review article chronic inflammation and cytokines in the...

Review ArticleChronic Inflammation and Cytokines in the TumorMicroenvironment

Glauben Landskron1 Marjorie De la Fuente1 Peti Thuwajit2

Chanitra Thuwajit2 and Marcela A Hermoso1

1 Disciplinary Program Institute of Biomedical Sciences School of Medicine University of Chile Independencia 10278380453 Santiago Chile

2 Department of Immunology School of Medicine Siriraj Hospital Mahidol University 2 Prannok Road Bangkok NoiBangkok 10700 Thailand

Correspondence should be addressed to Marcela A Hermoso mhermosomeduchilecl

Received 10 February 2014 Accepted 15 April 2014 Published 13 May 2014

Academic Editor Evelin Grage-Griebenow

Copyright copy 2014 Glauben Landskron et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Acute inflammation is a response to an alteration induced by a pathogen or a physical or chemical insult which functions toeliminate the source of the damage and restore homeostasis to the affected tissue However chronic inflammation triggers cellularevents that can promote malignant transformation of cells and carcinogenesis Several inflammatory mediators such as TNF-120572IL-6 TGF-120573 and IL-10 have been shown to participate in both the initiation and progression of cancer In this review we explorethe role of these cytokines in important events of carcinogenesis such as their capacity to generate reactive oxygen and nitrogenspecies their potential mutagenic effect and their involvement inmechanisms for epithelial mesenchymal transition angiogenesisandmetastasis Finally wewill provide an in-depth analysis of the participation of these cytokines in two types of cancer attributableto chronic inflammatory disease colitis-associated colorectal cancer and cholangiocarcinoma

1 Introduction

The role of inflammation in the development of cancerwas described as early as 1863 by Rudolf Virchow Hisobservations that inflammatory cells infiltrate tumors led himto hypothesize that cancer arises from inflammatory sites(ldquolymphoreticular infiltrationrdquo) [1 2] In the last decades Vir-chowrsquos postulation has been supported by abundant evidencethat various cancers are triggered by infection and chronicinflammatory disease [3]

Inflammation is a beneficial response activated to restoretissue injury and pathogenic agents However if inflam-mation is unregulated it can become chronic inducingmalignant cell transformation in the surrounding tissueThe inflammatory response shares various molecular targetsand signaling pathways with the carcinogenic process suchas apoptosis increased proliferation rate and angiogene-sis Furthermore the use of nonsteroidal anti-inflammatory

drugs (NSAIDs) has been shown to decrease incidence andmortality of several cancers [4]

In relation to chronic inflammatory-associated neo-plasias this review article explores the involvement ofcytokines in chronic inflammation and carcinogenesis focus-ing on inflammatory bowel disease-associated cancer andcholangiocarcinoma (CCA) induced by chronic inflamma-tion of biliary ducts that is primary sclerosing cholangitis(PSC) and liver fluke associated-CCA Both cancers areexamples of a localized long-term inflammatory processincreasing the risk of cancer

2 Chronic Inflammation as anInducer of Tumors

The immune response comprises a series of events triggeredin response to recognition of pathogens or tissue damageinvolving cells and soluble mediators such as cytokines of

Hindawi Publishing CorporationJournal of Immunology ResearchVolume 2014 Article ID 149185 19 pageshttpdxdoiorg1011552014149185

2 Journal of Immunology Research

the innate and adaptive immune system The main purposeof this inflammatory response is to remove the foreign agentdisturbing tissue homeostasis [5] In the normal physiologicalcontext after tissue repair or pathogen elimination theinflammation is resolved and the homeostatic state recovered[6]

It is now widely accepted that inadequately resolvedchronic inflammationmay increase the risk of cancer Severalpathologies illustrate this link such as endometriosis chronicprostatitis and chronic gastritis due to Helicobacter pylori(H pylori) inflammatory bowel diseases (IBD) and primarysclerosing cholangitis (PSC) (Table 1) Inflammation canincrease the risk of cancer by providing bioactive moleculesfrom cells infiltrating the tumor microenvironment includ-ing cytokines growth factors chemokines that maintain asustained proliferative rate cell survival signals to avoidapoptosis proangiogenic factors and extracellular matrix-modifying enzymes such as metalloproteinases that promoteepithelial-mesenchymal transition (EMT) and facilitate othercarcinogenesis programs such as genome instability repro-gramming of energy metabolism and immune evasion [7]Here we focus on key cytokines involved in tumor inductionand their role in EMT angiogenesis invasion andmetastasis

3 Cytokines Involved in Tumor Development

Cytokines are low-molecular-weight proteins that mediatecell-to-cell communication Immune and stromal cells suchas fibroblasts and endothelial cells synthesize them and theyregulate proliferation cell survival differentiation immunecell activation cell migration and death Depending on thetumormicroenvironment cytokines canmodulate an antitu-moral response but during chronic inflammation they canalso induce cell transformation and malignancy conditionalon the balance of pro- and anti-inflammatory cytokines theirrelative concentrations cytokine receptor expression contentand the activation state of surrounding cells [50]

31 Tumor Necrosis Factor (TNF-120572) As noted unresolvedinflammation can lead to malignancy Tumor necrosis factor(TNF-120572) is one inflammatory mediator that has been impli-cated in carcinogenesis due to its participation in chronicinflammatory diseases [51] Moore et al provided evidencethat TNF-120572-deficient mice are resistant to tetradecanoyl-phorbol-13-acetate- (TPA-) induced skin carcinogenesisTNF-120572 effect seems to be more significant in the earlystages of carcinogenesis including angiogenesis and invasionversus progression of carcinogenesis [52 53]While TNF-120572 isa prototypical proinflammatory cytokine evidence suggestsa double-edged role in carcinogenesis This cytokine isrecognized by two receptors TNF-120572 receptor-1 (TNF-120572R-1) ubiquitously expressed and TNF-120572R-2 expressed mainlyin immune cells [54] Trimerization occurs upon TNF-120572binding to TNF-120572-Rs leading to activation of at least four sig-naling pathways a proapoptotic pathway induced by caspase-8 interaction with Fas-associated death domain (FADD)an antiapoptotic platform activated by cellular inhibitor ofapoptosis protein-1 (cIAP-1) and interacting with TNF-120572R-associated factor 2 (TRAF2) a TRAF2- and JNK-mediated

AP-1 signaling pathway and a receptor interacting protein-(RIP-) induced NF-120581B [54]

There is controversy however regarding the role of TNF-120572 in cancer high concentrations of this cytokine can inducean antitumoral response in a murine model of sarcoma [55]FurthermoreWilliamB Coley a pioneer surgeon in the fielddiscovered that there was a reliable treatment response forsystemic bacterial filtrate injection in sarcoma patients [5556] However severe toxic side effects have been associatedwith systemically administered TNF-120572 such as hypotensionand organ failure [57] Local administration has been shownto be safer and effective as demonstrated by clinical trialsevaluating a TNF-120572-expressing adenovirus (TNFerade) genetherapy combined with chemotherapy [58 59] MoreoverTNF-120572-conjugate targeting peptides or single-chain antibodyfragments have also shown variable effects depending on thepatient [60]

In contrast low sustained TNF-120572 production levels caninduce a tumor phenotype [61] A TNF-120572 tumor promotionmechanism is based on reactive oxygen species (ROS) andreactive nitrogen species (RNS) generation which can induceDNAdamage hence facilitating tumorigenesis [62 63] TNF-120572-mediated inflammation has been linked to cancer forinstance increasedTNF-120572 levels in preneoplastic lesions havebeen detected inH pylori-positive gastric lesions throughHpylori-secreted TNF-120572-inducing protein (Tip120572) [64 65]

A study by Kwong et al explored TNF-120572-associatedtumorigenesis using an organoid of normal human ovarianepithelial cells exposed to a prolonged TNF-120572 dose Themodel demonstrated generation of a precancerous-like phe-notype with structural and functional changes such as tissuedisorganization epithelial polarity loss cell invasion andoverexpression of cancer markers [66]

According to these findings the pro- or antitumoral TNF-120572 response within the tumor microenvironment depends notonly on local concentration but also on its expression site inthe tumor Patients with elevated levels of TNF-120572 in tumorislets from non-small cell lung cancer mainly restricted tomacrophages and mast cells showed the highest survivalrates while patients with increased stromal TNF-120572 contentshowed lower survival rates [67]

There is also evidence that prolonged TNF-120572 exposurecan enhance the proportion of cancer stem cell phenotypesin oral squamous cell carcinoma increasing their tumor-forming sphere ability stem cell-transcription factor expres-sion and tumorigenicity [68]

32 Interleukin 6 (IL-6) Another proinflammatory cytokinewith a typical protumorigenic effect is IL-6 Elevated serumIL-6 levels have been detected in patients with systemiccancers as compared to healthy controls or patients withbenign diseases IL-6 has been proposed as a malignancypredictor with sensitivity and specificity of about 60ndash70and 58ndash90 respectively [69] However there are limitedstudies available that might be used to define cut-off valuesfor IL-6 as a diagnostic tool

IL-6 plays a key role in promoting proliferation andinhibition of apoptosis by binding to its receptor (IL-6R120572)

Journal of Immunology Research 3

Table 1 Cancer associated with chronic inflammatory disorders

Cancer Associated inflammatory stimuli ReferenceColorectal cancercolitis-associated cancer Inflammatory bowel diseases (ulcerative colitis and Crohnrsquos diseases) [8]Cholangiocarcinoma Liver fluke and primary sclerosing cholangitis [9]Gastric cancer Chronic gastritis (H Pylori) [10]Lung cancer Inflammation caused by asbestos infections smoking and silica [11]Prostate cancer E coli infection of prostate [12]Hepatocellular carcinoma Infection with hepatitis virus B and hepatitis virus C [13]Melanoma UV irradiation-associated skin inflammation [14]Endometrial carcinoma Endometriosis [15]Gall bladder carcinoma Gall bladder stone-associated chronic cholecystitis [16 17]Esophageal cancer Barrettrsquos esophagitis [18]

and coreceptor gp130 (glycoprotein 130) thus activating theJAKSTAT signaling pathway of the Janus kinases (JAK) andsignal transducers and activators of transcription (STATs)STAT1 and STAT3 [70] STATs belong to a family of tran-scription factors closely associated with the tumorigenic pro-cesses Several studies have highlighted the effect of the IL-6JAKSTAT signaling pathway on cancer initiation and pro-gression IL-6 can induce tumorigenesis by hypermethylationof tumor suppressor genes as well as by hypomethylation ofretrotransposon long interspersed nuclear element-1 (LINE-1) in oral squamous cell cancer lines in vitro [71] a frequentevent in various human cancers Furthermore IL-6 has beenshown to be produced primarily by stromal fibroblasts in agastric cancer mouse model however the deficient mousemodel exhibits reduced tumorigenesis when exposed to thecarcinogen N-methyl-N-nitrosourea [72]

IL-6 has a role in multiple myeloma development asdemonstrated by its ability to induce apoptosis by blockingthe IL-6RSTAT3 pathway in vitro [73] and the resistance ofIL-6minusminus mice to plasmacytoma induction [74]

Like TNF-120572 IL-6 facilitates tumor development by pro-moting conversion of noncancer cells into tumor stem cellsIn particular IL-6 secretion by noncancer stem cells in low-attachment culture conditions upregulates Oct4 gene expres-sion by activating the IL-6RJAKSTAT3 signaling pathway[75]

These findings have led researchers to propose IL-6 asa therapeutic target in cancer Several phase III clinicaltrials are currently evaluating antibodies against IL-6 or IL-6R as therapeutic alternatives Siltuximab (CNTO 328) amonoclonal antibody against IL-6 has shown promisingresults for non-small cell lung cancer ovarian cancer prostatecancer and multiple myeloma among others [76ndash80]

In this context as inflammatory cytokines are par-tially responsible for tumor induction an increase in anti-inflammatory cytokines should limit the risk of cancerand reduce activation of signaling pathways Nonethelessevidence suggests that anti-inflammatory cytokines such asTGF-120573 and IL-10 show more complex effects on tumordevelopment

33 Transforming Growth Factor 120573 (TGF-120573) TGF-120573 is apowerful pleiotropic cytokine with immune-suppressing and

anti-inflammatory properties Under physiological condi-tions TGF-120573 has a well-documented role in embryogenesiscell proliferation differentiation apoptosis adhesion andinvasion [81] Three isoforms have been identified TGF-1205731TGF-1205732 and TGF-1205733 TGF-120573s binds to the cognate type IIreceptor (TGF-120573 RII) inducing type I TGF-120573 receptor (TGF-120573 RI) phosphorylation and leading to the formation of aheterotetrameric complex that activates SMAD-dependenttranscription [82] SMAD transcription factors are struc-turally formed by a serine and threonine-rich linker regionthat connects two MAD (mothers against dpp) homologyregions Differential phosphorylation of these amino acidresidues contributes to various cellular functions includingcytostatic effects cell growth invasion extracellular matrixsynthesis cell cycle arrest and migration [83] Thereforedifferential phosphorylation of SMAD2 and SMAD3 by TGF-120573 receptor activation promotes their translocation into thenucleus where they form a complex with SMAD4 furtherbind to DNA associate with other transcription factors andinduce gene expression [82]

The role of TGF-120573 in cancer is complex and paradoxicalvarying by cell type and stage of tumorigenesis In earlystages TGF-120573 acts as a tumor suppressor inhibiting cell cycleprogression and promoting apoptosis Later TGF-120573 enhancesinvasion and metastasis by inducing epithelial-mesenchymaltransition (EMT) [84] In cancer induction TGF-120573 exertsa tumor suppressor effect through cyclin-dependent kinaseinhibitor (CKI) p21 upregulation and c-Myc downregulation[85] Using a conditional TGF-120573 RII knock-out mice modelGuasch et al found that highly proliferative epithelia (suchas rectal and genital) developed spontaneous squamous cellcarcinomas and furthermore showed accelerated carcinomaprogression Ras mutations and apoptosis reduction [86]suggesting that a deficient TGF-120573 pathway contributes totumorigenesis

There is consistent evidence demonstrating that TGF-120573signaling changes are involved in human cancer IncreasedTGF-1205731 mRNA and protein have been observed in gastriccarcinoma non-small cell lung cancer and colorectal andprostate cancer [87] and TGF-120573 receptor deletion or muta-tions have been associated with colorectal prostate breastand bladder cancer correlating with a more invasive andadvanced carcinoma higher degree of invasion and worseprognosis [88]


In the tumor microenvironment common sources ofTGF-120573 are cancer and stromal cells including immune cellsand fibroblasts [82] Bone matrix is also an abundant sourceof TGF-120573 and a common site for metastasis in many cancerscorrelating with the tumor-promoting and invasive effects ofthis cytokine [89]

Specific therapy targeting this cytokine in advanced can-cer patients has shown promising results in preclinical andclinical studies using TGF-120573 inhibitors specifically ligandtraps antisense oligonucleotides receptor kinase inhibitorsand peptide aptamers Nevertheless serious side effectsof systemic TGF-120573 inhibitors administration have beenreported indicating that further clinical trials are required toevaluate localized safe dose-effective therapies [89]

34 Interleukin 10 (IL-10) Interleukin 10 (IL-10) is known tobe a potent anti-inflammatory cytokine Almost all immunecells including T cells B cells monocytes macrophagesmast cells granulocytes dendritic cells and keratinocytesproduce IL-10 [90] Tumor cells can also secrete IL-10 as cantumor-infiltrating macrophages [91 92]

When IL-10 binds to its receptor Jak1 and Tyk2 tyrosinekinases phosphorylate an IL-10R intracellular domain allow-ing it to interact with STAT1 STAT3 and STAT5 favoringSTAT translocation into the nucleus and induction of targetgene expression [93]

