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Signaling Pathways Bridging Microbial-Triggered Inflammation and Cancer 2013
Signaling Pathways Bridging Microbial-Triggered Inflammation and Cancer 2013
Cellular Signalling
journal homepage: www.elsevier.com/locate/cellsig
Review
a r t i c l e i n f o a b s t r a c t
Article history: Microbial-triggered inflammation protects against pathogens and yet can paradoxically cause considerable sec-
Received 7 October 2012 ondary damage to host tissues that can result in tissue fibrosis 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
inflammation-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 inflammatory response induced by
Infection chronic infections with pathogens like the microbiota members Helicobacter spp., which have been associated
Inflammation 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 inflammatory 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-inflammatory cytokines, adhesion molecules, and growth factors may create a microenvironment
promoting neoplastic cell survival and proliferation. Recent findings on the implication of inflammatory
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 inflammation 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 inflammation, and cancer: lessons from microbiota . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
3.2. TLR signaling and inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
4. NF-κB, pathogen-triggered inflammation, and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
4.1. NF-κB, infection, and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
4.2. NF-κB signaling and carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
5. Pro-inflammatory cytokines and COX-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409
5.1. IL-1 and TNF-α . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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 Ngaoundéré, P.O. Box 454, Ngaoundéré, Cameroon/Biomedical Research Center, University of British
Columbia, 2222 Health Science Mall, Vancouver BC, Canada, V6T 1Z3. Tel.: +1 604 822 0441(office); 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) 403–416
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 inflammatory 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-inflammatory 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) 403–416
Table 2 factor-α [51], prostaglandin E2 [52], and reactive oxygen and nitro-
Various non-microbiota pathogens causing inflammation-associated carcinogenesis or gen species [53,54].
aggravating cancer aggressiveness.
Body failure to terminate inflammatory response results in its
Types of cancer chronicity, with the establishment of deleterious inflammatory cycles
Viruses Cytomegalovirus Glioblastoma [166], prostate cancer [167] [4,8,9]. The hallmarks of chronic inflammation are inflammatory 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 [64–66] 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-inflammatory cytokines and factors like TNF-α 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 inflammatory 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
munodeficiency virus. HPV: Human papillomavirus. cells [46,47], indicating that the modulation of factors fuelling chronic
inflammation 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 inflammatory cell regulatory network and activities against Acinetobacter spp. [63], non-microbiota pathogens as-
prevents the establishment of chronic inflammation. Conversely, limited sociated with various solid [64–66] 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 inflammation. Signaling pathways accounting for in, and the small molecule doxorubicin. The current findings indicate
inflammation-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 inflammation-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 inflammation-mediated lympho-
Many pathogens can cause chronic inflammations, including magenesis at its early stage [21]. Future studies addressing the relation-
the protozoan Trypanosoma brucei which causes inflammation- ship between bacteria and transforming cells may provide new insights
associated functional alterations [41,42], fungi like Cryptococcus in bacteria-triggered inflammation 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 inflammation (Table 2). The mechanisms by 3.1. TLRs, pathogen-triggered inflammation, 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 inflammation, 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 inflammatory 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-inflammatory mediators, of bystander bacteria to deeper tissues during Clostridium difficile in-
promoting anti-inflammatory response [44], and conversely, recent fection, by triggering neutrophil and monocyte recruitment to the
findings indicate that impaired phagocytosis promotes inflammation, 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 (C–C receptor type
inflamed tissue and immune cells. Such crosstalk would be mediated 2)- and CXCL1 (C–X–C motif ligand 1)/CXCR2 (C–X–C motif receptor
by the anti- and pro-inflammatory factors abundantly produced 2); mortality is markedly increased in MyD88-deficient mice follow-
by both infiltrating and resident cells [46,47]. Studies in a rat ing C. difficile 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 inflamma-
antibacterial tissue damage to tissue repair involving factors with tory diseases [67], indicating that perturbations of microbiota–PRR
both pro-inflammatory and anti-inflammatory effects of which the interactions may promote inflammation.
