cell growth acceleration ob-
served, via c-Jun/JNK signaling pathway. In addition, inltrating
CD11b + myeloid cells released high levels of phosphorylated STAT3
(p-Tyr705) in colonic tumors. These ndings indicate that gut
microbiota-triggered tumor growth acceleration observed in APC
(Min/+) mice is mediated by the c-Jun/JNK and STAT3 signaling
pathways in combination with anemia. These ndings point out the
complexity of the mechanisms accounting for the inammatory and
carcinogenic effects of microbiota bacteria.
3.2. TLR signaling and inammation
TLRs recognize bacterial, viral, and parasite PAMPs in the extracellu-
lar environment (TLR1, 2, 46, 11) or in endolysosomes (TLR3, 79,
10). They can bind several PAMPs/DAMPs and are thought to even
bind common self molecules such as heat shock proteins and brin-
ogen, suggesting a link between the stereotypic inammatory response
triggered by TLRs and autoimmune diseases [83,84]. Stimulation of
TLRs by the corresponding PAMPs or DAMPs initiates signaling cas-
cades leading to the activation of transcription factors, such as AP-1,
NF-B, and interferon regulatory factors (IRFs). TLR signaling is trans-
duced in the cytoplasm by a Toll/ IL-1 receptor (TIR) domain, which
is the docking site of TIR-containing cytoplasmic adaptor proteins
that are critical in orchestrating the signal transduction pathways
after TLR and IL-1 receptor activation. TIR adaptor molecules mainly in-
clude signaling proteins like MyD88, MyD88 adaptor-like (MAL), TRIF,
TRIF-related adaptor molecule (TRAM), and the negative regulator of
TLR pathways SARM (sterile-alpha and Armadillo motif containing
protein) [85,86]. Except for TLR3 all TLRs engage the adaptor MyD88,
however either directly as IL-1R (TLR5, 711, and heterodimeric
TLR1-TLR2 and TLR2-TLR6) or in association with the adaptor MAL/
TIRAP (Toll-IL-1 receptor (TIR) domain containing adaptor protein.
e.g. TLR4, and heterodimeric TLR1-TLR2 and TLR2-TLR6).
MyD88 signaling is transduced through a death domain (DD)
which mediates interactions with the DD of the serine/threonine ki-
nase IRAK4, the clustering of which would result in its autophospho-
rylation within the receptor complex, allowing a kinase activity-
dependent binding of IRAK4 DD to the DD of the related kinases
IRAK1 and 2 [87]. The MyD88IRAK4IRAK1/2 complex nucleate a
larger complex including, E3 ubiquitin ligases like TRAF6 (tumor ne-
crosis factor receptor associated factor 6), cIAP1 (cellular inhibitor
of apoptosis-1), and cIAP2, and the E2 ubiquitin-conjugating enzyme
Ubc13 (ubiquitin-conjugating enzyme E2N), in the case of TLR4
[88,89]. TRAF6 catalyzes the formation of polyubiquitin chains on ly-
sines within itself and in IL-1 receptor-associated kinase 1 (IRAK1),
promoting the K63-linked polyubiquitination of cIAPs and the re-
cruitment of adaptor proteins TAB2 and 3, resulting in the activation
of the mitogen-activated protein kinase (MAPK) kinasekinase
(MAPKKK) TAK1 (transforming growth factor--activated kinase 1)
408 M.J. Kipanyula et al. / Cellular Signalling 25 (2013) 403416
[89,90]. In addition, K63-linked poly-ubiquitin also binds the regula-
tory subunit of the NF-B inhibitor (IB) kinase (IKK) complex
termed as NEMO, allowing its recruitment to the TLR4 signaling
complex [91]. TAK1 mediates the activation of the downstream
MAPKs p38 and c-Jun N-terminal kinase (JNK), which are hijacked
by activating mutations in pathogen-related cancers like herpes
virus-associated Kaposi's sarcoma [92], and probably participate to
inammation-mediated carcinogenesis. Activated TAK1 complex
translocates into the cytosol, where it activates: i) the kinase MKK4
that results in the phosphorylation/activation of JNK [89]; ii) and
the related kinases MKK3 and MKK6 for the activation of p38 [93].
In turn, JNK stimulates the expression of pro-inammatory mediators
like TNF- through an AP1 transcription factor-dependent mecha-
nism [94], whereas p38 activates the cAMP response element-
binding (CREB), which results in the activation of the CCAAT-
enhancer-binding proteins (c/EBPs) family of transcription factors,
and in the subsequent induction of various genes involved in the in-
ammatory response, such as: cell adhesion molecules; chemokines
like CXCL-1 and CXCL-2; and cytokines like IL-1, IL-10, IL-12, and
IL-32 [95,96].