Several studies have indicated that IL-10 has both pro- andantitumoral effects IL-10 inhibits NF-120581B signaling thereforeit can downregulate proinflammatory cytokine expression[94] and act as an antitumoral cytokine Consistent withthis finding Berg et al demonstrated that IL-10-deficientmurine models are prone to bacteria-induced carcinogen-esis [95] whereas the adoptive transfer of IL-10-expressingCD4+CD25+ T cells into Rag2minusminus (lymphocyte-deficient)mice inhibits colorectal inflammation and carcinomas [9697]Moreover IL-10 can exert antitumoral activity in gliomasmelanomas and breast and ovarian carcinomas [98] througha mechanism involving MHC-I downregulation thus induc-ing NK-mediated tumor cell lysis [99]

Due to its immunosuppressive effect on dendritic cellsand macrophages IL-10 can dampen antigen presentationcell maturation and differentiation allowing tumor cells toevade immune surveillance mechanisms [100]

In addition and as previously described for IL-6 STAT3can also be activated by IL-10 although the cytokinesrsquocontradictory responses are determined by receptor andtime frame of STAT activation In particular IL-6 leadsto a transient rapidly declining STAT3 phosphorylationand nuclear localization whereas IL-10 induces a sustainedSTAT3 phosphorylation [101]Through STAT3 activation IL-10 can also have a protumorigenic effect mediated by anautocrine-paracrine loop [102] involving Bcl-2 upregulationand apoptosis resistance activation [103 104] Likewiseelevated IL-10 levels are associated with poor prognosis indiffuse B cell lymphoma [105] and expression by tumorcells and tumor-associated macrophages promote Burkittrsquoslymphoma through the increased production of a TNF-120572family member BAFF a tumor growthsurvival molecule[106]

4 Inflammatory Response and Malignancy

41 Inflammation-Induced Reactive Oxygen Species (ROS) andReactive Nitrogen Species (RNS) in the Carcinogenic ProcessIn an inflammatory response epithelial and immune cellactivation trigger ROS and RNS generation through induc-tion of NADPH oxidase and nitric oxide synthase (NOS)respectively NADPH oxidase is a protein complex composedof several membrane-associated subunits that catalyze thesuperoxide anion (O

2

minus∙) leading to superoxide dismutase-(SOD-) mediated hydrogen peroxide (H

2

O2

) productionNADPH oxidase is expressed in phagocytic and nonphago-cytic cells and cytochrome subunit isoforms are presentin different cell types (NOX2 in phagocytic cells such asmacrophages and neutrophils) (NOX1 3ndash5 and DUOX1 2 innonphagocytic cells) [107]On the other handNOS generatesnitric oxide (NO) from L-arginine which can be convertedinto RNS such as nitrogen dioxide (NO∙

2

) peroxynitrite(ONOOminus) and dinitrogen trioxide (N

2

O3

) Different NOSisoforms are produced depending on cell type inducibleNOS(iNOS) in phagocytic cells and constitutive in endothelial andneuronal (eNOS and nNOS) cells [108] ROS and RNS have apotent antimicrobial role in phagocytic cells and also act as asecond messenger in signaling transduction [109 110]

Phagocytic cell activation can directly induce reactiveoxygen and nitrogen species (collectively called RONS)activating NOX2 NADPH oxidase and iNOS [109] Further-more TNF-120572 IL-6 and TGF-120573 trigger RONS generation innonphagocytic cells [111ndash113]

Increased expression of NADPH oxidase and NOS andtheir products RONS has been identified in various cancerssuggesting that free radicals have a role in genesis andmalignant progression [63] In various chronic inflammatorydiseases such as H pylori-associated gastritis and inflam-matory bowel diseases (IBD) high RONS levels have beenobserved suggesting a role in cancer risk [114ndash116]

Different mechanisms have been proposed to clarifyRONS participation in cancer development RONS inducecell oxidative stress and damage of lipids proteins andDNA as well as production of 8-oxo-7 8-dihydro-21015840-deoxyguanosine (8-oxodG) which is actually used as aDNA damage marker Furthermore 8-oxodG can pair withadenine leading to transversion of GC to TA (GrarrTtransversion) Similarly ONOOminus can modify deoxyguano-sine to 8-nitrodeoxyguanosine which can spontaneouslygenerate an apurinic site favoring GrarrT transversion [19]Identification of these DNA damage markers in chronicinflammatory processes such asH pylori-associated gastritishepatitis and ulcerative colitis emphasizes the relevanceof RONS in pathologies with an increased risk of cancer(Figures 1(a) and 1(b)) [19 117 118] Moreover 8-oxodG and8-nitrodeoxyguanine immune-reactivity is increased in theliver of hepatitis C virus-derived chronic hepatitis patients[118]

Jaiswal et al found increased iNOS 3-nitrotyrosineand 8-oxodG in the livers of primary sclerosis cholangitis(PSC) patients [119] Furthermore RNS interfere with DNArepair as shown in cells overexpressing iNOS that are unableto repair modified 8-oxodG [119] Deficient DNA-repair


Macrophage Fibroblast

Injury orinfection

IL-6IL-8

Chemotaxis

Lymphocyte

Disruptedepithelialbarrier

RONS

TNF-120572

(a)

Th1

IL-10 TGF-120573

IFN-120574

DNA damage

RONS

NeutrophilTh17IL-17

Th2

Chronic injury orinfection

TNF-120572FibroblastIL-6

IL-8

Disruptedepithelial

barrier

M2 M120601 M1 M120601

(b)

Th1IFN-120574

Th17IL-17

IL-10

Th2

fibroblast

Neutrophil TNF-120572IL-6

IL-10

VEGFIL-8

M2 MΦ MMP-2TGF-120573 TGF-120573

120572-SMA+

(c)

TILsTAMs

CAFs

MMP-2TGF-120573IL-10VEGF Periostin

HGFTenascin-cCXCL12

IL-17

TGF-120573

(d)

Figure 1 Schematic illustration of the role of cytokines in carcinogenesis (a) During tissue injury or infection an immune response activatesthe expression of proinflammatory mediators such as TNF-120572 IL-6 and IL-8 frommacrophages and neutrophilsThese cytokines can disruptthe epithelial barrier induce RONS and promote the infiltration of other inflammatory cells (b) In chronic inflammation proinflammatorycytokines such as TNF-120572 can induce DNA damage through RONS which leads to tumor initiation TGF-120573 can promote malignanttransformation through EMT activation Cytokines derived from CD4+lymphocytes such as IFN-120574 IL-10 and IL-17 can participate inepithelial barrier disruption M2 phenotypic transitions of macrophages and angiogenesis respectively (c) Tumor growth and invasion arealso favored by proinflammatory cytokines that stimulate cell proliferation reduce apoptosis and enhance EMT and angiogenesis the latteris facilitated by VEGF and IL-8 Anti-inflammatory cytokines such as IL-10 and TGF-120573 contribute to tumor immune evasion (d) Tumor-associated macrophages (TAM) tumor-infiltrating lymphocytes (TIL) and cancer-associated fibroblasts (CAF) secrete several factors thatcontribute to tumor growth and metastasis while maintaining the immunosuppressive milieu

protein activity has been linked to enzyme S-nitrosylationattributable to increased RNS [120]

RONS are generated by cellular stress andmacromoleculemodification although they are also involved in the reg-ulation of signaling pathways such as survival and cellproliferation through Akt Erk12 and hypoxia-induciblefactor-1 (HIF-1) activation [121 122]

There is strong evidence linking carcinogenesis to inflam-matory response and RONS and therapeutic strategies forcancer prevention using free radicals and proinflammatorysignaling inhibitors have been evaluated in animal models[123ndash125]

42 Inflammation-Associated Tumor Growth Nowadays it isaccepted that chronic inflammation is important in gener-ating malignancy through the exposure of proinflammatory

cytokines and sustained activation of signaling pathways suchas NF-120581B and STAT3 Following cell transformation to amalignant state these cytokines are also involved in tumorgrowth by stimulating the proliferation of tumor cells and byevading immunosurveillance (Figures 1(b) and 1(c))

Several cytokines have growth factor activity a relevantcytokine is TNF-120572 In a study by Zhu et al they showed thatthe silencing of TNF-120572 in a gallbladder cell line decreasescell proliferation and invasion by an autocrine effect affectingthe activation of TNF-120572NF-120581BAKTBcl-2 pathway in thesecells [126] This is consistent with data previously observedby Luo et al who revealed that NF-120581B signaling is requiredto promote tumor cell proliferation in response to an inflam-matory stimulus and by inhibiting this transcription factoran antitumor signal led by TNF-120572TRAIL is triggered [20]However in a mouse model of ovarian cancer TNF-120572 can


also stimulate the secretion of other cytokines like IL-17 byCD4+ T cells and promote tumor growth indirectly [127]

The protumorigenic role of IL-17 has also been implicatedin other types of cancer In mice with carcinogen-inducedskin tumors those deficient in IL-17 receptor showed a lowertumor incidence and a diminished tumor size [128]

IL-6 is another typical proinflammatory cytokine withtumor growth effect mainly by activating JAK tyrosinekinases and the transcription factor STAT3 as seen in lungkidney and breast cancer in which a high expression ofSTAT3has been identified [70] Also in cell lines ofmalignantfibrous histiocytoma a high secretion of IL-6 and constitutiveactivation of STAT3 were reported reflecting an increase oftumor cell proliferation [129]

In cancer other molecules that may influence tumorgrowth by regulating the IL-6STAT3 signaling pathwayhave been reported Inflammatory mediators like Hmgb1IL-23 and IL17 can promote tumor growth by activatingIL-6STAT3 pathway in a mouse model of melanoma [130]In cholangiocarcinoma a high expression of the tumor sup-pressor gene regulator gankyrin favors tumor proliferationinvasion and metastasis through activation of IL-6STAT3signaling pathway [131] Furthermore embelin a derivativefrom Embelia ribes is known to inhibit XIAP (X-linkedinhibitor of apoptosis protein) and is able to impair tumorproliferation by interfering in IL-6STAT3 signaling [132]

Finally the anti-inflammatory cytokine IL-10 may alsocontribute to tumor growth In a mouse model of melanomatumors overexpressing IL-10 present a higher tumor growthmediated by an increase in tumor cell proliferation angiogen-esis and immune evasion [133]

43 Inflammation-Associated Epithelial Mesenchymal Tran-sition The epithelial mesenchymal transition (EMT) isan important process of cellular reprogramming duringembryogenesis and pathological events such as inflamma-tion wound healing and cancer [134 135] During EMTepithelial cells exhibit morphological changes acquiringfibroblast characteristics In this process structures involvedin epithelial cell-cell interaction such as tight junctionsadherens junctions desmosomes and gap junctions are lostand the cells undergo actin cytoskeleton reorganization andchanges in the expression profile of proteins allowing for cell-cell contact such as E-cadherin Furthermore expression offibroblast markers including fibronectin 120572-smooth muscleactin (120572-SMA) and matrix metalloproteinases is favoredduring EMT Cellular reprogramming is orchestrated by avariety of transcription factors such as Snail ZEB and thehelix-loop-helix (HLH) family [136 137] The mesenchymalphenotype provides increased motility that is associated withinvasiveness and metastasis of tumor cells [138 139]

One inflammatory mediator relevant in EMT is TGF-120573as demonstrated by its role in embryogenesis fibrosis andtumor development in various EMT models [137 140ndash142]SMAD2 SMAD3 and SMAD4 mediate EMT modulationvia TGF-120573 signaling [137] as shown by EMT inhibitionin SMAD3-deficient mice and by SMAD2- SMAD3- orSMAD4-dominant negative constructs in vitro [143 144]Extensive evidence supports the notion that EMT can be

induced by proinflammatory cytokines TNF-120572 and IL-6may synergistically nudge the TGF-120573 signaling pathwaytowards EMT progression (Figures 1(b) and 1(c)) [21 145]Both cytokines promote NF-120581B activation which regulatesthe expression of transcription factors involved in EMTorchestrating the effects of Snail1 Snail2 Twist ZEB1 andZEB2 [146 147] Moreover IL-6 induces cell invasivenessin EMT through increased vimentin and downregulated E-cadherin expression both mediated by the JAKSTAT3Snailsignaling pathway as shown in head and neck cancer [148]

Finally ROS production can promote EMT [149] there-fore exposing kidney epithelial cells to ROS induces TGF-120573expression the SMAD signaling pathway and EMT whereasantioxidants inhibit these processes [150]

44 Inflammation-Associated Angiogenesis Angiogenesiscomprises the processes leading to the generation of newblood vessels from an existing vascular network Angio-genesis in cancer development is important because thenew blood vessel network penetrates and supplies nutrientsand oxygen to tumor cells Several angiogenic factors secretedby tumor cells have been identified in particular vascularendothelial growth factor (VEGF) that is expressed inresponse to cytokines and growth factors as shown in Figures1(c) and 1(d) [151] Moreover characterization of tumor-associated macrophages (TAM) obtained from metastaticlymph nodes (MLN) in an animal model of melanomahas shown that MLN are constituted predominantly byTIE2+CD31+ infiltrating macrophages This subpopulationsignificantly overexpresses VEGF and is directly related toangiogenesis [152]

Fajardo et al showed that TNF-120572 might have a double-edged role in angiogenesis depending on the dose usedHigh TNF-120572 doses inhibited angiogenesis in mice subcu-taneously implanted with an angiogenesis disc-system anexperimental strategy used to induce newblood vessels whilelow doses promoted vascularization of the area [153] Theantiangiogenic effect of TNF-120572 is related to downregulationof 120572]1205733 and the angiotensin signaling pathway [154] whileproangiogenic responses have been associated with increasedVEGF VEGFR IL-8 and FGF expression [155]

On the other hand low TNF-120572 levels increase tumorgrowth induce angiogenesis of diverse tumors in miceand induce a subpopulation of tumor-associated myeloidcells coexpressing endothelial and myeloid markers withproangiogenicprovasculogenic properties [156]

The tumor source of TNF-120572 can be derived frommyeloidor tumor cells and through an autocrine activation canstimulate tumor growth and angiogenesis [157] Likewisetumors derived from TNF-120572 knockdown cells have a well-circumscribed phenotype with low vascularization and lessinvasiveness [157]

Another relevant angiogenic factor is IL-6 high lev-els correlate with VEGF content in colorectal and gastriccancer [158 159] Moreover IL-6 induces VEGF expressionin a dose-dependent manner in gastric cancer cell lines[160] Similarly IL-6 promotes angiogenesis by activating


the STAT3 pathway in cervical cancer [161] Together IL-6 secretion and the subsequent STAT3 phosphorylation areinvolved in the upregulation of angiogenic mediators suchas VEGF HIF1120572 the VEGFR2 coreceptor and neuropilin 2(NRP2) [162 163] In xenograft models of ovarian cancerreduced tumor neovascularization TAM infiltration andchemokine production were demonstrated after a challengewith siltuximab a high-affinity anti-IL-6 antibody [77]

A proangiogenic effect has also been attributed to TGF-120573[88]HighTGF-120573 levels in tumors correlatewith angiogenesisin prostate cancer [164] In addition TGF-120573 levels correlatewith VEGF expression in gastric carcinoma [165] These dataare consistent with the defective vasculogenesis shown inTGF-1205731 knockdown mice [166]

On the other hand anti-inflammatory IL-10 has beensuggested to have an antiangiogenic role in several cancermodels [167 168] Overexpression of mIL-10 in the KOC-2Stumor cell line had little effect on the VEGF-hyposecretoryphenotype suggesting that mIL-10-mediated inhibition ofangiogenesis is mediated by VEGF [169]

45 Inflammation-Associated Metastasis Metastasis is a pro-cess characterized by neoplastic cell spread to another organof different origin During metastasis the cells invade bloodand lymphatic vessels and circulate through the bloodstreamwith subsequent retention in another organ generating a newtumor focus