effects depend on the microenvironment at the inflamed 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) 403–416 407
orchestrate TLR crosstalk during inflammation [70,71]. Septic inflam- may have an effect on the prevention of colorectal cancer by scaveng-
mation evokes early responses which include activation of the gene ing toxic compounds or preventing their generation in situ [75]. This
encoding decorin; decorin protein level is increased in the plasma of hypothesis should be investigated, considering the importance for co-
septic patients and mouse models, and decorin increases the expres- lorectal cancer prophylaxis.
sion of pro-inflammatory molecules in cancer cells [70]. Interestingly, Interestingly, other recent studies have shown that infections with
the findings from recent studies aiming at unraveling the mecha- H. pylori activate oncogenic signaling pathways like Sonic Hedgehog
nisms used by decorin signaling to control inflammation and tumor [26] and Wnt [76,77], which have been reported anti-apoptotic ef-
growth revealed two mechanisms [70]: i) first, decorin may act as fects and the ability to confer stem-like properties to transforming
an endogenous ligand of TLR2 and TLR4 to stimulate the production cells in various solid and blood cancers (for review see [78,79] and
of pro-inflammatory molecules, including programmed cell death [80,81]), respectively. In the APCMin/+ mouse, an animal model of
protein 4 (PDCD4), in macrophages; ii) second, decorin may prevent human colon cancer where a mutation in the murine homolog of
translational repression of PDCD4 by decreasing the activity of the Wnt inhibitor APC gene is induced, a recent report has indicated
transforming growth factor (TGF)-β1 and the expression of the key that gut microbiota accelerate tumor growth in comparison with
regulator of oncogenic processes miR-21, which is also a translational wild type mice [82], suggesting a role for the Wnt signaling pathway
inhibitor of PDCD4. In addition, still in these studies, increases in in that context. Rapid tumor growth occurred concomitantly with
PDCD4 levels led to decreases in the expression of the anti- systemic anemia, suggesting a role for intestinal barrier damage and
inflammatory cytokine IL-10, thereby making the cytokine profile erythropoiesis-stimulating mitogens. The microbial cell wall compo-
more pro-inflammatory. Furthermore, increases in expression of nent LPS accounted for at least part of the cell growth acceleration ob-
pro-inflammatory molecules have been associated with tumor served, via c-Jun/JNK signaling pathway. In addition, infiltrating
growth promotion and poor patient outcomes in hepatocellular carci- CD11b + myeloid cells released high levels of phosphorylated STAT3
noma [72], for instance. (p-Tyr705) in colonic tumors. These findings indicate that gut
Experimental evidence suggests that TLRs are key players in microbiota-triggered tumor growth acceleration observed in APC
pathogen-triggered inflammation-mediated carcinogenesis. Gut-derived (Min/+) mice is mediated by the c-Jun/JNK and STAT3 signaling
LPS has demonstrated the ability to promote hepatocellular carcinoma pathways in combination with anemia. These findings point out the
development by activating TLR4 expression on myeloid-derived immune complexity of the mechanisms accounting for the inflammatory and
cells in different types of liver injury models, including concanavalin carcinogenic effects of microbiota bacteria.