On the other hand, IKK induces the activation of the NF-B transcrip-
tion factor, which results in subsequent transcriptional responses in-
volving the MAPKs of the extracellular-signal-regulated kinase (ERK)
family that, in turn, activate the ATF (activating transcription factors)/
CREB family of transcription factors, resulting in the induction of genes
involved in both pro- and anti-inammatory responses such as PTGS2
gene that encodes prostaglandin-endoperoxide synthase 2 or cyclooxy-
genase 2 (COX-2), involved in the synthesis of prostaglandins [97,98]. In
addition, the canonical IKK/NF-B signaling pathway can also accumu-
late in the nucleus and induce the expression of several other genes
encoding for inammatory-related molecules, including [98]: PRRs like
advanced glycation end product (AGE) receptors, chemokines like
CCL2 (MCP-1), CCL3 (MIP-1), CCL5 (RANTES) and CXCL1/2; growth
factors like GM-CSF (granulocyte macrophage colony-stimulating fac-
tor); adhesion molecules like E- and P-selectins , ICAM1 (intercellular
adhesion molecule 1) and VCAM1 (vascular cell adhesion molecule 1);
cytokines like IL-1, IL-12, and TNF-; metalloproteinases like MMP9;
the complement factor B; Caspase-11; but also, inhibitors of NF-B sig-
naling like A20 and IB- , the inhibitor of macrophage activation
CD200, the inhibitor of virus proliferation IFN (interferon)-, and the
pleiotropic cytokine IL-6. These observations indicate that NF-B can
induce and also regulate the inammatory response.
Emerging data suggest that TLR signaling role in pathogen-
triggered inammation and carcinogenesis is complex, and therefore,
requires further investigations. For instance, Smolinska and collabo-
rators [1] have investigated the role of Src family kinases, i.e. the
largest non-receptor tyrosine kinase family, in TLR signaling, using
primary human macrophages in combination with adenoviral
overexpression and small interfering RNA knockdown. The study re-
vealed that the Src kinase Hck has a key role in LPS/TLR4-induced
TNF- and IL-6 production. Furthermore, ndings have suggested
that Hck may mediate TLR4-induced transcription of both TNF-
and IL-6 by a mechanism that does not involve NF-B and MAPK
pathways, but rather leads to p38 MAPK-dependent activator protein
(AP-1) binding with a complex of c-fos and JunD, pointing out the
possibility of targeting Hck for the alleviation of excessive inam-
mation. More recent studies involving i.p. or s.c. injection of the
TLR3 interactor polyI:C (Polyinosinicpolycytidylic acid) to Lewis
lung carcinoma tumor-implant mice have shown that TLR3 signal-
ing induces tumor regression by converting tumor supporting
macrophages into tumor suppressors [99], anticipating, therefore,
that better characterization and understanding of the signaling
pathways mediated by TLR may provide novel pharmacologic tar-
gets against pathogen-associated cancers. Fig. 2 illustrates how
TLR signaling downstream targets integrate to induce inammato-
ry effects.
4. NF-B, pathogen-triggered inammation, and cancer
4.1. NF-B, infection, and cancer
As TLR pathways, many other inammatory signaling pathways
transduce their signal through NF-B activation, including pathways
mediated by the PRR members NLRs (nucleotide oligomerization
domain-like receptors) [98] and C-type lectin receptors [100]. NF-B
signaling pathway has a critical role in human diseases and carcinogen-
esis. Not surprisingly, mutations of NF-B signaling molecules have
been reported in several malignancies. For instance, the somatic
mutation of TNFAIP3, the gene encoding for the deubiquitinating factor
A20, is frequently reported in human B-cell lymphomas, including
Epstein-Barr virus-associated AIDS-related lymphoma [36] and
Kaposi's sarcoma [101], pointing out A20 as a tumor suppressor in
these blood cancers. In addition, in cancer cells collected from adult
T-cell leukemia patients (a fatal T-cell malignancy associated with
human T-cell leukemia virus type I infection), the suppression of
NF-B-dependent transcriptional activity by the IB kinase 2 inhibitor
IMD-0354 decreased cell survival [102]. Comparably, in EpsteinBarr
Virus (EBV)-associated immunoblastic lymphoma, which occurs in
immunocompromised patients such as those with AIDS or transplant
recipients upon primary EBV infection or following the reactivation
of a pre-existing latent EBV infection, the HIV protease inhibitor
ritonavir inhibits the tumor growth and inltration of EBV-positive
lymphoblastoid B cells by targeting NF-B signaling [103]. Tang
and collaborators [104] have recently demonstrated that Kaposi's
sarcoma-associated herpesvirus (KSHV) infection is necessary, al-
though, not sufcient for disease development without other cofac-
tors. The authors identied human immunodeciency type 1 (HIV-1)
Tat and herpes simplex virus 1/2 (HSV-1/2) as such cofactors. Interesting-
ly, the researchers also demonstrated that HSV-2 infection activate NF-B
signaling pathway, further suggesting a role of HSV-2 in the pathogenesis
of Kaposi's sarcoma. Recent studies based on a transgenic mouse model
have revealed that the prophylactic delivery of IL-15 affords protection
against a lethal HSV-2 challenge and metastasis of B16/F10 melanoma
cells through NF-B dependent induction of the chemokine CCL5 by my-
eloid immune cells [32]. NF-B may also bridge chronic inammation and
carcinogenesis in bacterial infection-related cancer such as gastric MALT
lymphomas associated with H. pylori and Ocular Adnexa MALT lympho-
mas of whose association with Chlamydia psittaci infection has been re-
cently demonstrated [105].