The metastatic cascade is modulated by the action ofseveral cytokines released by surrounding cells such as tumorassociatedmacrophages infiltrating lymphocytes and cancerassociated fibroblasts promoting tumor cell evasion anddissemination this process is depicted in Figure 1(d) Theinfluence of TNF-120572 has been investigated in various experi-mental animal models Administration of this cytokine leadsto a significant increase of the number of lung metastases[170 171] Kim et al proposed that tumor cells activatemyeloid cells to generate a microenvironment favorable formetastasis In Lewis lung carcinoma (LLC) cell conditioned-medium high levels of IL-6 and TNF-120572were induced in bonemarrow-derived macrophages [172] TNF-120572minusminus but not IL-6minusminus mice injected with LLC cells showed improved survivaland reduced lung tumormultiplicity suggesting a critical roleof TNF-120572 in LLC metastasis [172] In accordance with thesedata studies show that the use of anti-TNF-120572 antibodies aidsin decreasing metastasis [4 173] IL-6 in turn is upregulatedin various tumors and has been implicated in the capacity ofcancer cells to metastasize to bone [148 174 175]

In contrast IL-10 displays an antitumoral function Resti-tution of IL-10 in the A375P human melanoma cell linewhich does not produce endogenous IL-10 using a vectorcontaining murine IL-10 cDNA reverted tumor growth andlungmetastasesThis evidence suggests that IL-10 productionby tumor cells inhibits metastasis [167]

There is a strong relationship between EMT and metas-tasis suggesting that in the early stages of the metastaticcascade EMT enables migration and intravasation of tumorcells [176] For this reason inflammatory mediators involvedin EMT in particular TGF-120573 might play an important role inpromoting metastasis [138]

5 Colorectal Cancer and InflammatoryBowel Disease

Colorectal cancer is the third-most frequent cancer world-wide with a higher incidence in developed countries [177]A mortality rate of about 9 has been reported for both menand women with 5-year survival between 74 and 59 forearly stages (stages I to IIC) and 6 for stage IV [178]

Today it is widely accepted that IBDpatients have a higherrisk of CRC especially ulcerative colitis (UC) and to a muchlesser extent Crohnrsquos disease (CD) In a population-basedstudy in theUnited States standardized incidence ratios (SIR)of 24 (95 IC 06ndash60) in extensive UC or pancolitis and 19in CD (95 IC 07ndash41) were reported [8] The prevalenceof CRC in UC patients in the Asia-Pacific region rangesfrom 03 to 18 [179] In a Japanese study poorer survivalwas observed in patients with ulcerative colitis-associatedcolorectal cancer as compared to sporadic colorectal cancerpatients in advanced stages [180]

Risk factors involved in this process include a greaterextent of compromised tissue and sustained disease durationwith an onset of more than 7 years with risk increasing05ndash10 per year [181] Another risk factor is concomitantprimary sclerosing cholangitis (PSC) and UC with an OR479 95 CI (358 641) [182]

As noted previously several types of cancer are associatedwith chronic infections (Table 1) The IBD are multifactorialpathologies involving changes in the microbiota possiblyattributable to pathogens such as Mycobacterium aviumparatuberculosis and adherent-invasive Escherichia coli [183]These pathogens can induce an inflammatory response [184ndash186] which may be associated with higher risk of carcino-genesis however more studies demonstrating the chronicityof these infections in IBD patients and their potential role incarcinogenesis are needed

Various murine models of colitis-associated cancer(CAC) [187] have elucidated much of the carcinogenicprocess such as a genetic model of IL-10-deficient micethat develop spontaneous colitis and colonic neoplasms [44]and a DSS-induced colitis and carcinoma model DSS is amucosal irritant that induces damage similar to that seen inUC patients and through a dose-repeated regimen DSS-exposed mice develop tumors [188 189] An additionalchemically inducedmurinemodel involves an azoxymethane(AOM) stimulus combined with repeated DSS doses AOMis a mutagenic agent favoring mutation of the 120573-cateninprotooncogene inducing localization to the nucleus andincreasing iNOS and cyclooxygenase (COX-2) expression[190 191] Through the animal models we have learnedthat inflammatory cytokines chemokines and growth factorsplay crucial roles in CAC development However thesemodels have limitations as they do not always represent thecomplexity of themechanisms involved in CRC-IBD patients[187]

In IBDmany inflammatory cytokines are involved in car-cinogenesis such as TNF-120572 and IL-6 (Table 2) In untreatedUC patients mucosal TNF-120572 levels correlate with the degreeof swelling [192] Furthermore high IL-6 levels have beenobserved in intestinal biopsies from active IBD patients [193]


andmurinemodels have demonstrated a crucial role for thesetwo relevant proinflammatory cytokines in the initiation andprogression of CAC [33 194]

As noted above proinflammatory cytokines can inducethe generation of RONS a process that has been observed inIBD patients [115] increasing the risk of carcinogenesis [195]by promoting oxidative stress-mediated DNA damage [19]High ROS levels induced by chronic inflammation have beenassociated with early p53 mutations in CAC distinguishingit from sporadic colorectal cancer in which these mutationshave been identified in later stages of malignancy [196]Thus the mutagenic potential of RONS together with earlymutations of the p53 tumor suppressor gene has the potentialto increase the cumulative risk associated with genetic alter-ations predisposing to carcinogenesis in UC patients

There is abundant evidence for the role of EMT in CACprogression and the participation of TGF-120573 in EMT [38]Patients with IBD or CRC show elevated TGF-120573 levels [197198] In an IL-10-deficient CAC murine model incidenceof colorectal carcinoma was 65 at the age of 10ndash31 weeksand plasma TGF-120573 levels were higher than in their wild-typelittermates [44]Through in vitro assays a well-differentiatedcolon carcinoma cell line LIM1863 was shown to undergoEMT conversion with a migratory monolayer phenotype inresponse to TGF-120573 Moreover TNF-120572 stimulates IL-8 expres-sion which in turn accelerates TGF-120573-induced EMT [21]Therefore a proinflammatory stimulus favors the invasiveproperties of CAC potentiating EMT

As previously detailed angiogenesis is a relevant pro-cess in carcinogenesis Mucosal tissue from IBD patientsshows higher microvessel density a process associated withincreased expression of VEGF-induced inflammation [22199] Concomitantly the CAC mouse model replicated thehigher VEGF activity and blockade of VEGFR2 suppressedtumor development angiogenesis and cell proliferation[200]

Furthermore in an experimental murine cancer metasta-sis model in which tumor growth was stimulated by bacteriallipopolysaccharide (LPS) injection TNF-120572-induced NF-120581Bsignaling in tumor cells was essential for the generation ofmetastasis Moreover NF-120581B blockade resulted in reversionof LPS-induced tumor growth [20] Taken together theseeffects ofNF-120581B signaling indicate that it is a decisive pathwayfor driving metastasis

A recently described molecule involved in metastasis isperiostin an extracellularmatrix protein secreted in responseto mechanical stress and tissue repair by pericryptal andcancer associated fibroblasts (CAFs) Periostin is expressed ininvasive front of colon carcinoma suggesting its participationin tumor growth [201] Periostin expression dramaticallyenhances metastatic growth of colon cancer by both prevent-ing stress-induced apoptosis in cancer cells and augmentingendothelial cell survival to promote angiogenesis [202]

The inflammatory process associated with carcinogenesisin CAC is not limited to the above-mentioned cytokinesOther inflammatory mediators are also involved such asthe proinflammatory cytokine IL-17 which was found to beelevated in the mucosa and serum of active IBD patients[203] Furthermore IL-17 is overexpressed in tumors from

CAC patients and is associated with angiogenesis and poorprognosis markers [46]The protumorigenic role of IL-17 hasalso been observed in a IL-17-deficient mouse model of CACinduced with AOM and DSS where minor tumor formationand a decrease in proinflammatory markers were found forthe IL-17-deficientmice as compared to wild-typemice [204]

Another proinflammatory cytokine with a role in CAC isIL-21 which is elevated in the mucosa of IBD patients andin the CAC mouse model [49] Furthermore blockade ofthe IL-21 signaling pathway reduces tumor development andmucosal microenvironment inflammation [49]

Interferon-120574 (IFN-120574) is a proinflammatory cytokine withpleiotropic functions [205] Increased numbers of IFN-120574positive cells have been observed in IBD patients especiallyCrohnrsquos disease [27] possibly contributing to a chronicinflammatory setting Moreover IFN-120574-deficient mice didnot develop DSS-induced colitis [28] In early IBD pathogen-esis IFN-120574 plays an important role in increasing paracellularpermeability in T84 epithelial cells by inducing endocytosisof tight-junction (TJ) proteins occludin JAM-A and claudin-1 [29] In an IL-10-deficient model enterocolitis and tumorformation were dependent on the participation of IFN-120574 asblockage with a neutralizing antibody prevented colitis andcancer in young mice (less than 3 weeks old) However thiseffect was not seen in mice older than 3months emphasizingthe role of IFN-120574 as an early inducer of inflammation [95]

In an AOMTNBS-CAC murine model Osawa et alshowed that IFN-120574minusminus mice developed higher numbers oftumors than wild-type or IL-4minusminus mice This points to theantitumor immune response of IFN-120574 [30] In patientswith UC-associated cancer and a group of UC patientswith chronic severe inflammation the IFN-inducible genefamily 1-8U was overexpressed However the consequencesof increased IFN-120574 expression in UC and its contribution tocarcinogenesis remain unclear [31]

Other molecules induced by IFN-120574 have been alsoobserved in IBD patients such as IL-18 and IL-18 bindingprotein (IL-18BP) which have been furthermore associatedwith inflammation and cancer [32]

Interleukin 8 (IL-8) a member of the neutrophil-specificCXC subfamily of chemokines with the ELR (Glu-Leu-Arg) motif acts as a chemoattractant to neutrophils dur-ing acute inflammatory response [206] Increased levels ofthis chemokine have been reported in IBD patients [207]correlating histologically with areas of active inflammation[208] mainly associated with neutrophils and macrophages[209] Additionally colon cancer cells also express IL-8[210] in sporadic cancer higher levels of this cytokine wereobserved in tissue frommoderately and poorly differentiatedas compared to well-differentiated tumors [211] In additionIL-8 levels are directly correlated with metastatic potentialin colon cancer cell lines [210] Overexpression of IL-8 inHCT116 andCaco2 cell lines results in increased proliferationcell migration and invasion while in a tumor xenograftmodel IL-8-overexpressing cells formed larger tumors andshowed higher microvessel density [41] This in vivo effect ofIL-8 on angiogenesis is supported by a study using primarycultures of human intestinal microvascular endothelial cells


Table 2 Significance and role of cytokines in tumorigenesis

Cytokines Colitis-associated cancer (references) CCA (references)

TNF-120572

Tumor-promoting role in various stagesof carcinogenesis Related to RONSgeneration in IBD patients promotingoxidative stress-mediated DNA damageStimulates TGF-120573-induced EMT Inducessecretion of VEGF by human fibroblastspromoting angiogenesis Induces NF-120581Bsignaling a decisive pathway in drivingmetastasis in a model of CAC [19ndash22]

Essential for bile duct epithelial cellproliferation Impairs epithelial barrierfunction Disrupts cholangiocytetight-junction and influences theaggravation of bile duct cholestasisInduces a DNARNA-editing enzyme(AID) in CCA cells resulting in somaticmutation of several tumor-related genesand leading to cholangiogenesis EMTinduction in CCA cells in vitro [23ndash26]

IFN-120574

Increases in IFN-120574+ cells have beenobserved in IBD patients Deficient micedid not develop DSS-induced colitisIncreases paracellular permeability inearly IBD pathogenesis Deficient micedeveloped higher numbers of tumorssuggesting an antitumor immuneresponse of IFN-120574 In patients withUC-associated cancer and a group of UCpatients with chronic severeinflammation the IFN-inducible genefamily 1-8U was overexpressed InducesIL-18 and IL-18 binding protein (IL-18BP)in IBD which have been also associatedwith inflammation and cancer [27ndash32]

Reduces transepithelial electricalresistance Alters cholangiocytetight-junction leading to aggravation ofbile duct cholestasis [24]

IL-6

Induces oxidative stress A critical tumorpromoter during early CACtumorigenesis TAM-derived IL-6contributes to CAC in animal modelsCRC patients present with high levels ofIL-6 and VEGF [19 33ndash35]

Cholangiocyte and CCA cells can beactivated by proinflammatory cytokinesthrough the NF-120581B-dependent pathwayleading to overproduction of bile ductepithelium growth factor thus promotingcancer initiation and progression [36 37]

TGF-120573

Induces CAC progression promotingEMT In later stages of carcinogenesis itpromotes tumor growth by creating animmunotolerant tumor environment[38 39]

Promotes proliferation of bile ductepithelial cells and inducesEMT-mediated tumor aggressiveness[23 40]

IL-8

Colon cancer cell lines overexpressingIL-8 show enhanced proliferationmigration and angiogenesis IL-8induced by TNF-120572 accelerates EMT[21 41]

Secreted by cholangiocytes in response toproinflammatory cytokines and togetherwith MCP-1 and CCL-28 promotesleukocyte adhesion and retention ininjured biliary epithelial cells Injuredcholangiocytes then release IGF-1 andVEGF which can stimulate CCA cellgrowth [42 43]

IL-10IL-10minusminus mice develop colitis andcolorectal cancer similar toIBD-associated cancer in humans [44]

CCA can activate macrophagepolarization into M2 phenotype throughthe STAT-3 pathway leading to IL-10VEGF-A TGF-120573 and MMP-2production [45]

IL-17

Overexpressed in tumors from CACpatients and is associated withangiogenesis and poor prognosismarkers Secreted in tumors bymacrophagesmonocytes CD68+ Th17and Treg FOXP3+IL17+ cells [46 47]

Tumor-infiltrating lymphocytes IL-17+are found in CCA intratumoral areas andcorrelate with lymph node metastasisintrahepatic metastasis and advancedstages [48]


Table 2 Continued


IL-21

Enhanced in mucosa of IBD patients andin the CAC mouse model Blockade ofIL-21 signaling reduces tumordevelopment and mucosalmicroenvironment inflammation [49]

No available references for this cytokinein CCA

which respond to IL-8 through the CXCR2 receptor elicitingan angiogenic response [212]

These findings illustrate the complex role of cytokines inthe various events associated with the development of CACTherefore controlling the inflammatory process early in IBDis important for reducing risk of colorectal cancer

6 Primary Sclerosing Cholangitis- (PSC-) andLiver Fluke-AssociatedCholangiocarcinoma (CCA)

CCA is a malignant neoplasm originating from the epithelialcells lining the intra- or extrahepatic biliary ducts It is thesecond-most frequent liver cancer worldwide after hepato-cellular carcinoma Five-year survival is about 10 In theUnited States incidence of CCA in the Hispanic populationis 28 per 100000 in Asians 33 per 100000 and in non-Hispanic Caucasians and African-Americans 21 per 100000[213] However incidence varies widely from the highestreported rate of 113 per 100000 in the Khon Kaen provinceofThailand to as low as 01 per 100000 in Australia [214 215]

There are several factors that increase the risk for CCAincluding primary sclerosing cholangitis parasitic infectionbiliary-duct cysts hepatolithiasis viral infection and toxins[23 216] Primary sclerosing cholangitis (PSC) is character-ized by inflammation and fibrosis of biliary ducts leading tobiliary tract stricture The cumulative lifetime incidence ofCCA in PSC is around 20 [217] More than 50 of patientswith PSC develop CCA simultaneously or within 1 year ofdiagnosis [218]The incidence ofCCAafter PSCdiagnosis hasbeen reported in several studies at around 05ndash15 per year[217ndash219] CCA must be suspected in any new PSC patientpresentingwith jaundice suggesting chronic inflammation ofthe bile duct