A-induced hepatitis model, which mimics human viral hepatitis [3], fur-
ther indicating that gut microbiota and TLR4 signaling modulation may 3.2. TLR signaling and inflammation
represent potential avenues for therapeutic intervention aimed at treat-
ment of hepatitis virus-induced hepatitis and prevention of hepatocellu- TLRs recognize bacterial, viral, and parasite PAMPs in the extracellu-
lar carcinoma. Similarly, Ochi and collaborators [73] have found that lar environment (TLR1, 2, 4–6, 11) or in endolysosomes (TLR3, 7–9,
TLR4 signaling plays a key role in the cellular and molecular mechanisms 10). They can bind several PAMPs/DAMPs and are thought to even
bridging chronic pancreatic fibroinflammatory disease and pancreatic bind common “self” molecules such as heat shock proteins and fibrin-
carcinogenesis. These investigators observed that TLR4 signaling ogen, suggesting a link between the stereotypic inflammatory response
triggered by LPS exacerbates pancreatic inflammation and accelerates triggered by TLRs and autoimmune diseases [83,84]. Stimulation of
tumorigenesis, whereas TLR4 inhibition or blockade of the MyD88- TLRs by the corresponding PAMPs or DAMPs initiates signaling cas-
independent Toll/IL-1 receptor domain-containing adapter-inducing cades leading to the activation of transcription factors, such as AP-1,
interferon-β (TRIF) pathway have protective effects against pancreatic NF-κB, and interferon regulatory factors (IRFs). TLR signaling is trans-
cancer. Surprisingly, blockade of the MyD88-dependent pathway exacer- duced in the cytoplasm by a Toll/ IL-1 receptor (TIR) domain, which
bated pancreatic inflammation and malignant progression, through den- is the docking site of TIR-containing cytoplasmic adaptor proteins
dritic cell (DC)-mediated induction of pancreatic antigen-restricted that are critical in orchestrating the signal transduction pathways
Th2-deviated CD4 (+) T cells. Such pro-tumorigenic and fibro- after TLR and IL-1 receptor activation. TIR adaptor molecules mainly in-
inflammatory effects of MyD88 inhibition indicate the complexity of clude signaling proteins like MyD88, MyD88 adaptor-like (MAL), TRIF,
TLR signaling in carcinogenesis. TRIF-related adaptor molecule (TRAM), and the negative regulator of
In addition, Uronis and collaborators [74] have demonstrated that TLR pathways SARM (sterile-alpha and Armadillo motif containing
bacterial-induced inflammation drives progression from adenoma to protein) [85,86]. Except for TLR3 all TLRs engage the adaptor MyD88,
invasive carcinoma in azoxymethane (AOM oncogene)-exposed however either directly as IL-1R (TLR5, 7–11, and heterodimeric
IL-10 knockout mice, a model of colitis-associated colorectal cancer. TLR1-TLR2 and TLR2-TLR6) or in association with the adaptor MAL/
These investigators have observed colon tumors in 62% of TIRAP (Toll-IL-1 receptor (TIR) domain containing adaptor protein.
AOM-IL-10(−/−) mice against only 20% in AOM-wild-type mice; e.g. TLR4, and heterodimeric TLR1-TLR2 and TLR2-TLR6).
and tumor multiplicity directly correlated with the presence of MyD88 signaling is transduced through a death domain (DD)
colitis. Interestingly, IL-10(−/−) mice mono-associated with the which mediates interactions with the DD of the serine/threonine ki-
mildly colitogenic bacterium B. vulgatus displayed significantly re- nase IRAK4, the clustering of which would result in its autophospho-
duced colitis and colorectal tumor multiplicity; and germ-free rylation within the receptor complex, allowing a kinase activity-
AOM-treated IL-10(−/−) mice were devoid of tumors. In addition, dependent binding of IRAK4 DD to the DD of the related kinases
AOM-treated IL-10 (−/−) or MyD88 (−/−) mice displayed a re- IRAK1 and 2 [87]. The MyD88–IRAK4–IRAK1/2 complex nucleate a
duced mRNA expression of TNF-α and IL-12p40, a known component larger complex including, E3 ubiquitin ligases like TRAF6 (tumor ne-
of IL-12 and IL-23. These mice showed no signs of tumor develop- crosis factor receptor associated factor 6), cIAP1 (cellular inhibitor
ment, indicating that the TLR/MyD88 pathway is essential for of apoptosis-1), and cIAP2, and the E2 ubiquitin-conjugating enzyme
microbiota-induced development of colitis-associated colorectal can- Ubc13 (ubiquitin-conjugating enzyme E2N), in the case of TLR4
cer. These findings also indicate that intestinal microbiota modulation [88,89]. TRAF6 catalyzes the formation of polyubiquitin chains on ly-