4.2. NF-B signaling and carcinogenesis
NF-B may link inammation to cancer through its inherent abil-
ity to induce the production of adhesion molecules, MMPs, COX-2,
pro-inammatory cytokines, and reactive oxygen and nitrogen spe-
cies [98]. In normal inammatory response NF-B-induced adhesion
molecules, chemokines, and vasomodulatory molecules play a key
role in the processes resulting in immune cell inltration in infected
tissue. However, these processes are also crucial in the inammatory
microenvironment of cancer where adhesion molecules are used
by tumor cells to facilitate migration and positioning during the
metastatic process [72]. In addition, MMPs facilitate tumor invasion
through their proteolytic activity and consequent ability to modulate
vascular permeability, whereas pro-inammatory and growth factors
create a microenvironment favorable for cancer cell survival and
proliferation, as already mentioned. Interestingly, a feedback loop
between pro-inammatory cytokines, such as TNF-, for instance,
and NF-B activation has been suggested; such feedback loop may
be responsible for the constitutive activation of NF-B in inammato-
ry diseases, with crucial roles in the link between inammation and
cancers [106,107]. However, the nature of such feedback loop has
not yet been characterized.
 M.J. Kipanyula et al. / Cellular Signalling 25 (2013) 403416 409

Fig. 2. Toll-like receptor signaling and inammation. The interactions of pattern recognition receptors (PRRs), like toll-like receptors (TLRs) situated on the cell or endolysosome mem-
branes of mononuclear phagocytes, with pathogen-associated or danger associated molecule patterns trigger both the mitogen associated protein kinase (MAPK) kinase-kinase TAK1
(transforming growth factor--activated kinase 1) and the IB (inhibitor of nuclear factor B) kinase IKK signaling pathways. These pathways induce the production of either
pro-inammatory factors, or both pro- and anti-inammatory factors, according to the tissue microenvironment [98], including pro- and anti-inammatory cytokines, chemoattractant
molecules, adhesion molecules, growth factors, other PRR receptors. Activating mutations of the components of these pathways have been reported in various microbe-associated can-
cers (see text). CCL2/3/5: CC motif ligand 2,3 or 5 chemokines. cIAPs: cellular inhibitors of apoptosis. CXCL1/2: CXC motif ligand 1 or 2. ERK: extracellular-signal-regulated kinase. E3:
ubiquitin E3. GM-CSF: granulocyte macrophage colony-stimulating factor. ICAM-1: intercellular adhesion molecule 1. IFN-: interferon beta. IL: interleukin. IRAKs: interleukin-1
receptor-associated kinases. NF-kB: nuclear factor kappa B. TNF-: tumor necrosis factor alpha. TRAF6: tumor necrosis factor receptor associated factor 6. Ubc13: ubiquitin-
conjugating enzyme E2N. VCAM-1: vascular cell adhesion molecule 1.

Interestingly, in squamous epithelium human keratinocyte prolif-
eration induced by bacterial LPS was found to be dependent on NF-B
activation and subsequent cyclin D1 up-regulation [108]. Thus,
NF-B may also contribute to the genomic instability through its
antiapoptotic activities that prevent mutated precancerous cells
from being eliminated [109], and through the promotion of reactive
oxygen species production, which has the potential to cause carcino-
genic mutations [59,109]. In various experimental models where
tumor growth was increased by LPS/TLR4 signaling, the inhibition of
NF-B signaling in cancer cells by ancient microbial molecules
resulted in the regression of tumors and metastases [110,111],
pointing out NF-B as a new avenue for novel therapies.