Opisthorchis viverrini (O viverrini) and Clonorchis sinen-sis (C sinensis) have been classified by the InternationalAgency for Research on Cancer (IARC) as Group I (carcino-genic in humans) [220] and as the most common risk factorsfor CCA especially in East and Southeast Asia [221 222]The high incidence of O viverrini infection which is dueto the custom of eating raw fish containing the infectiousstage of the parasites was found to be correlated with thehigh prevalence of CCA in the northeastern part of Thailand[221] PSC hepatolithiasis and choledochal cysts are the riskfactors for CCA in areas where liver fluke is not endemicin Thailand [215] In addition biliary ascariasis caused byAscaris lumbricoides infection inChina India and some areasof South America has also been reported in association withCCA development [223 224]

Infection with hepatitis viruses can generate hepatocel-lular carcinomas especially hepatitis B in which more than80 of cases develop cancer [225] It is becoming moreaccepted that both hepatitis B and hepatitis C viruses maybe associated with biliary inflammation and can cause CCAApproximately 138 and 19 of CCA patients have positivefindings for hepatitis B and hepatitis C respectively [226]

Other etiologies that may or may not cause bile ductobstruction but result in the chronic inflammation of biliaryepithelial cells are proposed CCA risk factors includinggallstone formation choledochoenteric anastomosis andchemical and radiation exposure [23]

CCA like many other cancers in that its carcinogen-esis is a multistep process requires interaction betweenmutated biliary epithelial cells and environmental factorsMany hallmarks of cancer have been proposed and the listhas been continually updated over the years [7] The genesinvolved in controlling these properties have been found to bemutated in cancer patients In CCA several protooncogenesincluding K-ras [227ndash229] c-erbB-2 and c-Met [230] tumorsuppressor genes that is p53 and antiapoptotic genes suchas Bcl-2 Bcl-X(L) and Mcl-1 [231] are mutated In PSC-mediated CCA the mutation was detected in the promoterleading to the overexpression of p16INK4a and p14ARF cellcycle regulators [232]

During the genesis of CCA both PSC and parasitic infec-tions cause cholestasis and chronic inflammation of the bileduct which can induce the epithelial cells to produce a varietyof cytokines including IL-6 IL-8 TGF-120573 TNF-120572 platelet-derived growth factor (PDGF) and epidermal growth factor(EGF) (Table 2) [23]The release of IL-6 TGF-120573 TNF-120572 andPDGFA is essential for bile duct epithelial cell proliferationThe production of PDGFA and the overexpression of itsreceptors during cholangiocarcinogenesis in O viverrini-infected hamsters indicate the potential of these molecules todownregulate many antiproliferative factors and promote theangiogenesis pathway [233] In addition PDGFA expressionin CCA tissue and serum is correlated with patient survivaltime and has been proposed as a marker of poor prognosis[234]

TNF-120572 and IFN-120574 which are cytokines released dur-ing chronic inflammation can cause alteration of biliarybarrier function [24] whereas proinflammatory cytokinesalter cholangiocyte choleretic activity [42 43] When cholan-giocytes are exposed to these cytokines they respond bysecreting other molecules such as IL-8 MCP-1 and CCL-28 that can promote leukocyte adhesion and retention at thesite of inflammation leading to more damage of biliary cellsThe injured cholangiocytes can release insulin-like growth


factor-1 (IGF-1) and VEGF to stimulate CCA cell growth andangiogenesis respectively [235ndash238]

TNF-120572 can activate increased expression of AID(activation-induced cytidine deaminase a member of theDNARNA-editing enzyme family) in CCA-derived cellsbut not in PSC-derived epithelial cells [25] AID results inthe generation of somatic mutations of many tumor-relatedgenes including p53 c-Myc and CDKN2A (or INK4Ap16)promoter sequences This finding suggests a connectionbetween chronic inflammation and tumorigenesis viathe mutagenic activity of AID [25] In addition NF-120581B activation in cells by chronic inflammation-derivedcytokines might lead to the activation of active transcriptionfactors translocating into the nucleus and regulating theexpression of IL-6 TNF-120572 and several growth factors whichcan change the microenvironment for tumor promotion[36] Moreover the release of nitric oxide with the formationof 3-nitrotyrosine and other reactive oxidants can inhibitthe DNA-repair process which allows for oxidative DNAdamage to cells and thus promotes tumor formation [239]

Cholangiocytes and CCA cells do not act alone but aresurrounded by several types of cells generally known asmicroenvironmental cells Fibroblasts are the main microen-vironmental cells and their function in stimulating theacquired hallmark capabilities of cancer cells is well-known[240] Activated CCA-associated fibroblast phenotypes werefound to show increased expression of 120572-SMA [241] Inter-estingly these fibroblasts were isolated from CCA tissuesobtained from patients and mapped for the specific geneexpression pattern resulting in the expression of severalcancer-promoting proteins [242] Researchers have sinceidentified several substances that can be produced by CCA-associated fibroblasts including periostin hepatocyte growthfactor (HGF) tenascin-C and CXCL-12 [243 244] Interest-ingly these soluble factors are involved in several tumorigenicproperties leading to the progression and metastasis of thecancerThese findings suggest that fibroblasts their secretingproducts and the activated pathways in the cancer cells couldbe promising targets for attenuation of disease progression[243 245]

Many immune cells are known to surround cancer cellswith detrimental or beneficial effects on cancer progressiondepending on the profile of substances secreted into thetumor microenvironment The substances secreted fromCCA cells were studied in vitro with human macrophagesand the results exhibited M2 polarization of macrophagesas well as overproduction of cytokines and other bioactivemolecules including IL-10 VEGF-A TGF-120573 and matrixmetalloproteinase- (MMP-) 2 [45] In intrahepatic CCA thetumor-infiltrating lymphocytes IL-17+ and FOXP3+ CD66b+neutrophils and microvessels were predominantly found inthe intratumor area whereas CD8+ lymphocytes were mostabundant in the tumor invasive front [48] Although IL-17levels have never been reported for CCA this study suggestedfor the first time that intratumor IL-17+ lymphocytes andneutrophils could be used as a marker of poor prognosis inCCA

TGF-120573 was studied with CCA cell lines and theresults demonstrated the potential of TGF-120573 to induce

EMT-mediated cancer progression via the Snail transcriptionfactor leading to increasing levels of vimentin S100A4collagen type 1 and MMP-2 production [40] EMT levelis closely associated with aggressiveness of the disease andcould be proposed as a marker of poor prognosis MoreoverTNF-120572has been recently reported to have the ability to induceEMT of CCA cells [26]

In conclusion the chronic inflammation-driven cytokin-es released from biliary cells fibroblasts or immune cellsinto the microenvironment of the bile duct epithelium mayfacilitate cell immortalization evasion of apoptosis andautonomous proliferation in untransformed cells leading tothe development of CCA [23] In addition cytokines mayhelp activate invasion metastasis and EMT-mediated CCAprogression

7 Conclusion

The tumor microenvironment formed by stromal cells infil-trating immune cells and tumor cells contains factors thatcan promote carcinogenesis Ample evidence supports theinvolvement of cytokines in events leading to the initiationpromotion invasion and metastasis of cancer (Figure 1) Ina chronic inflammatory process cytokines such as TNF-120572 and IL-6 induce the generation of free radicals that candamage DNA potentially causing mutations that lead totumor initiation Tumor growth is also favored by proin-flammatory cytokines that stimulate cell proliferation andreduce apoptosis while anti-inflammatory cytokines such asIL-10 and TGF-120573 contribute to tumor immune evasion Theinvasive properties of tumors are related to the activation ofthe epithelial-mesenchymal transition program triggered byTGF-120573 and enhanced by proinflammatory cytokines suchas TNF-120572 and IL-6 Proinflammatory cytokines also playan important role in angiogenesis and metastasis In thelatter chemokines such as IL-8 have an important role in cellmigration to other tissues

Although we observed that many cytokines contributeto carcinogenesis their pro- or antitumoral roles depend onthe balance of these different inflammatory mediators andthe stage of tumor development For this reason studyingthe role of these mediators in different tumors or stagesof development is essential for designing new personalizedtreatments using these potential therapeutic targets

In this line the potential role of cytokines has beenreported as a diagnostic marker for cancer The determi-nation of the serum levels of cytokines such as IL-6 or IL-10 might be associated with a tumorigenic process or poorprognosis [69 105] However further prospective studies areneeded to determine trusted cut-off values of circulatingcytokine to establish a direct relationship with cancer

In the field of therapy several clinical trials have beenimplemented in order to evaluate inhibitors of cytokinesreceptors or neutralizing antibodies that prevent the sus-tained exposure to these inflammatory mediators that pro-mote tumor progression [80 103] On the other handfrom the findings of Coley [56] who associates an infec-tious process with the control of tumor progression arises


the idea to cause an acute inflammation to activate antitumorresponse mechanisms [58]

While progress has been made in the understanding ofthe mechanisms of these cytokines in the tumorigenic pro-cess establishing a relationship between cytokines expressionand disease progression survival and response to therapyremains a major challenge

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Authorsrsquo Contribution

Glauben Landskron and Marjorie De la Fuente are con-tributed equally to this paper

Acknowledgments

The figures were produced using Servier Medical Art fromwwwserviercom Funding was received from FONDECYT1120577 (MAH) and CONICYT REDES130037 (MAH)

References

[1] R Virchow Die Krankhaften Geschwulste Berlin Germany1863

[2] F Balkwill and A Mantovani ldquoInflammation and cancer backto VirchowrdquoThe Lancet vol 357 no 9255 pp 539ndash545 2001

[3] S P Hussain and C C Harris ldquoInflammation and canceran ancient link with novel potentialsrdquo International Journal ofCancer vol 121 no 11 pp 2373ndash2380 2007

[4] L Yan G M Anderson M DeWitte and M T NakadaldquoTherapeutic potential of cytokine and chemokine antagonistsin cancer therapyrdquo European Journal of Cancer vol 42 no 6 pp793ndash802 2006

[5] RMedzhitov ldquoOrigin and physiological roles of inflammationrdquoNature vol 454 no 7203 pp 428ndash435 2008

[6] L V Norling and C N Serhan ldquoProfiling in resolving inflam-matory exudates identifies novel anti-inflammatory and pro-resolving mediators and signals for terminationrdquo Journal ofInternal Medicine vol 268 no 1 pp 15ndash24 2010

[7] D Hanahan and R AWeinberg ldquoHallmarks of cancer the nextgenerationrdquo Cell vol 144 no 5 pp 646ndash674 2011

[8] T Jess E V Loftus Jr F S Velayos et al ldquoRisk of intestinalcancer in inflammatory bowel disease a population-basedstudy from olmsted county Minnesotardquo Gastroenterology vol130 no 4 pp 1039ndash1046 2006

[9] A Zabron R J Edwards and S Khan ldquoThe challenge ofcholangiocarcinoma dissecting the molecular mechanisms ofan insidious cancerrdquo Disease Models amp Mechanisms vol 6 no2 pp 281ndash292 2013

[10] T Yoshida J Kato I Inoue et al ldquoCancer development based onchronic active gastritis and resulting gastric atrophy as assessedby serum levels of pepsinogen andHelicobacter pylori antibodytiterrdquo International Journal of Cancer vol 134 no 6 pp 1445ndash1457 2014

[11] H Vainio and P Boffetta ldquoMechanisms of the combinedeffect of asbestos and smoking in the etiology of lung cancerrdquo

Scandinavian Journal of Work Environment and Health vol 20no 4 pp 235ndash242 1994

[12] J N Krieger D E Riley R L Vesella D C Miner S O Rossand P H Lange ldquoBacterial DNA sequences in prostate tissuefrom patients with prostate cancer and chronic prostatitisrdquoJournal of Urology vol 164 no 4 pp 1221ndash1228 2000

[13] H B El-Serag ldquoEpidemiology of viral hepatitis and hepato-cellular carcinomardquo Gastroenterology vol 142 no 6 pp 1264ndash1273 2012

[14] R K SinghMGutman R Reich andM Bar-Eli ldquoUltraviolet Birradiation promotes tumorigenic and metastatic properties inprimary cutaneous melanoma via induction of interleukin 8rdquoCancer Research vol 55 no 16 pp 3669ndash3674 1995

[15] A S Bats Y Zafrani P Pautier P Duvillard and P MoriceldquoMalignant transformation of abdominal wall endometriosis toclear cell carcinoma case report and review of the literaturerdquoFertility and Sterility vol 90 no 4 pp 1197e13ndash1197e16 2008

[16] J G Fox F E Dewhirst Z Shen et al ldquoHepatic Helicobacterspecies identified in bile and gallbladder tissue from Chileanswith chronic cholecystitisrdquoGastroenterology vol 114 no 4 I pp755ndash763 1998

[17] B Levin ldquoGallbladder carcinomardquo Annals of Oncology vol 10no 4 pp S129ndashS130 1999

[18] A J Cameron and H A Carpenter ldquoBarrettrsquos esophagushigh-grade dysplasia and early adenocarcinoma a pathologicalstudyrdquo American Journal of Gastroenterology vol 92 no 4 pp586ndash591 1997

[19] M Murata R Thanan N Ma and S Kawanishi ldquoRole ofnitrative and oxidative DNA damage in inflammation-relatedcarcinogenesisrdquo Journal of Biomedicine and Biotechnology vol2012 Article ID 623019 11 pages 2012

[20] J-L Luo S Maeda L-C Hsu H Yagita and M KarinldquoInhibition of NF-120581B in cancer cells converts inflammation-induced tumor growth mediated by TNF120572 to TRAIL-mediatedtumor regressionrdquo Cancer Cell vol 6 no 3 pp 297ndash305 2004

[21] R C Bates and A M Mercurio ldquoTumor necrosis factor-120572stimulates the epithelial-tomesenchymal transition of humancolonic organoidsrdquo Molecular Biology of the Cell vol 14 no 5pp 1790ndash1800 2003

[22] S Danese M Sans C de la Motte et al ldquoAngiogenesis as anovel component of inflammatory bowel disease pathogenesisrdquoGastroenterology vol 130 no 7 pp 2060ndash2073 2006

[23] R Al-Bahrani Y Abuetabh N Zeitouni and C Sergi ldquoCholan-giocarcinoma risk factors environmental influences and onco-genesisrdquo Annals of Clinical amp Laboratory Science vol 43 no 2pp 195ndash210 2013

[24] S Hanada M Harada H Koga et al ldquoTumor necrosis factor-120572and interferon-120574 directly impair epithelial barrier function incultured moused cholangiocytesrdquo Liver International vol 23no 1 pp 3ndash11 2003

[25] J Komori H Marusawa T Machimoto et al ldquoActivation-induced cytidine deaminase links bile duct inflammation tohuman cholangiocarcinomardquoHepatology vol 47 no 3 pp 888ndash896 2008

[26] A Techasen N Namwat W Loilome et al ldquoTumor necrosisfactor-120572 (TNF-120572) stimulates the epithelial-mesenchymal transi-tion regulator Snail in cholangiocarcinomardquoMedical Oncologyvol 29 no 5 pp 3083ndash3091 2012

[27] L Camoglio A A Te Velde A J Tigges P K Das and SJ H Van Deventer ldquoAltered expression of interferon-120574 andinterleukin-4 in inflammatory bowel diseaserdquo InflammatoryBowel Diseases vol 4 no 4 pp 285ndash290 1998


[28] R Ito M Shin-Ya T Kishida et al ldquoInterferon-gamma iscausatively involved in experimental inflammatory bowel dis-ease in micerdquo Clinical and Experimental Immunology vol 146no 2 pp 330ndash338 2006

[29] M Bruewer A Luegering T Kucharzik et al ldquoProinflamma-tory cytokines disrupt epithelial barrier function by apoptosis-independent mechanismsrdquo Journal of Immunology vol 171 no11 pp 6164ndash6172 2003

[30] E Osawa A Nakajima T Fujisawa et al ldquoPredominant Thelper type 2-inflammatory responses promote murine coloncancersrdquo International Journal of Cancer vol 118 no 9 pp2232ndash2236 2006