may decrease cancer risk in inflammatory bowel disease. Accordingly, sines within itself and in IL-1 receptor-associated kinase 1 (IRAK1),
it has been hypothesized that probiotics, i.e. live microorganisms con- promoting the K63-linked polyubiquitination of cIAPs and the re-
ferring a health benefit on the host when administered in adequate cruitment of adaptor proteins TAB2 and 3, resulting in the activation
amounts, are capable of transient modulation of the microbiota, that of the mitogen-activated protein kinase (MAPK) kinase–kinase
have been successfully used to manage inflammatory bowel disease (MAPKKK) TAK1 (transforming growth factor-β-activated kinase 1)
408 M.J. Kipanyula et al. / Cellular Signalling 25 (2013) 403–416
[89,90]. In addition, K63-linked poly-ubiquitin also binds the regula- 4. NF-κB, pathogen-triggered inflammation, and cancer
tory subunit of the NF-κB inhibitor (IκB) kinase (IKK) complex
termed as “NEMO”, allowing its recruitment to the TLR4 signaling 4.1. NF-κB, infection, and cancer
complex [91]. TAK1 mediates the activation of the downstream
MAPKs p38α and c-Jun N-terminal kinase (JNK), which are hijacked As TLR pathways, many other inflammatory signaling pathways
by activating mutations in pathogen-related cancers like herpes transduce their signal through NF-κB activation, including pathways
virus-associated Kaposi's sarcoma [92], and probably participate to mediated by the PRR members NLRs (nucleotide oligomerization
inflammation-mediated carcinogenesis. Activated TAK1 complex domain-like receptors) [98] and C-type lectin receptors [100]. NF-κB
translocates into the cytosol, where it activates: i) the kinase MKK4 signaling pathway has a critical role in human diseases and carcinogen-
that results in the phosphorylation/activation of JNK [89]; ii) and esis. Not surprisingly, mutations of NF-κB signaling molecules have
the related kinases MKK3 and MKK6 for the activation of p38α [93]. been reported in several malignancies. For instance, the somatic
In turn, JNK stimulates the expression of pro-inflammatory mediators mutation of TNFAIP3, the gene encoding for the deubiquitinating factor
like TNF-α through an AP1 transcription factor-dependent mecha- A20, is frequently reported in human B-cell lymphomas, including
nism [94], whereas p38α activates the cAMP response element- Epstein-Barr virus-associated AIDS-related lymphoma [36] and
binding (CREB), which results in the activation of the CCAAT- Kaposi's sarcoma [101], pointing out A20 as a tumor suppressor in
enhancer-binding proteins (c/EBPs) family of transcription factors, these blood cancers. In addition, in cancer cells collected from adult
and in the subsequent induction of various genes involved in the in- T-cell leukemia patients (a fatal T-cell malignancy associated with
flammatory response, such as: cell adhesion molecules; chemokines human T-cell leukemia virus type I infection), the suppression of
like CXCL-1 and CXCL-2; and cytokines like IL-1, IL-10, IL-12, and NF-κB-dependent transcriptional activity by the IκB kinase 2 inhibitor
IL-32 [95,96]. IMD-0354 decreased cell survival [102]. Comparably, in Epstein–Barr
On the other hand, IKK induces the activation of the NF-κB transcrip- Virus (EBV)-associated immunoblastic lymphoma, which occurs in
tion factor, which results in subsequent transcriptional responses in- immunocompromised patients such as those with AIDS or transplant
volving the MAPKs of the extracellular-signal-regulated kinase (ERK) recipients upon primary EBV infection or following the reactivation
family that, in turn, activate the ATF (activating transcription factors)/ of a pre-existing latent EBV infection, the HIV protease inhibitor
CREB family of transcription factors, resulting in the induction of genes ritonavir inhibits the tumor growth and infiltration of EBV-positive
involved in both pro- and anti-inflammatory responses such as PTGS2 lymphoblastoid B cells by targeting NF-κB signaling [103]. Tang
gene that encodes prostaglandin-endoperoxide synthase 2 or cyclooxy- and collaborators [104] have recently demonstrated that Kaposi's
genase 2 (COX-2), involved in the synthesis of prostaglandins [97,98]. In sarcoma-associated herpesvirus (KSHV) infection is necessary, al-
addition, the canonical IKKβ/NF-κB signaling pathway can also accumu- though, not sufficient for disease development without other cofac-
late in the nucleus and induce the expression of several other genes tors. The authors identified human immunodeficiency type 1 (HIV-1)