5. Pro-inammatory cytokines and COX-2
Several pro-inammatory cytokines have been associated with
inammation-mediated carcinogenesis triggered by pathogenic mi-
croorganisms. Numerous data point out IL-1, TNF-, IL-32, IL-23,
and IL-6 as pivotal. In addition, recent ndings indicate that IL-8
and IL-29 can team up with the pro-inammatory factor COX-2 to
trigger/sustain infection-related carcinogenesis.
5.1. IL-1 and TNF-
The pro-inammatory cytokines IL-1 and TNF- released by PRR
signaling amplify the inammatory response through signaling
pathways like NF-B and the oncogenic MAPK. TNF- mediates its
pro-inammatory effects through TNF receptor 1 (TNFR1), a type 1
transmembrane protein with a cysteine-rich extracellular domains
(CRDs) that binds TNF-. The DD of TNFR1 cytoplasmic tail interacts
with the DD of the adaptor TRADD, which allows the binding of RIP1
to TNFR1 that results in the recruitment of TRAF-2, an adaptor for
the ubiquitin ligases cIAP1 and cIAP2 [98]. On the other hand, IL-1
triggers IL-1R/MyD88 signaling that plays key roles in cancer devel-
opment, as revealed for instance by a recent study investigating ma-
lignant transformation of keratinocytes [112]. More specically,
genetic and pharmacological approaches showed that the differenti-
ation and pro-inammatory effects of oncogenic Ras/MAPK in
keratinocytes requires IL-1/IL-1R/MyD88 signaling, which phos-
phorylates the NF-B inhibitor IB, resulting in NF-B activation.
Recent reports have indicated key roles for IL-1R/MyD88 and
TNFR1/TRADD signaling pathways in inammation-related carci-
nogenesis. For instance, a population based study performed in
Argentine women has revealed a link between TNF- promoter
polymorphisms in human papillomavirus infection and cervical
cancer risk [113]. Another recent population-based study con-
ducted in Brazil has addressed the effect of pro-inammatory
cytokine gene polymorphisms on the development of gastric
cancer in H. pylori-infected patients [114]. Some IL-1 mutations
(IL-1-511 C/C and IL-1-511 C/T alleles) appeared to be
associated with chronic gastritis in H. pylori-positive patients,
whereas associations of an IL-1 mutation (IL-1-511 C/C geno-
type) and of a TNF- mutation (TNF--308) with gastric cancer
were shown. Thus, IL-1 and TNF- gene polymorphisms may be
associated with chronic gastritis and gastric cancer development
in H. pylori-infected individuals.
410 M.J. Kipanyula et al. / Cellular Signalling 25 (2013) 403416
5.2. IL-32
The role of the new pro-inammatory cytokine IL-32 over-
expressed in inammatory diseases and gastric cancer has been in-
vestigated in H. pylori infection [115]. In this study, IL-32 expression
paralleled human gastric tissue pathology, with higher expressions
in H. pylori-associated gastritis and gastric cancer tissue. Interestingly,
H. pylori-induced expression of IL-32 was NF-B-dependent, and as-
sociated with the expression of pro-inammatory molecules, includ-
ing CXCL1/2, and IL-8, suggesting a role for IL-32 in the regulation
of cytokine expression in H. pylori-infected gastric mucosa. Similarly,
in studies assessing IL-32 role in hepatitis C virus-related liver inam-
mation, IFN- exerted a signicant additive effect on TNF--induced
but not IL-1-induced expression of IL-32 in CD14 + monocytes,
through a mechanism dependent on both NF-B and Janus kinase/
signal transducers and activators of transcription (JAK/STAT) signal-
ing [116]. IL-1 and TNF- signicantly induced IL-32 expression in
Huh-7.5 liver cells. Viral infection of Huh-7.5 cells resulted in an
11-fold increase of IL-32 mRNA expression. In addition, IL-32
overexpression has been also observed in human hepatoma cells,
and its expression was increased by pro-inammatory stimuli.
These observations point out IL-32 as a novel pro-inammatory cyto-
kine involved in HCV-associated liver inammation and cancer. Fur-
ther investigation on the mechanism controlling the interaction of
this cytokine with viral infection may provide better understanding
of the link between infection-triggered inammation and carcinogen-
esis in gastric and hepatic tissue. Interestingly, IL-32 overexpression
studies in surgically resected or biopsied specimens from patients
with localized clear cell renal cell carcinoma (CCRCC) have suggested
that IL-32 is also associated with high recurrence rates of renal cell
carcinoma (RCC) further suggesting that it may be a novel prognostic
factor that may be useful for predicting the outcomes of the disease in
such patients [117].