[31] T Hisamatsu M Watanabe H Ogata et al ldquoInterferon-inducible gene family 1-8U expression in colitis-associatedcolon cancer and severely inflamedmucosa in ulcerative colitisrdquoCancer Research vol 59 no 23 pp 5927ndash5931 1999

[32] J Paulukat M Bosmann M Nold et al ldquoExpression andrelease of IL-18 binding protein in response to IFN-120574rdquo Journalof Immunology vol 167 no 12 pp 7038ndash7043 2001

[33] S Matsumoto T Hara K Mitsuyama et al ldquoEssential rolesof IL-6 trans-signaling in colonic epithelial cells induced bythe IL-6soluble-IL-6 receptor derived from lamina propriamacrophages on the development of colitis-associated prema-lignant cancer in a murine modelrdquo Journal of Immunology vol184 no 3 pp 1543ndash1551 2010

[34] S Grivennikov E Karin J Terzic et al ldquoIL-6 and Stat3 arerequired for survival of intestinal epithelial cells and develop-ment of colitis-associated cancerrdquo Cancer Cell vol 15 no 2 pp103ndash113 2009

[35] K Middleton J Jones Z Lwin and J I G CowardldquoInterleukin-6 an angiogenic target in solid tumoursrdquo CriticalReviews in OncologyHematology vol 89 no 1 pp 129ndash1392014

[36] A M Elsharkawy and D A Mann ldquoNuclear factor-120581B and thehepatic inflammation-fibrosis-cancer axisrdquoHepatology vol 46no 2 pp 590ndash597 2007

[37] F Meng H Wehbe-Janek R Henson H Smith and T PatelldquoEpigenetic regulation of microRNA-370 by interleukin-6 inmalignant human cholangiocytesrdquo Oncogene vol 27 no 3 pp378ndash386 2008

[38] R C Bates and A M Mercurio ldquoThe epithelial-mesenchymaltransition (EMT) and colorectal cancer progressionrdquo CancerBiology andTherapy vol 4 no 4 pp 365ndash370 2005

[39] L A Feagins ldquoRole of transforming growth factor-120573 in inflam-matory bowel disease and colitis-associated colon cancerrdquoInflammatory Bowel Diseases vol 16 no 11 pp 1963ndash1968 2010

[40] Y Sato K Harada K Itatsu et al ldquoEpithelial-mesenchymaltransition induced by transforming growth factor-1205731snailactivation aggravates invasive growth of cholangiocarcinomardquoAmerican Journal of Pathology vol 177 no 1 pp 141ndash152 2010

[41] Y Ning P C Manegold Y K Hong et al ldquoInterleukin-8is associated with proliferation migration angiogenesis andchemosensitivity in vitro and in vivo in colon cancer cell linemodelsrdquo International Journal of Cancer vol 128 no 9 pp2038ndash2049 2011

[42] C Spirlı L Fabris E Duner et al ldquoCytokine-stimulatednitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytesrdquo Gastroenterology vol124 no 3 pp 737ndash753 2003

[43] C Spiral MH Nathanson R Fiorotto et al ldquoProinflammatorycytokines inhibit secretion in rat bile duct epitheliumrdquo Gas-troenterology vol 121 no 1 pp 156ndash169 2001

[44] S Sturlan G Oberhuber B G Beinhauer et al ldquoInterleukin-10-deficient mice and inflammatory bowel disease associatedcancer developmentrdquoCarcinogenesis vol 22 no 4 pp 665ndash6712001

[45] H Hasita Y Komohara H Okabe et al ldquoSignificance of alter-natively activated macrophages in patients with intrahepaticcholangiocarcinomardquo Cancer Science vol 101 no 8 pp 1913ndash1919 2010

[46] J Liu Y Duan X Cheng et al ldquoIL-17 is associated with poorprognosis and promotes angiogenesis via stimulating VEGFproduction of cancer cells in colorectal carcinomardquo Biochemicaland Biophysical Research Communications vol 407 no 2 pp348ndash354 2011

[47] E Gounaris N R Blatner K Dennis et al ldquoT-regulatorycells shift from a protective anti-inflammatory to a cancer-promoting proinflammatory phenotype in polyposisrdquo CancerResearch vol 69 no 13 pp 5490ndash5497 2009

[48] F-MGuQGaoG-M Shi et al ldquoIntratumoral IL-17+ cells andneutrophils show strong prognostic significance in intrahepaticcholangiocarcinomardquoAnnals of Surgical Oncology vol 19 no 8pp 2506ndash2514 2012

[49] C Stolfi A Rizzo E Franze et al ldquoInvolvement of interleukin-21 in the regulation of colitis-associated colon cancerrdquo Journalof Experimental Medicine vol 208 no 11 pp 2279ndash2290 2011

[50] B F Zamarron and W Chen ldquoDual roles of immune cellsand their factors in cancer development and progressionrdquoInternational Journal of Biological Sciences vol 7 no 5 pp 651ndash658 2011

[51] C Popa M G Netea P L C M Van Riel J W M VanDer Meer and A F H Stalenhoef ldquoThe role of TNF-120572 inchronic inflammatory conditions intermediary metabolismand cardiovascular riskrdquo Journal of Lipid Research vol 48 no4 pp 751ndash762 2007

[52] R J Moore D M Owens G Stamp et al ldquoMice deficient intumor necrosis factor-alpha are resistant to skin carcinogene-sisrdquo Nature Medicine vol 5 no 7 pp 828ndash831 1999

[53] P Szlosarek K A Charles and F R Balkwill ldquoTumour necrosisfactor-120572 as a tumour promoterrdquoEuropean Journal of Cancer vol42 no 6 pp 745ndash750 2006

[54] G Chen and D V Goeddel ldquoTNF-R1 signaling a beautifulpathwayrdquo Science vol 296 no 5573 pp 1634ndash1635 2002

[55] E A Havell W Fiers and R J North ldquoThe antitumor functionof tumor necrosis factor (TNF)mdashI Therapeutic action of TNFagainst an established murine sarcoma is indirect immuno-logically dependent and limited by severe toxicityrdquo Journal ofExperimental Medicine vol 167 no 3 pp 1067ndash1085 1988

[56] B Wiemann and C O Starnes ldquoColeyrsquos toxins tumor necrosisfactor and cancer research a historical perspectiverdquo Pharmacol-ogy andTherapeutics vol 64 no 3 pp 529ndash564 1994

[57] F J Lejeune C Ruegg and D Lienard ldquoClinical applications ofTNF-alpha in cancerrdquo Current Opinion in Immunology vol 10no 5 pp 573ndash580 1998

[58] JMHerman A TWildHWang et al ldquoRandomized phase IIImulti-institutional study of TNFerade biologicwith fluorouraciland radiotherapy for locally advanced pancreatic cancer finalresultsrdquo Journal of Clinical Oncology vol 31 no 7 pp 886ndash8942013

[59] K J Chang T Reid N Senzer et al ldquoPhase I evaluation ofTNFerade Biologic plus chemoradiotherapy before esophagec-tomy for locally advanced resectable esophageal cancerrdquo Gas-trointestinal Endoscopy vol 75 pp 1139ndash1146 2012


[60] G M Anderson M T Nakada and M DeWitte ldquoTumornecrosis factor-120572 in the pathogenesis and treatment of cancerrdquoCurrent Opinion in Pharmacology vol 4 no 4 pp 314ndash3202004

[61] F Balkwill ldquoTNF-120572 in promotion and progression of cancerrdquoCancer andMetastasis Reviews vol 25 no 3 pp 409ndash416 2006

[62] C-H Woo Y-W Eom M-H Yoo et al ldquoTumor necrosisfactor-120572 generates reactive oxygen species via a cytosolic phos-pholipase A2-linked cascaderdquo Journal of Biological Chemistryvol 275 no 41 pp 32357ndash32362 2000

[63] S P Hussain L J Hofseth and C C Harris ldquoRadical causes ofcancerrdquoNature Reviews Cancer vol 3 no 4 pp 276ndash285 2003

[64] L A Noach N B Bosma J Jansen F J Hoek S J H VanDeventer and G N J Tytgat ldquoMucosal tumor necrosis factor-120572 interleukin-1120573 and interleukin-8 production in patientswith helicobacter pylori infectionrdquo Scandinavian Journal ofGastroenterology vol 29 no 5 pp 425ndash429 1994

[65] M Suganuma T Watanabe K Yamaguchi A Takahashi andH Fujiki ldquoHuman gastric cancer development with TNF-120572-inducing protein secreted from Helicobacter pylorirdquo CancerLetters vol 322 no 2 pp 133ndash138 2012

[66] J Kwong L C Franky K-K Wong et al ldquoInflammatorycytokine tumor necrosis factor 120572 confers precancerous pheno-type in an organoid model of normal human ovarian surfaceepithelial cellsrdquo Neoplasia vol 11 no 6 pp 529ndash541 2009

[67] C M Ohri A Shikotra R H Green D A Waller and PBradding ldquoTumour necrosis factor-alpha expression in tumourislets confers a survival advantage in non-small cell lung cancerrdquoBMC Cancer vol 10 article 323 2010

[68] S H Lee H S Hong Z X Liu et al ldquoTNF120572 enhances cancerstem cell-like phenotype via Notch-Hes1 activation in oralsquamous cell carcinoma cellsrdquo Biochemical and BiophysicalResearch Communications vol 424 no 1 pp 58ndash64 2012

[69] K Heikkila S Ebrahim and D A Lawlor ldquoSystematic reviewof the association between circulating interleukin-6 (IL-6) andcancerrdquo European Journal of Cancer vol 44 no 7 pp 937ndash9452008

[70] D R Hodge E M Hurt and W L Farrar ldquoThe role of IL-6and STAT3 in inflammation and cancerrdquo European Journal ofCancer vol 41 no 16 pp 2502ndash2512 2005

[71] J A Gasche J Hoffmann C R Boland and A GoelldquoInterleukin-6 promotes tumorigenesis by altering DNAmethylation in oral cancer cellsrdquo International Journal ofCancer vol 129 no 5 pp 1053ndash1063 2011

[72] H Kinoshita Y Hirata H Nakagawa et al ldquoInterleukin-6mediates epithelial-stromal interactions and promotes gastrictumorigenesisrdquo PLoS ONE vol 8 no 4 Article ID e60914 2013

[73] M Chatterjee T Stuhmer P Herrmann K Bommert BDorken and R C Bargou ldquoCombined disruption of both theMEKERKand the IL-6RSTAT3 pathways is required to induceapoptosis of multiple myeloma cells in the presence of bonemarrow stromal cellsrdquo Blood vol 104 no 12 pp 3712ndash37212004

[74] D M Hilbert M Kopf B A Mock G Kohler and S RudikoffldquoInterleukin 6 is essential for in vivo development of B lineageneoplasmsrdquo Journal of ExperimentalMedicine vol 182 no 1 pp243ndash248 1995

[75] S-Y Kim J W Kang X Song et al ldquoRole of the IL-6-JAK1-STAT3-Oct-4 pathway in the conversion of non-stem cancercells into cancer stem-like cellsrdquo Cell Signaling vol 25 no 4pp 961ndash969 2013

[76] L Song B Rawal J A Nemeth and E BHaura ldquoJAK1 activatesSTAT3 activity in non-small-cell lung cancer cells and IL-6neutralizing antibodies can suppress JAK1-STAT3 signalingrdquoMolecular Cancer Therapeutics vol 10 no 3 pp 481ndash494 2011

[77] J Coward H Kulbe P Chakravarty et al ldquoInterleukin-6 as atherapeutic target in human ovarian cancerrdquo Clinical CancerResearch vol 17 no 18 pp 6083ndash6096 2011

[78] R Kurzrock P M Voorhees C Casper et al ldquoA phase Iopen-label study of siltuximab an anti-IL-6 monoclonal anti-body in patients with B-cell non-Hodgkin lymphoma multiplemyeloma or Castleman diseaserdquo Clinical Cancer Research vol19 no 13 pp 3659ndash3670 2013

[79] J-F Rossi S Negrier N D James et al ldquoA phase III studyof siltuximab (CNTO 328) an anti-interleukin-6 monoclonalantibody in metastatic renal cell cancerrdquo British Journal ofCancer vol 103 no 8 pp 1154ndash1162 2010

[80] T B Dorff B Goldman J K Pinski et al ldquoClinical andcorrelative results of SWOG S0354 a phase II trial of CNTO328(siltuximab) a monoclonal antibody against interleukin-6in chemotherapy-pretreated patients with castration-resistantprostate cancerrdquo Clinical Cancer Research vol 16 no 11 pp3028ndash3034 2010

[81] J F Santibanez M Quintanilla and C Bernabeu ldquoTGF-120573TGF-120573 receptor system and its role in physiological andpathological conditionsrdquoClinical Science vol 121 no 6 pp 233ndash251 2011

[82] J Massague ldquoTGFbeta in cancerrdquo Cell vol 134 no 2 pp 215ndash230 2008

[83] K Matsuzaki ldquoSmad phospho-isoforms direct context-dependent TGF-120573 signalingrdquo Cytokine amp Growth FactorReviews vol 24 no 4 pp 385ndash399 2013

[84] C D Morrison J G Parvani and W P Schiemann ldquoTherelevance of the TGF-120573 Paradox to EMT-MET programsrdquoCancer Letters vol 341 no 1 pp 30ndash40 2013

[85] A Malliri W Andrew Yeudall M Nikolic D H CrouchE Kenneth Parkinson and B Ozanne ldquoSensitivity to trans-forming growth factor 1205731-induced growth arrest is commonin human squamous cell carcinoma cell lines c-MYC down-regulation and p21(waf1) induction are important early eventsrdquoCell Growth and Differentiation vol 7 no 10 pp 1291ndash13041996

[86] G Guasch M Schober H A Pasolli E B Conn L Polakand E Fuchs ldquoLoss of TGFamp signaling destabilizes homeostasisand promotes squamous cell carcinomas in stratified epitheliardquoCancer Cell vol 12 no 4 pp 313ndash327 2007

[87] B Bierie and H L Moses ldquoTGF-120573 and cancerrdquo Cytokine andGrowth Factor Reviews vol 17 no 1-2 pp 29ndash40 2006

[88] L Levy and C S Hill ldquoAlterations in components of the TGF-120573superfamily signaling pathways in human cancerrdquoCytokine andGrowth Factor Reviews vol 17 no 1-2 pp 41ndash58 2006

[89] E C Connolly J Freimuth and R J Akhurst ldquoComplexitiesof TGF-120573 targeted cancer therapyrdquo International Journal ofBiological Sciences vol 8 no 7 pp 964ndash978 2012

[90] R Sabat GGrutz KWarszawska et al ldquoBiology of interleukin-10rdquo Cytokine and Growth Factor Reviews vol 21 no 5 pp 331ndash344 2010

[91] N L Costa M C Valadares P P C Souza et al ldquoTumor-associated macrophages and the profile of inflammatorycytokines in oral squamous cell carcinomardquoOral Oncology vol49 no 3 pp 216ndash223 2013


[92] G A Gastl J S Abrams D M Nanus et al ldquoInterleukin-10production by human carcinoma cell lines and its relationshipto interleukin-6 expressionrdquo International Journal of Cancervol 55 no 1 pp 96ndash101 1993

[93] D S Finbloom and K D Winestock ldquoIL-10 induces thetyrosine phosphorylation of tyk2 and Jak1 and the differentialassembly of STAT1120572 and STAT3 complexes in humanT cells andmonocytesrdquo Journal of Immunology vol 155 no 3 pp 1079ndash1090 1995

[94] A J G Schottelius M W Mayo R Balfour Sartor and AS Baldwin Jr ldquoInterleukin-10 signaling blocks inhibitor of 120581Bkinase activity and nuclear factor 120581B DNA bindingrdquo Journal ofBiological Chemistry vol 274 no 45 pp 31868ndash31874 1999