encoding for inflammatory-related molecules, including [98]: PRRs like Tat and herpes simplex virus 1/2 (HSV-1/2) as such cofactors. Interesting-
advanced glycation end product (AGE) receptors, chemokines like ly, the researchers also demonstrated that HSV-2 infection activate NF-κB
CCL2 (MCP-1), CCL3 (MIP-1α), CCL5 (RANTES) and CXCL1/2; growth signaling pathway, further suggesting a role of HSV-2 in the pathogenesis
factors like GM-CSF (granulocyte macrophage colony-stimulating fac- of Kaposi's sarcoma. Recent studies based on a transgenic mouse model
tor); adhesion molecules like E- and P-selectins , ICAM1 (intercellular have revealed that the prophylactic delivery of IL-15 affords protection
adhesion molecule 1) and VCAM1 (vascular cell adhesion molecule 1); against a lethal HSV-2 challenge and metastasis of B16/F10 melanoma
cytokines like IL-1β, IL-12, and TNF-α; metalloproteinases like MMP9; cells through NF-κB dependent induction of the chemokine CCL5 by my-
the complement factor B; Caspase-11; but also, inhibitors of NF-κB sig- eloid immune cells [32]. NF-κB may also bridge chronic inflammation and
naling like A20 and IκB-α , the inhibitor of macrophage activation carcinogenesis in bacterial infection-related cancer such as gastric MALT
CD200, the inhibitor of virus proliferation IFN (interferon)-β, and the lymphomas associated with H. pylori and Ocular Adnexa MALT lympho-
pleiotropic cytokine IL-6. These observations indicate that NF-κB can mas of whose association with Chlamydia psittaci infection has been re-
induce and also regulate the inflammatory response. cently demonstrated [105].
Emerging data suggest that TLR signaling role in pathogen-
triggered inflammation and carcinogenesis is complex, and therefore,
requires further investigations. For instance, Smolinska and collabo- 4.2. NF-κB signaling and carcinogenesis
rators [1] have investigated the role of Src family kinases, i.e. the
largest non-receptor tyrosine kinase family, in TLR signaling, using NF-κB may link inflammation to cancer through its inherent abil-
primary human macrophages in combination with adenoviral ity to induce the production of adhesion molecules, MMPs, COX-2,
overexpression and small interfering RNA knockdown. The study re- pro-inflammatory cytokines, and reactive oxygen and nitrogen spe-
vealed that the Src kinase Hck has a key role in LPS/TLR4-induced cies [98]. In normal inflammatory response NF-κB-induced adhesion
TNF-α and IL-6 production. Furthermore, findings have suggested molecules, chemokines, and vasomodulatory molecules play a key
that Hck may mediate TLR4-induced transcription of both TNF-α role in the processes resulting in immune cell infiltration in infected
and IL-6 by a mechanism that does not involve NF-κB and MAPK tissue. However, these processes are also crucial in the inflammatory
pathways, but rather leads to p38 MAPK-dependent activator protein microenvironment of cancer where adhesion molecules are used
(AP-1) binding with a complex of c-fos and JunD, pointing out the by tumor cells to facilitate migration and positioning during the
possibility of targeting Hck for the alleviation of excessive inflam- metastatic process [72]. In addition, MMPs facilitate tumor invasion
mation. More recent studies involving i.p. or s.c. injection of the through their proteolytic activity and consequent ability to modulate
TLR3 interactor polyI:C (Polyinosinic–polycytidylic acid) to Lewis vascular permeability, whereas pro-inflammatory and growth factors
lung carcinoma tumor-implant mice have shown that TLR3 signal- create a microenvironment favorable for cancer cell survival and
ing induces tumor regression by converting tumor supporting proliferation, as already mentioned. Interestingly, a feedback loop
macrophages into tumor suppressors [99], anticipating, therefore, between pro-inflammatory cytokines, such as TNF-α, for instance,
that better characterization and understanding of the signaling and NF-κB activation has been suggested; such feedback loop may
pathways mediated by TLR may provide novel pharmacologic tar- be responsible for the constitutive activation of NF-κB in inflammato-
gets against pathogen-associated cancers. Fig. 2 illustrates how ry diseases, with crucial roles in the link between inflammation and
TLR signaling downstream targets integrate to induce inflammato- cancers [106,107]. However, the nature of such feedback loop has
ry effects. not yet been characterized.