5.3. IL-8 and IL-29
Data from recent reports have demonstrated that hepatitis B virus
(HBV), a major causative factor associated with the development of
cirrhosis and hepatocellular carcinoma, induces a novel inammation
network involving at least three inammatory factors, i.e. IL-29 (or
IFN-1), IL-8, and COX-2. Yu and collaborators [118] reported that
IL-29 inhibits HBV replication and IL-8 attenuates the expression of
IL-10R2 and the anti-HBV activity of IL-29, favoring the establishment
of persistent viral infection. It increased expressions of IL-29, IL-8, and
COX-2 genes in HBV-infected patients and in HBV-expressing cells
was also observed. Furthermore, in HBV-transfected human lympho-
cytes and hepatocytes, the expression of COX-2 was enhanced by IL-8
production, which in turn appeared to be IL-29-dependent. Interest-
ingly, COX-2 decreased the production of IL-8, and the latter
decreased the expression of IL-29. From these ndings they have hy-
pothesized that HBV infection induces a novel inammation cytokine
network involving at least the three inammatory factors IL-29, IL-8,
and COX-2, which regulate each other through positive regulation
and negative feedback. Still in these studies, the enhancement of
COX-2 expression by IL-8 proved to be mediated through the tran-
scription factors CREB and c/EBP, and in addition MAPK signaling
pathways such as ERK and JNK were also involved in the regulation
of COX-2. These ndings provide new insights for the understanding
of the mechanism by which inammatory factors regulate each other
in response to HBV infection and probably in the infection-related
carcinogenesis. Overexpression of IL-8 has been reported in several
human cancers, including for instance, colon cancer, where serum
IL-8 levels is decreased in patients following anticancer treatment
[119]; melanoma, where the suppression of cancer cell invasion prop-
erties correlates with a downregulation of IL-8 and MAPK phosphor-
ylation, including p38, JNK, and ERK-1/2 [120]; prostate cancer,
where pathogenic roles of mutations affecting the IL-8/CXCR2/P53
signaling pathway have been shown [121]; ovary cancer, where IL-8
overexpression is associated with increased tumor growth and
metastases [122]; and breast cancer, where the production of IL-8 ac-
tivates matrix metalloproteinases and promotes invasion of breast
epithelial and cancer cells [123].
5.4. COX-2
COX-2 expression can also be induced by a wide range of stimuli,
including LPS, pro-inammatory cytokines, such as IL-1 and TNF-,
and a growth factor like EGF (epidermal growth factor). The products
of COX-2 enzyme are prostaglandins, which are key mediators of in-
ammation. Various non-steroidal anti-inammatory drugs (NSAIDs)
affect COX-2 activity by covalent modication or competition for a
substrate binding site. Indeed the long-term use of NSAIDs was
shown by population-based studies to reduce the risk of several can-
cers [124]. COX-2 is also overexpressed in various types of cancer and
involved in cellular proliferation, antiapoptotic activity, angiogenesis,
and an increase of metastasis. A recent report demonstrates that
COX-2 pathway can also be induced by cigarette smoke in human
lung broblasts, suggesting a possible mechanism for the cigarette
smoking-triggered cancer-prone inammatory lung diseases [125].
The functions of COX-2 in linking inammation to cancer are now be-
coming a subject of intense investigation. However, there are contro-
versies regarding the exact role of COX-2 in the transformation from
inammation to cancer. A recent study using an esophageal rat
model indirectly supports a notion that COX-2 induction might con-
tribute to the progression of cancers from inammation [126].
COX-2 inhibitor, celecoxib inhibits the COX-2 pathway and delays
the development and progression from esophageal inammation,
metaplasia, to adenocarcinoma. In addition, another recent study
demonstrated that COX-2 may be sufcient to cause inammation
and the subsequent cancerous aberrations. Within this study, it was
found that the forced expression of COX-2 transgene under the con-
trol of a keratin-5 promoter causes spontaneous inammation-
associated transitional cell hyperplasia and transitional cell carcino-
ma in urinary bladders of transgenic mice [127]. Nevertheless,
COX-2 expression would be independent of the degree of inamma-
tion, but related to the premalignant cells that already existed in the
tissue, in the context of Barrett's esophageal epithelium [128], there-
fore suggesting that COX-2 expression plays an important role in en-
hancing cancer development but is not an indispensable factor for the
transformation of epithelial cells in the scenario of chronic inamma-
tion. This notion is also supported by a recent immunohistochemical
study of human prostate cancers in which the local chronic inamma-
tion has been found to be able to up-regulate COX-2 expression in ad-
jacent tumor cells and induced angiogenesis [127]. Further research
in this area is needed to understand the specic role of COX-2 in
linking microbial-triggered inammation and cancer. Interestingly,
arachidonic acids, substrates for COX-2 to produce prostaglandins,
can be converted by another enzyme lipoxygenases to leukotrienes,
which were suggested to be another missing link between inamma-
tion and cancer [129].