[95] D J Berg N Davidson R Kuhn et al ldquoEnterocolitis and coloncancer in interleukin-10-deficient mice are associated withaberrant cytokine production and CD4+ Th1-like responsesrdquoJournal of Clinical Investigation vol 98 no 4 pp 1010ndash10201996

[96] S E Erdman T Poutahidis M Tomczak et al ldquoCD4+ CD25+regulatory T lymphocytes inhibit microbially induced coloncancer in Rag2-deficient micerdquo American Journal of Pathologyvol 162 no 2 pp 691ndash702 2003

[97] S E Erdman V P Rao T Poutahidis et al ldquoCD4+CD25+regulatory lymphocytes require interleukin 10 to interruptcolon carcinogenesis in micerdquo Cancer Research vol 63 no 18pp 6042ndash6050 2003

[98] W-W Lin and M Karin ldquoA cytokine-mediated link betweeninnate immunity inflammation and cancerrdquo Journal of ClinicalInvestigation vol 117 no 5 pp 1175ndash1183 2007

[99] N Kundu and A M Fulton ldquoInterleukin-10 inhibits tumormetastasis downregulatesMHC class I and enhancesNK lysisrdquoCellular Immunology vol 180 no 1 pp 55ndash61 1997

[100] H Hamidullah B Changkija and R Konwar ldquoRole ofinterleukin-10 in breast cancerrdquo Breast Cancer Research andTreatment vol 133 no 1 pp 11ndash21 2012

[101] D A BraunM Fribourg and S C Sealfon ldquoCytokine responseis determined by duration of receptor and signal transducersand activators of transcription 3 (STAT3) activationrdquo Journal ofBiological Chemistry vol 288 no 5 pp 2986ndash2993 2013

[102] B Sredni M Weil G Khomenok et al ldquoAmmoniumtrichloro(dioxoethylene-oorsquo)tellurate (AS101) sensitizes tumorsto chemotherapy by inhibiting the tumor interleukin 10autocrine looprdquo Cancer Research vol 64 no 5 pp 1843ndash18522004

[103] S Alas C Emmanouilides and B Bonavida ldquoInhibition ofinterleukin 10 by Rituximab results in down-regulation ofBcl-2 and sensitization of B-cell non-Hodgkinrsquos lymphoma toapoptosisrdquo Clinical Cancer Research vol 7 no 3 pp 709ndash7232001

[104] L Zeng C OrsquoConnor J Zhang AM Kaplan andD A CohenldquoIL-10 promotes resistance to apoptosis andmetastatic potentialin lung tumor cell linesrdquo Cytokine vol 49 no 3 pp 294ndash3022010

[105] E Lech-Maranda J Bienvenu A-S Michallet et al ldquoElevatedIL-10 plasma levels correlatewith poor prognosis in diffuse largeB-cell lymphomardquo European Cytokine Network vol 17 no 1 pp60ndash66 2006

[106] C A Ogden J D Pound B K Batth et al ldquoEnhancedapoptotic cell clearance capacity and B cell survival factorproduction by IL-10-activated macrophages implications forBurkittrsquos lymphomardquo Journal of Immunology vol 174 no 5 pp3015ndash3023 2005

[107] K Bedard and K-H Krause ldquoThe NOX family of ROS-generatingNADPHoxidases physiology and pathophysiologyrdquoPhysiological Reviews vol 87 no 1 pp 245ndash313 2007

[108] U Forstermann and W C Sessa ldquoNitric oxide synthasesregulation and functionrdquo European Heart Journal vol 33 no7 pp 829ndash837 2012

[109] R S Flannagan G Cosıo and S Grinstein ldquoAntimicrobialmechanisms of phagocytes and bacterial evasion strategiesrdquoNature Reviews Microbiology vol 7 no 5 pp 355ndash366 2009

[110] T Finkel ldquoReactive oxygen species and signal transductionrdquoIUBMB Life vol 52 no 1-2 pp 3ndash6 2001

[111] D Yang S G Elner Z-M Bian G O Till H R Petty andVMElner ldquoPro-inflammatory cytokines increase reactive oxygenspecies throughmitochondria and NADPH oxidase in culturedRPE cellsrdquo Experimental Eye Research vol 85 no 4 pp 462ndash472 2007

[112] A Sturrock B Cahill K Norman et al ldquoTransforming growthfactor-1205731 induces Nox4 NAD(P)H oxidase and reactive oxygenspecies-dependent proliferation in human pulmonary arterysmooth muscle cellsrdquo American Journal of Physiology LungCellular and Molecular Physiology vol 290 no 4 pp L661ndashL673 2006

[113] M da Silva Krause A Bittencourt P I Homem de Bittencourtet al ldquoPhysiological concentrations of interleukin-6 directlypromote insulin secretion signal transduction nitric oxiderelease and redox status in a clonal pancreatic 120573-cell line andmouse isletsrdquo Journal of Endocrinology vol 214 no 3 pp 301ndash311 2012

[114] G Rieder J A Hofmann R A Hatz M Stolte and GA Enders ldquoUp-regulation of inducible nitric oxide synthasein Helicobacter pylori-associated gastritis may represent anincreased risk factor to develop gastric carcinoma of theintestinal typerdquo International Journal of Medical Microbiologyvol 293 no 6 pp 403ndash412 2003

[115] D Rachmilewitz J S Stamler D Bachwich F Karmeli ZAckerman and D K Podolsky ldquoEnhanced colonic nitric oxidegeneration and nitric oxide synthase activity in ulcerative colitisand Crohnrsquos diseaserdquo Gut vol 36 no 5 pp 718ndash723 1995

[116] L J Hofseth S Saito S Perwez Hussain et al ldquoNitric oxide-induced cellular stress and p53 activation in chronic inflam-mationrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 100 no 1 pp 143ndash148 2003

[117] N Ma Y Adachi Y Hiraku et al ldquoAccumulation of 8-nitroguanine in human gastric epithelium induced by Heli-cobacter pylori infectionrdquo Biochemical and Biophysical ResearchCommunications vol 319 no 2 pp 506ndash510 2004

[118] S Horiike S Kawanishi M Kaito et al ldquoAccumulation of 8-nitroguanine in the liver of patients with chronic hepatitis CrdquoJournal of Hepatology vol 43 no 3 pp 403ndash410 2005

[119] M Jaiswal N F LaRusso R A Shapiro T R Billiar andG J Gores ldquoNitric oxide-mediated inhibition of DNA repairpotentiates oxidative DNA damage in cholangiocytesrdquo Gas-troenterology vol 120 no 1 pp 190ndash199 2001

[120] C-H Tang W Wei and L Liu ldquoRegulation of DNA repair byS-nitrosylationrdquo Biochimica et Biophysica Acta vol 1820 no 6pp 730ndash735 2012

[121] Q Li G-B Fu J-T Zheng et al ldquoNADPH oxidase sub-unit p22(phox)-mediated reactive oxygen species contributeto angiogenesis and tumor growth through AKT and ERK12signaling pathways in prostate cancerrdquo Biochimica et BiophysicaActa vol 1833 no 12 pp 3375ndash3385 2013


[122] S-N Jung W K Yang J Kim et al ldquoReactive oxygen speciesstabilize hypoxia-inducible factor-1 alpha protein and stimulatetranscriptional activity via AMP-activated protein kinase inDU145 human prostate cancer cellsrdquo Carcinogenesis vol 29 no4 pp 713ndash721 2008

[123] C V Rao C Indranie B Simi P T Manning J R Connorand B S Reddy ldquoChemopreventive properties of a selectiveinducible nitric oxide synthase inhibitor in colon carcinogen-esis administered alone or in combination with celecoxib aselective cyclooxygenase-2 inhibitorrdquo Cancer Research vol 62no 1 pp 165ndash170 2002

[124] M Takahashi T Kitahashi R Ishigamori et al ldquoIncreasedexpression of inducible nitric oxide synthase (iNOS) inN-nitrosobis(2-oxopropyl)amine-induced hamster pancreaticcarcinogenesis and prevention of cancer development byONO-1714 an iNOS inhibitorrdquoCarcinogenesis vol 29 no 8 pp 1608ndash1613 2008

[125] B Li R Alli P Vogel and T L Geiger ldquoIL-10 modulates DSS-induced colitis through a macrophage-ROS-NO axisrdquoMucosalImmunology 2013

[126] G Zhu Q Du X Wang et al ldquoTNF-120572 promotes gallbladdercancer cell growth and invasion through autocrine mecha-nismsrdquo International Journal of Molecular Medicine 2014

[127] K A Charles H Kulbe R Soper et al ldquoThe tumor-promotingactions of TNF-120572 involve TNFR1 and IL-17 in ovarian cancer inmice and humansrdquo Journal of Clinical Investigation vol 119 no10 pp 3011ndash3023 2009

[128] D He H Li N Yusuf et al ldquoIL-17 mediated inflammationpromotes tumor growth and progression in the skinrdquo PLoSONE vol 7 no 2 Article ID e32126 2012

[129] T Shouda K Hiraoka S Komiya et al ldquoSuppression of IL-6production and proliferation by blocking STAT3 activation inmalignant soft tissue tumor cellsrdquo Cancer Letters vol 231 no 2pp 176ndash184 2006

[130] Q Tang J Li H Zhu et al ldquoHmgb1-IL-23-IL-17-IL-6-Stat3axis promotes tumor growth in murine models of melanomardquoMediators of Inflammation vol 2013 Article ID 713859 13 pages2013

[131] T Zheng X Hong and J Wang ldquoGankyrin promotes tumorgrowth and metastasis through activation of IL-6STAT3 sig-naling in human cholangiocarcinomardquo Hepatology vol 59 no3 pp 935ndash946 2014

[132] Y Dai H Jiao G Teng et al ldquoEmbelin reduces colitis-associated tumorigenesis through limiting IL-6STAT3 signal-ingrdquoMolecular Cancer Therapeutics 2014

[133] M L Garcıa-Hernandez R Hernandez-Pando P Gariglio andJ Berumen ldquoInterleukin-10 promotes B16-melanomagrowth byinhibition of macrophage functions and induction of tumourand vascular cell proliferationrdquo Immunology vol 105 no 2 pp231ndash243 2002

[134] B Baum J Settleman andM P Quinlan ldquoTransitions betweenepithelial andmesenchymal states in development and diseaserdquoSeminars in Cell and Developmental Biology vol 19 no 3 pp294ndash308 2008

[135] R Kalluri and R A Weinberg ldquoThe basics of epithelial-mesenchymal transitionrdquo Journal of Clinical Investigation vol119 no 6 pp 1420ndash1428 2009

[136] J P Thiery and J P Sleeman ldquoComplex networks orchestrateepithelial-mesenchymal transitionsrdquo Nature Reviews MolecularCell Biology vol 7 no 2 pp 131ndash142 2006

[137] J Xu S Lamouille and R Derynck ldquoTGF-Β-induced epithelialtomesenchymal transitionrdquoCell Research vol 19 no 2 pp 156ndash172 2009

[138] J P Thiery ldquoEpithelial-mesenchymal transitions in tumourprogressionrdquo Nature Reviews Cancer vol 2 no 6 pp 442ndash4542002

[139] V Tirino R Camerlingo K Bifulco et al ldquoTGF-1205731 exposureinduces epithelial to mesenchymal transition both in CSCsand non-CSCs of the A549 cell line leading to an increase ofmigration ability in the CD133+ A549 cell fractionrdquo Cell Deathamp Disease vol 4 no 5 article e620 2013

[140] V Ellenrieder S F Hendler W Boeck et al ldquoTransforminggrowth factor 1205731 treatment leads to an epithelial-mesenchymaltransdifferentiation of pancreatic cancer cells requiring extra-cellular signal-regulated kinase 2 activationrdquo Cancer Researchvol 61 no 10 pp 4222ndash4228 2001

[141] B C Willis J M Liebler K Luby-Phelps et al ldquoInductionof epithelial-mesenchymal transition in alveolar epithelial cellsby transforming growth factor-1205731 potential role in idiopathicpulmonary fibrosisrdquoAmerican Journal of Pathology vol 166 no5 pp 1321ndash1332 2005

[142] T Yamagishi K Ando H Nakamura and Y NakajimaldquoExpression of the Tgf1205732 gene during chick embryogenesisrdquoAnatomical Record vol 295 no 2 pp 257ndash267 2012

[143] M Sato Y Muragaki S Saika A B Roberts and A OoshimaldquoTargeted disruption of TGF-1205731Smad3 signaling protectsagainst renal tubulointerstitial fibrosis induced by unilateralureteral obstructionrdquo Journal of Clinical Investigation vol 112no 10 pp 1486ndash1494 2003

[144] U Valcourt M Kowanetz H Niimi C-H Heldin and AMoustakas ldquoTGF-120573 and the Smad signaling pathway supporttranscriptomic reprogramming during epithelial-mesenchymalcell transitionrdquo Molecular Biology of the Cell vol 16 no 4 pp1987ndash2002 2005

[145] A Abulaiti Y Shintani S Funaki et al ldquoInteraction betweennon-small-cell lung cancer cells and fibroblasts via enhance-ment of TGF-120573 signaling by IL-6rdquo Lung Cancer vol 82 no 2pp 204ndash213 2013

[146] H J Maier U Schmidt-StraszligburgerM A Huber EMWiede-mann H Beug and T Wirth ldquoNF-120581B promotes epithelial-mesenchymal transition migration and invasion of pancreaticcarcinoma cellsrdquo Cancer Letters vol 295 no 2 pp 214ndash2282010

[147] M Kumar D F Allison N N Baranova et al ldquoNF-120581B regulatesmesenchymal transition for the induction of non-small celllung cancer initiating cellsrdquo PLoS ONE vol 8 no 7 Article IDe68597 2013

[148] A Yadav B Kumar J Datta T N Teknos and P KumarldquoIL-6 promotes head and neck tumor metastasis by inducingepithelial-mesenchymal transition via the JAK-STAT3-SNAILsignaling pathwayrdquoMolecular Cancer Research vol 9 no 12 pp1658ndash1667 2011

[149] Z Wang Y Li and F H Sarkar ldquoSignaling mechanism(S) ofreactive oxygen species in epithelial-mesenchymal transitionreminiscent of cancer stem cells in tumor progressionrdquo CurrentStem Cell Research andTherapy vol 5 no 1 pp 74ndash80 2010

[150] D Y Rhyu Y YangHHa et al ldquoRole of reactive oxygen speciesin TGF-1205731-inducedmitogen-activated protein kinase activationand epithelial-mesenchymal transition in renal tubular epithe-lial cellsrdquo Journal of the American Society of Nephrology vol 16no 3 pp 667ndash675 2005


[151] Y Cao ldquoTumor angiogenesis and therapyrdquo Biomedicine andPharmacotherapy vol 59 no 2 pp S340ndashS343 2005

[152] O-H Kim G-H Kang H Noh et al ldquoProangiogenicTIE2+CD31+) macrophages are the predominant populationof tumor-associated macrophages infiltrating metastatic lymphnodesrdquoMolecules and Cells vol 36 no 5 pp 432ndash438 2013

[153] L F Fajardo H H Kwan J Kowalski S D Prionas and A CAllison ldquoDual role of tumor necrosis factor-120572 in angiogenesisrdquoAmerican Journal of Pathology vol 140 no 3 pp 539ndash544 1992

[154] R R Weichselbaum D W Kufe S Hellman et al ldquoRadiation-induced tumour necrosis factor-120572 expression clinical applica-tion of transcriptional and physical targeting of gene therapyrdquoThe Lancet Oncology vol 3 no 11 pp 665ndash671 2002

[155] S YoshidaMOno T Shono et al ldquoInvolvement of interleukin-8 vascular endothelial growth factor and basic fibroblastgrowth factor in tumor necrosis factor alpha-dependent angio-genesisrdquoMolecular and Cellular Biology vol 17 no 7 pp 4015ndash4023 1997