M.J. Kipanyula et al. / Cellular Signalling 25 (2013) 403–416 409
Fig. 2. Toll-like receptor signaling and inflammation. 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-β-activated kinase 1) and the IκB (inhibitor of nuclear factor κB) kinase IKK signaling pathways. These pathways induce the production of either
pro-inflammatory factors, or both pro- and anti-inflammatory factors, according to the tissue microenvironment [98], including pro- and anti-inflammatory 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: C–C motif ligand 2,3 or 5 chemokines. cIAPs: cellular inhibitors of apoptosis. CXCL1/2: C–X–C 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-β: interferon beta. IL: interleukin. IRAKs: interleukin-1
receptor-associated kinases. NF-kB: nuclear factor kappa B. TNF-α: 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- transmembrane protein with a cysteine-rich extracellular domains
eration induced by bacterial LPS was found to be dependent on NF-κB (CRDs) that binds TNF-α. The DD of TNFR1 cytoplasmic tail interacts
activation and subsequent cyclin D1 up-regulation [108]. Thus, with the DD of the adaptor TRADD, which allows the binding of RIP1
NF-κB may also contribute to the genomic instability through its to TNFR1 that results in the recruitment of TRAF-2, an adaptor for
antiapoptotic activities that prevent mutated precancerous cells the ubiquitin ligases cIAP1 and cIAP2 [98]. On the other hand, IL-1
from being eliminated [109], and through the promotion of reactive triggers IL-1R/MyD88 signaling that plays key roles in cancer devel-
oxygen species production, which has the potential to cause carcino- opment, as revealed for instance by a recent study investigating ma-
genic mutations [59,109]. In various experimental models where lignant transformation of keratinocytes [112]. More specifically,
tumor growth was increased by LPS/TLR4 signaling, the inhibition of genetic and pharmacological approaches showed that the differenti-
NF-κB signaling in cancer cells by ancient microbial molecules ation and pro-inflammatory effects of oncogenic Ras/MAPK in
resulted in the regression of tumors and metastases [110,111], keratinocytes requires IL-1α/IL-1R/MyD88 signaling, which phos-
pointing out NF-κB as a new avenue for novel therapies. phorylates the NF-κB inhibitor IκBα, resulting in NF-κB activation.
Recent reports have indicated key roles for IL-1R/MyD88 and
5. Pro-inflammatory cytokines and COX-2 TNFR1/TRADD signaling pathways in inflammation-related carci-
nogenesis. For instance, a population based study performed in
Several pro-inflammatory cytokines have been associated with Argentine women has revealed a link between TNF-α promoter
inflammation-mediated carcinogenesis triggered by pathogenic mi- polymorphisms in human papillomavirus infection and cervical
croorganisms. Numerous data point out IL-1, TNF-α, IL-32, IL-23, cancer risk [113]. Another recent population-based study con-
and IL-6 as pivotal. In addition, recent findings indicate that IL-8 ducted in Brazil has addressed the effect of pro-inflammatory
and IL-29 can team up with the pro-inflammatory factor COX-2 to cytokine gene polymorphisms on the development of gastric
trigger/sustain infection-related carcinogenesis. cancer in H. pylori-infected patients [114]. Some IL-1β mutations
(IL-1β-511 C/C and IL-1β-511 C/T alleles) appeared to be
5.1. IL-1 and TNF-α associated with chronic gastritis in H. pylori-positive patients,
whereas associations of an IL-1β mutation (IL-1β-511 C/C geno-
The pro-inflammatory cytokines IL-1 and TNF-α released by PRR type) and of a TNF-α mutation (TNF-α-308) with gastric cancer
signaling amplify the inflammatory response through signaling were shown. Thus, IL-1β and TNF-α gene polymorphisms may be
pathways like NF-κB and the oncogenic MAPK. TNF-α mediates its associated with chronic gastritis and gastric cancer development
pro-inflammatory effects through TNF receptor 1 (TNFR1), a type 1 in H. pylori-infected individuals.