6. Oxygen/nitrogen species and microbial-triggered cancer
6.1. Oxidative and nitrative stress
Recent studies have strongly indicated that oxidative and nitrative
stress is a major player in inammation-associated carcinogenesis.
Various oxygen and nitrogen species and products have been associ-
ated with microbial triggered inammation-associated cancer. For in-
stance, genital infection by high risk HPV, the main etiologic factor of
cervical cancer, is not per se sufcient to induce tumor development
and oxidative stress was recently pointed out as a key pathogenic
 M.J. Kipanyula et al. / Cellular Signalling 25 (2013) 403416
factor cooperating with this pathogenic agent to induce carcinogene-
sis. A study involving tissues collected from patients revealed that in
dysplastic tissues the oxidative modication of DNA and proteins
involved in cell morphogenesis and terminal differentiation may pro-
vide the conditions for the neoplastic progression; in addition, cancer
tissues seem to attain an improved control on oxidative damage and
selectively reduced carbonyl adducts on key detoxifying/pro-survival
proteins [130]. Inducible nitric oxide synthase (iNOS) is an enzyme-
catalyzing nitric oxide (NO) production induced by TNF-, IL-1,
and NF-B, among other inammatory factors [131], which was
found to be overexpressed in chronic inammatory diseases and var-
ious types of cancer [132]. Similarly, in the chronic inammation in-
duced by liver uke (Opisthorchis viverrini) infection, the major risk
factor for cholangiocarcinoma in Northeastern Thailand, increases
levels of pro-inammatory cytokines, NF-B, COX-2, iNOS activity,
and disturb the homeostasis of oxidants/anti-oxidants and DNA re-
pair enzymes [133]. Thus, oxidative and nitrative stress-related DNA
damage may occur as the consequence of the overproduction of reac-
tive oxygen and nitrogen species in inamed target cells. Similarly,
nitrative DNA damage via NF-B activation leading to tumor develop-
ment have been reported in urinary bladder cancer associated with
infections with the parasite Schistosoma haematobium [134].
Another recent study [135] has revealed that NO derived iNOS can
induce apoptosis in H. pylori through a pERK pc-Fos/c-Jun
c-Myc ornithine decarboxylase (ODC) spermine oxidase (SMO)
pathway. Indeed alterations in the availability and metabolism into
polyamines of L-arginine (L-Arg), controlled by NOS and arginase
enzymes, through mechanisms like competition for L-Arg substrate
by H. pylori arginase and induction of host macrophage arginase II
(Arg2) may explain failure of this apoptotic process, and contribute
therefore to the deregulation of the host immune response to the in-
fections. Targeting such signaling pathways may serve as potential
therapeutic targets in H. pylori-associated carcinogenesis.
The intestinal commensal Gram-negative bacteria of the Entero-
bacter spp. have been signicantly associated with solid cancer
development [136] and more severe disease in cancer patients
[137]. Interestingly, E. faecalis produces extracellular superoxide and
promotes chromosome instability via infected macrophage-induced
bystander effects mediated by 4-hydroxy-2-nonenal (4-HNE), a dif-
fusible breakdown product of -6 polyunsaturated fatty acids; and
IL-10 knockout mice colonized with superoxide-producing E faecalis
developed inammation and colorectal cancer, whereas colonization
with a superoxide-decient strain resulted in inammation but not
cancer [138]. The potential of antioxidants as anti-tumorigenic agents
of has been revealed by a transgenic Rac1 model of Kaposi's sarcoma
[139], the major HIV-associated malignancy, whose hallmark is the
proliferation of spindle cells, inammatory inltrate, and aberrant an-
giogenesis caused by Kaposi's sarcoma herpesvirus (KSHV) infection
[104]. The expression of Rac1, a small GTPase triggering reactive oxy-
gen species (ROS) production by NADPH-oxidases, is sufcient to
cause Kaposi's sarcoma-like tumors in transgenic mice through
mechanisms involving ROS-driven proliferation mechanisms, AKT
signaling, and hypoxia-inducible factor 1 (HIF-1)-related angio-
genesis, pointing out host and viral genes triggering Rac1 or ROS pro-
duction as key determinants of Kaposi's sarcoma onset and potential
chemopreventive or therapeutic targets [139]. A growing body of
evidence has pointed out the ROS product HIF-1 as a major player
in microbial-triggered carcinogenesis.