[156] B Li A Vincent J Cates D M Brantley-Sieders D BPolk and P P Young ldquoLow levels of tumor necrosis factor 120572increase tumor growth by inducing an endothelial phenotypeof monocytes recruited to the tumor siterdquo Cancer Research vol69 no 1 pp 338ndash348 2009

[157] H Kulbe R Thompson J L Wilson et al ldquoThe inflammatorycytokine tumor necrosis factor-120572 generates an autocrine tumor-promoting network in epithelial ovarian cancer cellsrdquo CancerResearch vol 67 no 2 pp 585ndash592 2007

[158] A Eldesoky A Shouma Y Mosaad and A Elhawary ldquoClinicalrelevance of serum vascular endothelial growth factor andinterleukin-6 in patients with colorectal cancerrdquo Saudi Journalof Gastroenterology vol 17 no 3 pp 170ndash173 2011

[159] H K Kim K S Song Y S Park et al ldquoElevated levels ofcirculating platelet microparticles VEGF IL-6 and RANTESin patients with gastric cancer possible role of a metastasispredictorrdquo European Journal of Cancer vol 39 no 2 pp 184ndash191 2003

[160] S-P Huang M-S Wu C-T Shun et al ldquoInterleukin-6increases vascular endothelial growth factor and angiogenesisin gastric carcinomardquo Journal of Biomedical Science vol 11 no4 pp 517ndash527 2004

[161] L-H Wei M-L Kuo C-A Chen et al ldquoInterleukin-6 pro-motes cervical tumor growth byVEGF-dependent angiogenesisvia a STAT3 pathwayrdquo Oncogene vol 22 no 10 pp 1517ndash15272003

[162] L W Feurino Y Zhang U Bharadwaj et al ldquoIL-6 stimulatesTh2 type cytokine secretion and upregulates VEGF and NRP-1 expression in pancreatic cancer cellsrdquo Cancer Biology andTherapy vol 6 no 7 pp 1096ndash1100 2007

[163] S R Boreddy R P Sahu and S K Srivastava ldquoBenzylisothiocyanate suppresses pancreatic tumor angiogenesis andinvasion by inhibiting HIF-120572VEGFRho-GTPases pivotal roleof STAT-3rdquo PLoS ONE vol 6 no 10 Article ID e25799 2011

[164] PWikstrom P Stattin I Franck-Lissbrant et al ldquoTransforminggrowth factor beta1 is associated with angiogenesis metastasisand poor clinical outcome in prostate cancerrdquo Prostate vol 37no 1 pp 19ndash29 1998

[165] H Saito S Tsujitani S Oka et al ldquoThe expression of trans-forming growth factor-beta1 is significantly correlated withthe expression of vascular endothelial growth factor and poorprognosis of patients with advanced gastric carcinomardquoCancervol 86 no 8 pp 1455ndash1462 1999

[166] M C Dickson J S Martin F M Cousins A B KulkarniS Karlsson and R J Akhurst ldquoDefective haematopoiesis andvasculogenesis in transforming growth factor-1205731 knock outmicerdquo Development vol 121 no 6 pp 1845ndash1854 1995

[167] S Huang K Xie C D Bucana S E Ullrich and M Bar-Eli ldquoInterleukin 10 suppresses tumor growth and metastasis ofhuman melanoma cells potential inhibition of angiogenesisrdquoClinical Cancer Research vol 2 no 12 pp 1969ndash1979 1996

[168] M E Stearns J Rhim and M Wang ldquoInterleukin 10 (IL-10)inhibition of primary human prostate cell- induced angiogene-sis IL-10 stimulation of tissue inhibitor of metalloproteinase-1and inhibition of matrix metalloproteinase (MMP)-2MMP-9secretionrdquo Clinical Cancer Research vol 5 no 1 pp 189ndash1961999

[169] T Kohno H Mizukami M Suzuki et al ldquoInterleukin-10-mediated inhibition of angiogenesis and tumor growth in micebearing VEGF-producing ovarian cancerrdquoCancer Research vol63 no 16 pp 5091ndash5094 2003

[170] P Orosz B Echtenacher W Falk J Ruschoff D Weber and DNMannel ldquoEnhancement of experimentalmetastasis by tumornecrosis factorrdquo Journal of Experimental Medicine vol 177 no5 pp 1391ndash1398 1993

[171] P Orosz A Kruger M Hubbe J Ruschoff P Von Hoegen andD N Mannel ldquoPromotion of experimental liver metastasis bytumor necrosis factorrdquo International Journal of Cancer vol 60no 6 pp 867ndash871 1995

[172] S Kim H Takahashi W-W Lin et al ldquoCarcinoma-producedfactors activate myeloid cells through TLR2 to stimulate metas-tasisrdquo Nature vol 457 no 7225 pp 102ndash106 2009

[173] J-H Egberts V Cloosters A Noack et al ldquoAnti-tumor necrosisfactor therapy inhibits pancreatic tumor growth and metasta-sisrdquo Cancer Research vol 68 no 5 pp 1443ndash1450 2008

[174] G D Roodman ldquoRole of stromal-derived cytokines and growthfactors in bone metastasisrdquo Cancer vol 97 no 3 pp 733ndash7382003

[175] K Tawara J T Oxford and C L Jorcyk ldquoClinical significanceof interleukin (IL)-6 in cancer metastasis to bonePotential ofanti-IL-6 therapiesrdquo Cancer Management and Research vol 3no 1 pp 177ndash189 2011

[176] T R Samatov AG Tonevitsky andU Schumacher ldquoEpithelial-mesenchymal transition focus on metastatic cascade alterna-tive splicing non-coding RNAs and modulating compoundsrdquoMolecular Cancer vol 12 no 1 article 107 2013

[177] J Ferlay H-R Shin F Bray D Forman C Mathers and DM Parkin ldquoEstimates of worldwide burden of cancer in 2008GLOBOCAN2008rdquo International Journal of Cancer vol 127 no12 pp 2893ndash2917 2010

[178] R Siegel DNaishadham andA Jemal ldquoCancer statistics 2013rdquoCA Cancer Journal for Clinicians vol 63 pp 11ndash30 2013

[179] C J Ooi K M Fock G K Makharia et al ldquoThe Asia-Pacificconsensus on ulcerative colitisrdquo Journal of Gastroenterology andHepatology vol 25 no 3 pp 453ndash468 2010

[180] T Watanabe T Konishi J Kishimoto K Kotake T Mutoand K Sugihara ldquoUlcerative colitis-associated colorectal cancershows a poorer survival than sporadic colorectal cancer anationwide Japanese studyrdquo Inflammatory Bowel Diseases vol17 no 3 pp 802ndash808 2011

[181] T A Ullman and S H Itzkowitz ldquoIntestinal inflammation andcancerrdquo Gastroenterology vol 140 no 6 pp 1807ndash1816 2011

[182] R M Soetikno O S Lin P A Heidenreich H S Youngand M O Blackstone ldquoIncreased risk of colorectal neoplasia


in patiets with primary sclerosing cholangitis and ulcerativecolitis a meta-analysisrdquo Gastrointestinal Endoscopy vol 56 no1 pp 48ndash54 2002

[183] B Chassaing and A Darfeuillemichaud ldquoThe commensalmicrobiota and enteropathogens in the pathogenesis of inflam-matory bowel diseasesrdquo Gastroenterology vol 140 no 6 pp1720ndash1728 2011

[184] M de la Fuente L Franchi and D Araya ldquoEscherichia coliisolates from inflammatory bowel diseases patients survivein macrophages and activate NLRP3 inflammasomerdquo Interna-tional Journal of Medical Microbiology 2014

[185] M Sasaki S V Sitaraman B A Babbin et al ldquoInvasiveEscherichia coli are a feature of Crohnrsquos diseaserdquo LaboratoryInvestigation vol 87 no 10 pp 1042ndash1054 2007

[186] H Nakase H Tamaki M Matsuura T Chiba and K OkazakildquoInvolvement of Mycobacterium avium subspecies paratuber-culosis in TNF-120572 production from macrophage possible linkbetween MAP and immune response in Crohnrsquos diseaserdquoInflammatory Bowel Diseases vol 17 no 11 pp e140ndashe142 2011

[187] E Mizoguchi M Kanneganti and M Mino-Kenudson ldquoAni-mal models of colitis-associated carcinogenesisrdquo Journal ofBiomedicine and Biotechnology vol 2011 Article ID 342637 23pages 2011

[188] I Okayasu M Yamada T Mikami T Yoshida J Kannoand T Ohkusa ldquoDysplasia and carcinoma development in arepeated dextran sulfate sodium-induced colitismodelrdquo JournalofGastroenterology andHepatology vol 17 no 10 pp 1078ndash10832002

[189] H S Cooper SMurthy K Kido H Yoshitake andA FlaniganldquoDysplasia and cancer in the dextran sulfate sodium mousecolitis model Relevance to colitis-associated neoplasia in thehuman a study of histopathology B-catenin and p53 expressionand the role of inflammationrdquo Carcinogenesis vol 21 no 4 pp757ndash768 2000

[190] T Tanaka H Kohno R Suzuki Y Yamada S Sugie andH Mori ldquoA novel inflammation-related mouse colon carcino-genesis model induced by azoxymethane and dextran sodiumsulfaterdquo Cancer Science vol 94 no 11 pp 965ndash973 2003

[191] M Takahashi M Mutoh T Kawamori T Sugimura andK Wakabayashi ldquoAltered expression of 120573-catenin induciblenitric oxide synthase and cyclooxygenase-2 in azoxymethane-induced rat colon carcinogenesisrdquo Carcinogenesis vol 21 no 7pp 1319ndash1327 2000

[192] T Olsen R Goll G Cui et al ldquoTissue levels of tumor necrosisfactor-alpha correlates with grade of inflammation in untreatedulcerative colitisrdquo Scandinavian Journal of Gastroenterology vol42 no 11 pp 1312ndash1320 2007

[193] K Kusugami A Fukatsu M Tanimoto et al ldquoElevation ofinterleukin-6 in inflammatory bowel disease is macrophage-and epithelial cell-dependentrdquo Digestive Diseases and Sciencesvol 40 no 5 pp 949ndash959 1995

[194] B K Popivanova K Kitamura YWu et al ldquoBlocking TNF-120572 inmice reduces colorectal carcinogenesis associated with chroniccolitisrdquo Journal of Clinical Investigation vol 118 no 2 pp 560ndash570 2008

[195] D N Seril J Liao G-Y Yang and C S Yang ldquoOxidativestress and ulcerative colitis-associated carcinogenesis studies inhumans and animal modelsrdquo Carcinogenesis vol 24 no 3 pp353ndash362 2003

[196] S P Hussain P Amstad K Raja et al ldquoIncreased p53 mutationload in noncancerous colon tissue from ulcerative colitis a

cancer-prone chronic inflammatory diseaserdquo Cancer Researchvol 60 no 13 pp 3333ndash3337 2000

[197] H Tsushima S Kawata S Tamura et al ldquoHigh levels oftransforming growth factor in patients with colorectal cancerassociation with disease progressionrdquoGastroenterology vol 110no 2 pp 375ndash382 1996

[198] I C Lawrance L Maxwell and W Doe ldquoInflammation loca-tion but not type determines the increase in TGF-1205731 andIGF-1 expression and collagen deposition in IBD intestinerdquoInflammatory Bowel Diseases vol 7 no 1 pp 16ndash26 2001

[199] F Scaldaferri S Vetrano M Sans et al ldquoVEGF-A linksangiogenesis and inflammation in inflammatory bowel diseasepathogenesisrdquo Gastroenterology vol 136 no 2 pp 585ndash5952009

[200] M J Waldner S Wirtz A Jefremow et al ldquoVEGF receptorsignaling links inflammation and tumorigenesis in colitis-associated cancerrdquo Journal of Experimental Medicine vol 207no 13 pp 2855ndash2868 2010

[201] Y Kikuchi T G Kashima T Nishiyama et al ldquoPeriostinis expressed in pericryptal fibroblasts and cancer-associatedfibroblasts in the colonrdquo Journal of Histochemistry and Cyto-chemistry vol 56 no 8 pp 753ndash764 2008

[202] S Bao G Ouyang X Bai et al ldquoPeriostin potently promotesmetastatic growth of colon cancer by augmenting cell survivalvia the AktPKB pathwayrdquoCancer Cell vol 5 no 4 pp 329ndash3392004

[203] S Fujino A Andoh S Bamba et al ldquoIncreased expression ofinterleukin 17 in inflammatory bowel diseaserdquo Gut vol 52 no1 pp 65ndash70 2003

[204] Y S Hyun D S Han A R Lee C S Eun J Youn and H-YKim ldquoRole of IL-17A in the development of colitis-associatedcancerrdquo Carcinogenesis vol 33 no 4 pp 931ndash936 2012

[205] M A Farrar and R D Schreiber ldquoThe molecular cell biologyof interferon-120574 and its receptorrdquoAnnual Review of Immunologyvol 11 pp 571ndash611 1993

[206] A Harada N Sekido T Akahoshi T Wada N Mukaida andK Matsushima ldquoEssential involvement of interleukin-8 (IL-8)in acute inflammationrdquo Journal of Leukocyte Biology vol 56 no5 pp 559ndash564 1994

[207] R Daig T Andus E Aschenbrenner W Falk J Scholmerichand V Gross ldquoIncreased interleukin 8 expression in the colonmucosa of patients with inflammatory bowel diseaserdquo Gut vol38 no 2 pp 216ndash222 1996

[208] L Mazzucchelli C Hauser K Zgraggen et al ldquoExpression ofinterleukin-8 gene in inflammatory bowel disease is related tothe histological grade of active inflammationrdquoAmerican Journalof Pathology vol 144 no 5 pp 997ndash1007 1994

[209] M C Grimm S K O Elsbury P Pavli and W F DoeldquoInterleukin 8 cells of origin in inflammatory bowel diseaserdquoGut vol 38 no 1 pp 90ndash98 1996

[210] A LiM L Varney andR K Singh ldquoExpression of interleukin 8and its receptors in human colon carcinoma cells with differentmetastatic potentialsrdquoClinical Cancer Research vol 7 no 10 pp3298ndash3304 2001

[211] T Cacev S Radosevic S Krizanac and S Kapitanovic ldquoInflu-ence of interleukin-8 and interleukin-10 on sporadic coloncancer development and progressionrdquo Carcinogenesis vol 29no 8 pp 1572ndash1580 2008

[212] J Heidemann H Ogawa M B Dwinell et al ldquoAngiogeniceffects of interleukin 8 (CXCL8) in human intestinal microvas-cular endothelial cells are mediated by CXCR2rdquo Journal ofBiological Chemistry vol 278 no 10 pp 8508ndash8515 2003


[213] J E Everhart and C E Ruhl ldquoBurden of digestive diseases inthe United Statesmdashpart III liver biliary tract and pancreasrdquoGastroenterology vol 136 no 4 pp 1134ndash1144 2009

[214] Y Shaib and H B El-Serag ldquoThe epidemiology of cholangio-carcinomardquo Seminars in Liver Disease vol 24 no 2 pp 115ndash1252004

[215] B Sripa and C Pairojkul ldquoCholangiocarcinoma lessons fromThailandrdquo Current Opinion in Gastroenterology vol 24 no 3pp 349ndash356 2008

[216] G L Tyson and H B El-Serag ldquoRisk factors for cholangiocar-cinomardquo Hepatology vol 54 no 1 pp 173ndash184 2011

[217] J Fevery C Verslype G Lai R Aerts andW van SteenbergenldquoIncidence diagnosis and therapy of cholangiocarcinoma inpatients with primary sclerosing cholangitisrdquoDigestive Diseasesand Sciences vol 52 no 11 pp 3123ndash3135 2007