410 M.J. Kipanyula et al. / Cellular Signalling 25 (2013) 403–416
factor cooperating with this pathogenic agent to induce carcinogene- the unique cells making use of glycolysis mediated by HIF-1 for ATP
sis. A study involving tissues collected from patients revealed that in generation constitutively even during normoxia, whereas other cell
dysplastic tissues the oxidative modification of DNA and proteins types use this metabolic system only during hypoxia [141]. Recent
involved in cell morphogenesis and terminal differentiation may pro- studies from Staples et al. [142] have demonstrated that severe hyp-
vide the conditions for the neoplastic progression; in addition, cancer oxia during monocyte to macrophage differentiation as observed in
tissues seem to attain an improved control on oxidative damage and tumors, wounds, arthritic joints, and other sites of inflammation, re-
selectively reduced carbonyl adducts on key detoxifying/pro-survival sults in macrophages with a pattern of gene expression distinct
proteins [130]. Inducible nitric oxide synthase (iNOS) is an enzyme- from those maturing in normoxia, characterized by a transcriptionally
catalyzing nitric oxide (NO) production induced by TNF-α, IL-1β, up-regulated HIF-1α mRNA, pointing out HIF-1 as an important play-
and NF-κB, among other inflammatory factors [131], which was er in chronic inflammation. Hara and colleagues [141] reported that
found to be overexpressed in chronic inflammatory diseases and var- the deletion of the Mint3/Apba3 gene in mice abrogates macrophage
ious types of cancer [132]. Similarly, in the chronic inflammation in- functions and increases resistance to LPS-induced septic shock, indi-
duced by liver fluke (Opisthorchis viverrini) infection, the major risk cating a malfunction of TLR4 response. Interestingly, the ATP level
factor for cholangiocarcinoma in Northeastern Thailand, increases in macrophages of mutant mice lacking Apba3 gene was reduced to
levels of pro-inflammatory cytokines, NF-κB, COX-2, iNOS activity, 60% of the level observed in wild type cells: Reductions of
and disturb the homeostasis of oxidants/anti-oxidants and DNA re- ATP-dependent activities such as glycolysis, cytokine production,
pair enzymes [133]. Thus, oxidative and nitrative stress-related DNA and motility were observed as well, indicating that unraveling the
damage may occur as the consequence of the overproduction of reac- specific function of APBA3 in macrophages might allow the develop-
tive oxygen and nitrogen species in inflamed target cells. Similarly, ment of therapeutics regulating aberrant macrophage function during
nitrative DNA damage via NF-κB activation leading to tumor develop- infection and the subsequent inflammatory response, and will allow
ment have been reported in urinary bladder cancer associated with further understanding of mechanisms governing septic shock associ-
infections with the parasite Schistosoma haematobium [134]. ated TLR4 inflammatory response.
Another recent study [135] has revealed that NO derived iNOS can HIF-1α is expressed in acute and chronically inflamed site [143].
induce apoptosis in H. pylori through a pERK → pc-Fos/c-Jun → HIF-1 regulates the transcription of several genes in response to hyp-
c-Myc → ornithine decarboxylase (ODC) → spermine oxidase (SMO) oxic stress and changes in growth factors, and plays an important role
pathway. Indeed alterations in the availability and metabolism into in tumor angiogenesis and growth. Crohn disease-associated E. coli
polyamines of L-arginine (L-Arg), controlled by NOS and arginase promote gastrointestinal inflammatory disorders by activation of
enzymes, through mechanisms like competition for L-Arg substrate HIF-dependent responses. Mimouna et al. [143] have reported that
by H. pylori arginase and induction of host macrophage arginase II HIF-1α is maximally expressed in inflamed ileal epithelium of
(Arg2) may explain failure of this apoptotic process, and contribute Crohn disease patients, in concomitance with the expression of
therefore to the deregulation of the host immune response to the in- CEACAM6 (carcinoembryonic antigen-related cell adhesion molecule
fections. Targeting such signaling pathways may serve as potential 6 or CD66c), a protein that acts as a receptor of adherent-invasive
therapeutic targets in H. pylori-associated carcinogenesis. E. coli. The expression of CEACAM6 in transgenic mice expressing
The intestinal commensal Gram-negative bacteria of the Entero- this receptor induced the production of HIF-1α and the activation of
bacter spp. have been significantly associated with solid cancer VEGF receptor signaling, and downstream analyses on human intesti-
development [136] and more severe disease in cancer patients nal epithelial cells silenced for hif-1α, highlighted the crucial role of
[137]. Interestingly, E. faecalis produces extracellular superoxide and CEACAM6 in the production of the latter pro-angiogenic factors,
promotes chromosome instability via infected macrophage-induced highlighting the crucial role of adherent-invasive E. coli as promoter
bystander effects mediated by 4-hydroxy-2-nonenal (4-HNE), a dif- of inflammatory disorders and neoplastic cell favoring environment
fusible breakdown product of ω-6 polyunsaturated fatty acids; and in the gastrointestinal tract. HIF-1α protein plays a major role in
IL-10 knockout mice colonized with superoxide-producing E faecalis mediating this effect, and therefore may represent a good target for
developed inflammation and colorectal cancer, whereas colonization colorectal cancer treatment.