6.2. Hypoxia-inducible factor 1
HIF-1 is a heterodimeric transcription factor and key regulator
responsible for the induction of genes that facilitate adaptation and
survival of cells during hypoxia. HIF-1 consists of a constitutively
expressed subunit HIF-1 and an oxygen sensitive subunit HIF-1
(or its paralogs HIF-2 and HIF-3) [140]. Macrophages would be
411
the unique cells making use of glycolysis mediated by HIF-1 for ATP
generation constitutively even during normoxia, whereas other cell
types use this metabolic system only during hypoxia [141]. Recent
studies from Staples et al. [142] have demonstrated that severe hyp-
oxia during monocyte to macrophage differentiation as observed in
tumors, wounds, arthritic joints, and other sites of inammation, re-
sults in macrophages with a pattern of gene expression distinct
from those maturing in normoxia, characterized by a transcriptionally
up-regulated HIF-1 mRNA, pointing out HIF-1 as an important play-
er in chronic inammation. Hara and colleagues [141] reported that
the deletion of the Mint3/Apba3 gene in mice abrogates macrophage
functions and increases resistance to LPS-induced septic shock, indi-
cating a malfunction of TLR4 response. Interestingly, the ATP level
in macrophages of mutant mice lacking Apba3 gene was reduced to
60% of the level observed in wild type cells: Reductions of
ATP-dependent activities such as glycolysis, cytokine production,
and motility were observed as well, indicating that unraveling the
specic function of APBA3 in macrophages might allow the develop-
ment of therapeutics regulating aberrant macrophage function during
infection and the subsequent inammatory response, and will allow
further understanding of mechanisms governing septic shock associ-
ated TLR4 inammatory response.
HIF-1 is expressed in acute and chronically inamed site [143].
HIF-1 regulates the transcription of several genes in response to hyp-
oxic stress and changes in growth factors, and plays an important role
in tumor angiogenesis and growth. Crohn disease-associated E. coli
promote gastrointestinal inammatory disorders by activation of
HIF-dependent responses. Mimouna et al. [143] have reported that
HIF-1 is maximally expressed in inamed ileal epithelium of
Crohn disease patients, in concomitance with the expression of
CEACAM6 (carcinoembryonic antigen-related cell adhesion molecule
6 or CD66c), a protein that acts as a receptor of adherent-invasive
E. coli. The expression of CEACAM6 in transgenic mice expressing
this receptor induced the production of HIF-1 and the activation of
VEGF receptor signaling, and downstream analyses on human intesti-
nal epithelial cells silenced for hif-1, highlighted the crucial role of
CEACAM6 in the production of the latter pro-angiogenic factors,
highlighting the crucial role of adherent-invasive E. coli as promoter
of inammatory disorders and neoplastic cell favoring environment
in the gastrointestinal tract. HIF-1 protein plays a major role in
mediating this effect, and therefore may represent a good target for
colorectal cancer treatment.
A phase II study trial in patients diagnosed with HPV revealed the
presence of non-HIF-1 ligand-induced VEGF, which was associated
with a high risk head and neck squamous cell carcinomas' [144], indi-
cating the presence of activating mutations hijacking the HIF-1 recep-
tor signaling pathway. Comparably, angiogenesis promotion through
the enhancement of HIF-1 and VEGF expressions induced by the
overexpression of HPV type 16 oncoproteins has been reported in
non-small cell lung cancer cells [145]. HPV E7 oncoprotein enhances
HIF-1-mediated transcription by inhibiting binding of histone
deacetylases HDAC1, HDAC4, and HDAC7 to increase the expression
of pro-angiogenic factors in cervical cancer cells [146], indicating
that HPV oncoproteins may induce a microenvironment favorable to
their replication through epigenetic control of various genes, includ-
ing genes encoding for HIF-1 and the genes it regulates.