[218] P Charatcharoenwitthaya F B Enders K C Halling andK D Lindor ldquoUtility of serum tumor markers imaging andbiliary cytology for detecting cholangiocarcinoma in primarysclerosing cholangitisrdquo Hepatology vol 48 no 4 pp 1106ndash11172008

[219] K Burak P Angulo T M Pasha K Egan J Petz and K DLindor ldquoIncidence and risk factors for cholangiocarcinoma inprimary sclerosing cholangitisrdquo American Journal of Gastroen-terology vol 99 no 3 pp 523ndash526 2004

[220] V Bouvard R Baan K Straif et al ldquoA review of humancarcinogensmdashpart B biological agentsrdquo The Lancet Oncologyvol 10 no 4 pp 321ndash322 2009

[221] B Sripa J M Bethony P Sithithaworn et al ldquoOpisthorchiasisand Opisthorchis-associated cholangiocarcinoma in Thailandand Laosrdquo Acta Tropica vol 120 no 1 pp S158ndashS168 2011

[222] K L Min Y-H Ju S Franceschi et al ldquoClonorchis sinensisinfection and increasing risk of cholangiocarcinoma in therepublic of koreardquo American Journal of Tropical Medicine andHygiene vol 75 no 1 pp 93ndash96 2006

[223] X ZhouW Peng DW T Crompton and J Xiong ldquoTreatmentof biliary ascariasis in Chinardquo Transactions of the Royal Societyof Tropical Medicine and Hygiene vol 93 no 6 pp 561ndash5641999

[224] M Mukhopadhyay ldquoBiliary ascariasis in the Indian subconti-nent a study of 42 casesrdquo Saudi Journal of Gastroenterology vol15 no 2 pp 121ndash124 2009

[225] A M Di Bisceglie ldquoHepatitis B and hepatocellular carcinomardquoHepatology vol 49 no 5 pp S56ndashS60 2009

[226] T Y Lee S S Lee S W Jung et al ldquoHepatitis B virus infectionand intrahepatic cholangiocarcinoma in Korea a case-controlstudyrdquo American Journal of Gastroenterology vol 103 no 7 pp1716ndash1720 2008

[227] T Isa S Tomita A Nakachi et al ldquoAnalysis of microsatelliteinstability K-ras gene mutation and p53 protein overexpressionin intrahepatic cholangiocarcinomardquo Hepato-Gastroenterologyvol 49 no 45 pp 604ndash608 2002

[228] Y Wang Y Yamaguchi H Watanabe K Ohtsubo T Wak-abayashi and N Sawabu ldquoUsefulness of p53 gene mutations inthe supernatant of bile for diagnosis of biliary tract carcinomacomparison with K-ras mutationrdquo Journal of Gastroenterologyvol 37 no 10 pp 831ndash839 2002

[229] T Itoi K Takei Y Shinohara et al ldquoK-ras codon 12 andp53 mutations in biopsy specimens and bile from biliary tractcancersrdquo Pathology International vol 49 no 1 pp 30ndash37 1999

[230] S-I Aishima K-I Taguchi K Sugimachi M Shimada KSugimachi andM Tsuneyoshi ldquoc-erbB-2 and c-Met expression

relates to cholangiocarcinogenesis and progression of intrahep-atic cholangiocarcinomardquo Histopathology vol 40 no 3 pp269ndash278 2002

[231] A C Okaro A R Deery R R Hutchins and B R DavidsonldquoThe expression of antiapoptotic proteins Bcl-2 Bcl-xL andMcl-1 in benign dysplastic and malignant biliary epitheliumrdquoJournal of Clinical Pathology vol 54 no 12 pp 927ndash932 2001

[232] M Taniai H Higuchi L J Burgart and G J Gores ldquop16INK4apromoter mutations are frequent in primary sclerosing cholan-gitis (PSC) and PSC-associated cholangiocarcinomardquoGastroen-terology vol 123 no 4 pp 1090ndash1098 2002

[233] S Boonjaraspinyo Z Wu T Boonmars et al ldquoOverexpres-sion of PDGFA and its receptor during carcinogenesis ofOpisthorchis viverrini-associated cholangiocarcinomardquo Para-sitology International vol 61 no 1 pp 145ndash150 2012

[234] S Boonjaraspinyo T Boonmars Z Wu et al ldquoPlatelet-derivedgrowth factor may be a potential diagnostic and prognosticmarker for cholangiocarcinomardquo Tumor Biology vol 33 no 5pp 1785ndash1802 2012

[235] D J Drucker ldquoBiological actions and therapeutic potential ofthe glucagon-like peptidesrdquoGastroenterology vol 122 no 2 pp531ndash544 2002

[236] M Marzioni G Alpini S Saccomanno et al ldquoGlucagon-likepeptide-1 and its receptor agonist exendin-4 modulate cholan-giocyte adaptive response to cholestasisrdquo Gastroenterology vol133 no 1 pp 244ndash255 2007

[237] E Gaudio B Barbaro D Alvaro et al ldquoVascular endothelialgrowth factor stimulates rat cholangiocyte proliferation via anautocrine mechanismrdquo Gastroenterology vol 130 no 4 pp1270ndash1282 2006

[238] E Gaudio B Barbaro D Alvaro et al ldquoAdministration ofr-VEGF-A prevents hepatic artery ligation-induced bile ductdamage in bile duct ligated ratsrdquoAmerican Journal of PhysiologyGastrointestinal and Liver Physiology vol 291 no 2 pp G307ndashG317 2006

[239] A E Sirica M H Nathanson G J Gores and N F LaRussoldquoPathobiology of biliary epithelia and cholangiocarcinomaproceedings of theHenryM and Lillian StrattonBasic ResearchSingle-Topic Conferencerdquo Hepatology vol 48 no 6 pp 2040ndash2046 2008

[240] D Hanahan and L M Coussens ldquoAccessories to the crimefunctions of cells recruited to the tumor microenvironmentrdquoCancer Cell vol 21 no 3 pp 309ndash322 2012

[241] C Chuaysri P Thuwajit A Paupairoj S Chau-In TSuthiphongchai and C Thuwajit ldquoAlpha-smooth muscleactin-positive fibroblasts promote biliary cell proliferation andcorrelate with poor survival in cholangiocarcinomardquo OncologyReports vol 21 no 4 pp 957ndash969 2009

[242] K Utispan PThuwajit Y Abiko et al ldquoGene expression profil-ing of cholangiocarcinoma-derived fibroblast reveals alterationsrelated to tumor progression and indicates periostin as a poorprognostic markerrdquoMolecular Cancer vol 9 article 13 2010

[243] A E Sirica ldquoThe role of cancer-associated myofibroblasts inintrahepatic cholangiocarcinomardquo Nature Reviews Gastroen-terology and Hepatology vol 9 no 1 pp 44ndash54 2012

[244] S Rizvi and G J Gores ldquoPathogenesis diagnosis and manage-ment of cholangiocarcinomardquo Gastroenterology vol 145 no 6pp 1215ndash1229 2013

[245] A E SiricaD J Campbell andC I Dumur ldquoCancer-associatedfibroblasts in intrahepatic cholangiocarcinomardquo Current Opin-ion in Gastroenterology vol 27 no 3 pp 276ndash284 2011

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


the innate and adaptive immune system The main purposeof this inflammatory response is to remove the foreign agentdisturbing tissue homeostasis [5] In the normal physiologicalcontext after tissue repair or pathogen elimination theinflammation is resolved and the homeostatic state recovered[6]

It is now widely accepted that inadequately resolvedchronic inflammationmay increase the risk of cancer Severalpathologies illustrate this link such as endometriosis chronicprostatitis and chronic gastritis due to Helicobacter pylori(H pylori) inflammatory bowel diseases (IBD) and primarysclerosing cholangitis (PSC) (Table 1) Inflammation canincrease the risk of cancer by providing bioactive moleculesfrom cells infiltrating the tumor microenvironment includ-ing cytokines growth factors chemokines that maintain asustained proliferative rate cell survival signals to avoidapoptosis proangiogenic factors and extracellular matrix-modifying enzymes such as metalloproteinases that promoteepithelial-mesenchymal transition (EMT) and facilitate othercarcinogenesis programs such as genome instability repro-gramming of energy metabolism and immune evasion [7]Here we focus on key cytokines involved in tumor inductionand their role in EMT angiogenesis invasion andmetastasis

3 Cytokines Involved in Tumor Development

Cytokines are low-molecular-weight proteins that mediatecell-to-cell communication Immune and stromal cells suchas fibroblasts and endothelial cells synthesize them and theyregulate proliferation cell survival differentiation immunecell activation cell migration and death Depending on thetumormicroenvironment cytokines canmodulate an antitu-moral response but during chronic inflammation they canalso induce cell transformation and malignancy conditionalon the balance of pro- and anti-inflammatory cytokines theirrelative concentrations cytokine receptor expression contentand the activation state of surrounding cells [50]

31 Tumor Necrosis Factor (TNF-120572) As noted unresolvedinflammation can lead to malignancy Tumor necrosis factor(TNF-120572) is one inflammatory mediator that has been impli-cated in carcinogenesis due to its participation in chronicinflammatory diseases [51] Moore et al provided evidencethat TNF-120572-deficient mice are resistant to tetradecanoyl-phorbol-13-acetate- (TPA-) induced skin carcinogenesisTNF-120572 effect seems to be more significant in the earlystages of carcinogenesis including angiogenesis and invasionversus progression of carcinogenesis [52 53]While TNF-120572 isa prototypical proinflammatory cytokine evidence suggestsa double-edged role in carcinogenesis This cytokine isrecognized by two receptors TNF-120572 receptor-1 (TNF-120572R-1) ubiquitously expressed and TNF-120572R-2 expressed mainlyin immune cells [54] Trimerization occurs upon TNF-120572binding to TNF-120572-Rs leading to activation of at least four sig-naling pathways a proapoptotic pathway induced by caspase-8 interaction with Fas-associated death domain (FADD)an antiapoptotic platform activated by cellular inhibitor ofapoptosis protein-1 (cIAP-1) and interacting with TNF-120572R-associated factor 2 (TRAF2) a TRAF2- and JNK-mediated

AP-1 signaling pathway and a receptor interacting protein-(RIP-) induced NF-120581B [54]

There is controversy however regarding the role of TNF-120572 in cancer high concentrations of this cytokine can inducean antitumoral response in a murine model of sarcoma [55]FurthermoreWilliamB Coley a pioneer surgeon in the fielddiscovered that there was a reliable treatment response forsystemic bacterial filtrate injection in sarcoma patients [5556] However severe toxic side effects have been associatedwith systemically administered TNF-120572 such as hypotensionand organ failure [57] Local administration has been shownto be safer and effective as demonstrated by clinical trialsevaluating a TNF-120572-expressing adenovirus (TNFerade) genetherapy combined with chemotherapy [58 59] MoreoverTNF-120572-conjugate targeting peptides or single-chain antibodyfragments have also shown variable effects depending on thepatient [60]

In contrast low sustained TNF-120572 production levels caninduce a tumor phenotype [61] A TNF-120572 tumor promotionmechanism is based on reactive oxygen species (ROS) andreactive nitrogen species (RNS) generation which can induceDNAdamage hence facilitating tumorigenesis [62 63] TNF-120572-mediated inflammation has been linked to cancer forinstance increasedTNF-120572 levels in preneoplastic lesions havebeen detected inH pylori-positive gastric lesions throughHpylori-secreted TNF-120572-inducing protein (Tip120572) [64 65]

A study by Kwong et al explored TNF-120572-associatedtumorigenesis using an organoid of normal human ovarianepithelial cells exposed to a prolonged TNF-120572 dose Themodel demonstrated generation of a precancerous-like phe-notype with structural and functional changes such as tissuedisorganization epithelial polarity loss cell invasion andoverexpression of cancer markers [66]

According to these findings the pro- or antitumoral TNF-120572 response within the tumor microenvironment depends notonly on local concentration but also on its expression site inthe tumor Patients with elevated levels of TNF-120572 in tumorislets from non-small cell lung cancer mainly restricted tomacrophages and mast cells showed the highest survivalrates while patients with increased stromal TNF-120572 contentshowed lower survival rates [67]

There is also evidence that prolonged TNF-120572 exposurecan enhance the proportion of cancer stem cell phenotypesin oral squamous cell carcinoma increasing their tumor-forming sphere ability stem cell-transcription factor expres-sion and tumorigenicity [68]

32 Interleukin 6 (IL-6) Another proinflammatory cytokinewith a typical protumorigenic effect is IL-6 Elevated serumIL-6 levels have been detected in patients with systemiccancers as compared to healthy controls or patients withbenign diseases IL-6 has been proposed as a malignancypredictor with sensitivity and specificity of about 60ndash70and 58ndash90 respectively [69] However there are limitedstudies available that might be used to define cut-off valuesfor IL-6 as a diagnostic tool

IL-6 plays a key role in promoting proliferation andinhibition of apoptosis by binding to its receptor (IL-6R120572)























2


2

O2


2


2

O3








Injury orinfection

IL-6IL-8

Chemotaxis

Lymphocyte


RONS

TNF-120572

(a)

Th1

IL-10 TGF-120573

IFN-120574

DNA damage

RONS

NeutrophilTh17IL-17

Th2



IL-8

Disruptedepithelial

barrier

M2 M120601 M1 M120601

(b)

Th1IFN-120574

Th17IL-17

IL-10

Th2

fibroblast


IL-10

VEGFIL-8

M2 MΦ MMP-2TGF-120573 TGF-120573

120572-SMA+

(c)

TILsTAMs

CAFs


HGFTenascin-cCXCL12

IL-17

TGF-120573

(d)























































TNF-120572



IFN-120574



IL-6



TGF-120573



IL-8





IL-17




Table 2 Continued


IL-21






















7 Conclusion












Acknowledgments


References






































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






































2


2

O2


2


2

O3








Injury orinfection

IL-6IL-8

Chemotaxis

Lymphocyte


RONS

TNF-120572

(a)

Th1

IL-10 TGF-120573

IFN-120574

DNA damage

RONS

NeutrophilTh17IL-17

Th2



IL-8

Disruptedepithelial

barrier

M2 M120601 M1 M120601

(b)

Th1IFN-120574

Th17IL-17

IL-10

Th2

fibroblast


IL-10

VEGFIL-8

M2 MΦ MMP-2TGF-120573 TGF-120573

120572-SMA+

(c)

TILsTAMs

CAFs


HGFTenascin-cCXCL12

IL-17

TGF-120573

(d)























































TNF-120572



IFN-120574



IL-6



TGF-120573



IL-8





IL-17




Table 2 Continued


IL-21






















7 Conclusion












Acknowledgments


References






































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















Injury orinfection

IL-6IL-8

Chemotaxis

Lymphocyte


RONS

TNF-120572

(a)

Th1

IL-10 TGF-120573

IFN-120574

DNA damage

RONS

NeutrophilTh17IL-17

Th2



IL-8

Disruptedepithelial

barrier

M2 M120601 M1 M120601

(b)

Th1IFN-120574

Th17IL-17

IL-10

Th2

fibroblast


IL-10

VEGFIL-8

M2 MΦ MMP-2TGF-120573 TGF-120573

120572-SMA+

(c)

TILsTAMs

CAFs


HGFTenascin-cCXCL12

IL-17

TGF-120573

(d)























































TNF-120572



IFN-120574



IL-6



TGF-120573



IL-8





IL-17




Table 2 Continued


IL-21






















7 Conclusion












Acknowledgments


References






































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of































































TNF-120572



IFN-120574



IL-6



TGF-120573



IL-8





IL-17




Table 2 Continued


IL-21






















7 Conclusion












Acknowledgments


References






































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table 2 Continued


IL-21






















7 Conclusion












Acknowledgments


References






































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























7 Conclusion












Acknowledgments


References






































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























Acknowledgments


References






































































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article chronic inflammation and cytokines in the...

Documents