with a superoxide-deficient strain resulted in inflammation but not A phase II study trial in patients diagnosed with HPV revealed the
cancer [138]. The potential of antioxidants as anti-tumorigenic agents presence of non-HIF-1 ligand-induced VEGF, which was associated
of has been revealed by a transgenic Rac1 model of Kaposi's sarcoma with a high risk head and neck squamous cell carcinomas' [144], indi-
[139], the major HIV-associated malignancy, whose hallmark is the cating the presence of activating mutations hijacking the HIF-1 recep-
proliferation of spindle cells, inflammatory infiltrate, and aberrant an- tor signaling pathway. Comparably, angiogenesis promotion through
giogenesis caused by Kaposi's sarcoma herpesvirus (KSHV) infection the enhancement of HIF-1α and VEGF expressions induced by the
[104]. The expression of Rac1, a small GTPase triggering reactive oxy- overexpression of HPV type 16 oncoproteins has been reported in
gen species (ROS) production by NADPH-oxidases, is sufficient to non-small cell lung cancer cells [145]. HPV E7 oncoprotein enhances
cause Kaposi's sarcoma-like tumors in transgenic mice through HIF-1-mediated transcription by inhibiting binding of histone
mechanisms involving ROS-driven proliferation mechanisms, AKT deacetylases HDAC1, HDAC4, and HDAC7 to increase the expression
signaling, and hypoxia-inducible factor 1α (HIF-1α)-related angio- of pro-angiogenic factors in cervical cancer cells [146], indicating
genesis, pointing out host and viral genes triggering Rac1 or ROS pro- that HPV oncoproteins may induce a microenvironment favorable to
duction as key determinants of Kaposi's sarcoma onset and potential their replication through epigenetic control of various genes, includ-
chemopreventive or therapeutic targets [139]. A growing body of ing genes encoding for HIF-1 and the genes it regulates.
evidence has pointed out the ROS product HIF-1 as a major player Hepatitis C virus (HCV) infection is a major risk factor for the de-
in microbial-triggered carcinogenesis. velopment of hepatocellular carcinoma [13]. HCV gene expression in-
duces oxidative stress, which in turn induces the stabilization of
6.2. Hypoxia-inducible factor 1 HIF-1α, followed by VEGF and angiogenic cytokine release, leading
to tumorigenic neovascularization in vivo [147]. Such HIF-1α stabili-
HIF-1 is a heterodimeric transcription factor and key regulator zation requests the activation of NF-κB, STAT-3, PI3K/Akt, and
responsible for the induction of genes that facilitate adaptation and p42/44 mitogen-activated protein kinase. A study aimed at clarifying
survival of cells during hypoxia. HIF-1 consists of a constitutively whether human papillomavirus (HPV) directly affects the oncogene-
expressed subunit HIF-1β and an oxygen sensitive subunit HIF-1α sis and biologic behavior of tonsillar cancer revealed that compared
(or its paralogs HIF-2α and HIF-3α) [140]. Macrophages would be with HPV-negative patients, HPV-positive tonsillar cancer patients
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