Hepatitis C virus (HCV) infection is a major risk factor for the de-
velopment of hepatocellular carcinoma [13]. HCV gene expression in-
duces oxidative stress, which in turn induces the stabilization of
HIF-1, followed by VEGF and angiogenic cytokine release, leading
to tumorigenic neovascularization in vivo [147]. Such HIF-1 stabili-
zation requests the activation of NF-B, STAT-3, PI3K/Akt, and
p42/44 mitogen-activated protein kinase. A study aimed at clarifying
whether human papillomavirus (HPV) directly affects the oncogene-
sis and biologic behavior of tonsillar cancer revealed that compared
with HPV-negative patients, HPV-positive tonsillar cancer patients
412 M.J. Kipanyula et al. / Cellular Signalling 25 (2013) 403416
have a HIF-1- overexpression [148]. Furthermore, recent studies
have suggested that HCV glycoproteins would perturb tight and
adherens junction protein expression, and increase hepatoma migra-
tion and expression of epithelial to mesenchymal transition markers
Snail and Twist via stabilizing HIF-1 and genes it regulates. As men-
tioned earlier, HIF- regulates various genes involved in tumor
growth and metastasis, including VEGF and transforming growth
factor-beta (TGF-), whose neutralization showed different roles for
VEGF and TGF- in regulating hepatoma polarity and migration, re-
spectively, indicating a dual role for HIF-1 in the cellular processes
that are deregulated in many human cancers and in the viral life
cycle [149]. Similarly, hypoxia and HIF-1 up-regulate both latent
and lytic Kaposi's sarcoma-associated herpesvirus replication and
may play a central role in the life cycle of this virus [150]. From
these observations, it appears that HIF-1 expressed during carcino-
genesis is aimed at oncogenic virus maintenance, and carcinogenic
effects would just be bystander effects. Therefore, targeting HIF-1
may alter oncogenic virus maintenance and suppress carcinogenesis.
HIF-1alpha is overexpressed in a majority of human cancers [151],
and accordingly, may represent a potent therapeutic agent for cancer.
The natural compound deguelin, which inhibits tumor growth and
blocks tumor angiogenesis in mice, decreases the expression of
HIF-1 and of its target genes, including VEGF, in H1299 non-small
cell lung cancer cells in normoxic and hypoxic conditions [151]. In
study addressing the possibility to use the oncolytic reovirus as a
cancer therapeutic agent, reovirus infection suppressed HIF-1 levels
in renal carcinoma and colon cancer cells through a proteosomal
activity-dependent mechanism, resulting in cancer cell apoptosis
[152]. Knockdown of HIF-1 expression constructed by adenovirus-
mediated RNA interference tools inhibits the invasion and growth of
hepatocellular carcinoma cell lines cultured under hypoxia condi-
tions; angiogenesis as well as mobility of vascular cells to tumor
were suppressed as well [153]. In addition, a more recent study
revealed that HIF-1 and NF-B targeting induces an overexpression
of the von Hippel-Lindau protein, which in turn enhances the efcacy
of the anticancer drug doxorubicin in hepatocellular carcinoma cell
lines [154].
7. Concluding remarks
Pathogen entry in the body classically triggers inammatory re-
sponse, which is a defensive mechanism aimed at destroying the
pathogen itself and eliminating damage/danger-associated mole-
cules, to prevent further tissue injury. However, experimental and
clinical data indicate that a signicant fraction of cancer cases are
caused by infectious agents mediating chronic inammation.
During chronic inammation immune cells release agents, such as
peroxynitrite, superoxide, and MMIF, which are able to trigger or sus-
tain carcinogenic DNA damage induced in host cells by genotoxic
pathogens. In addition, the high amounts of pro-inammatory fac-
tors, adhesion molecules, and growth factors produced may favor
neoplastic cell survival. A growing body of evidence has strongly
linked a spate of inammatory signaling pathways as bridging factors
between pathogen-triggered inammation and cancer. Inammatory
signaling pathways such as TLR/MyD88, pro-inammatory cytokine,
NF-B, and COX-2 pathways have been implicated in forging the
link between inammation and carcinogenesis. Nonetheless, it is
conceivable that these signaling pathways could become likely thera-
peutic targets to break the growing link between inammation and
different types of cancer. It is thus anticipated that vigorous future
investigations of these pathways and their interactions may provide
better understanding of the association between chronic inammation
and cancer, particularly in microbiota associated cancers, consider-
ing that these microorganisms inhabit the body all over the
lifetime.
Disclosure
All authors have participated to the bibliographic research, to
manuscript preparation, and have approved the nal version of the
manuscript.
Authors declare no competing nancial interest.
Acknowledgments
Authors are grateful to their respective institutions for constant
support and particularly to Dr. Mazzini for his insightful observations.
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