Mechanisms of Immune Signaling in Colitis-Associated Cancer

The inflammatory bowel diseases ulcerative colitis and Crohn's disease are associated with an increased risk for the development of colorectal cancer. During recent years, several immune signaling pathways have been linked to colitis-associated cancer (CAC), largely owing to the availability of suitable preclinical models. Among these, chronic intestinal inflammation has been shown to support tumor initiation through oxidative stress–induced mutations. A proinflammatory microenvironment that develops, possibly as a result of defective intestinal barrier function and host–microbial interactions, enables tumor promotion. Several molecular pathways such as tumor necrosis factor/nuclear factor-κB or interleukin 6/signal transducer and activator of transcription 3 signaling have been identified as important contributors to CAC development and could be promising therapeutic targets for the prevention and treatment of CAC. The inflammatory bowel diseases ulcerative colitis and Crohn's disease are associated with an increased risk for the development of colorectal cancer. During recent years, several immune signaling pathways have been linked to colitis-associated cancer (CAC), largely owing to the availability of suitable preclinical models. Among these, chronic intestinal inflammation has been shown to support tumor initiation through oxidative stress–induced mutations. A proinflammatory microenvironment that develops, possibly as a result of defective intestinal barrier function and host–microbial interactions, enables tumor promotion. Several molecular pathways such as tumor necrosis factor/nuclear factor-κB or interleukin 6/signal transducer and activator of transcription 3 signaling have been identified as important contributors to CAC development and could be promising therapeutic targets for the prevention and treatment of CAC. SummaryThis review discusses recent data on immune signaling pathways involved in the pathogenesis of colitis-associated cancer. These include molecular mechanisms activating the innate and adaptive immune system and thereby contributing to cancer initiation and promotion in inflammatory bowel diseases.Concepts about inflammation-associated cancer development go back to Rudolph Virchow's observation of increased immune cell infiltration at tumor sites more than 150 years ago.1Balkwill F. Mantovani A. Inflammation and cancer: back to Virchow?.Lancet. 2001; 357: 539-545Abstract Full Text Full Text PDF PubMed Scopus (5803) Google Scholar Today, inflammatory conditions including infection and immune-mediated disease increase the risk of cancer. Well-known examples in the gastrointestinal tract are the increased risk for gastric cancer and gastric lymphoma in Helicobacter pylori infection and the increased risk for colorectal cancer (CRC) in inflammatory bowel disease (IBD).2Terzic J. Grivennikov S. Karin E. et al.Inflammation and colon cancer.Gastroenterology. 2010; 138: 2101-2114 e5Abstract Full Text Full Text PDF PubMed Scopus (1377) Google Scholar This review discusses recent data on immune signaling pathways involved in the pathogenesis of colitis-associated cancer. These include molecular mechanisms activating the innate and adaptive immune system and thereby contributing to cancer initiation and promotion in inflammatory bowel diseases. The first reports of colorectal cancer in IBD patients occurred in the early 1900s, when Crohn and Rosenberg3Crohn B. Rosenberg H. The sigmoidoscopic picture of chronic ulcerative colitis (non-specific).Am J Med Sci. 1925; 170: 220-228Crossref Google Scholar described a case of colonic adenocarcinoma in a patient with long-term ulcerative colitis (UC). The CRC risk in IBD patients initially was attributed mostly to UC and not to Crohn's disease (CD) because epidemiologic studies in the 1960s had proposed an up to 10 times greater CRC risk in UC, but not in CD, patients in comparison with the general population.4Morson B.C. Cancer in ulcerative colitis.Gut. 1966; 7: 425-426Crossref PubMed Scopus (47) Google Scholar Disease extent and duration are regarded as the most important parameters affecting the individual CRC risk in patients with UC. Recent data also have shown an association between the degree of inflammation and the development of colonic neoplasia.5Rubin D.T. Huo D. Kinnucan J.A. et al.Inflammation is an independent risk factor for colonic neoplasia in patients with ulcerative colitis: a case-control study.Clin Gastroenterol Hepatol. 2013; 11 (e1–4): 1601-1608Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 6Nieminen U. Jussila A. Nordling S. et al.Inflammation and disease duration have a cumulative effect on the risk of dysplasia and carcinoma in IBD: a case-control observational study based on registry data.Int J Cancer. 2014; 134: 189-196Crossref PubMed Scopus (62) Google Scholar Additional risk factors include primary sclerosing cholangitis and a family history of CRC.7Lakatos P.L. Lakatos L. Risk for colorectal cancer in ulcerative colitis: changes, causes and management strategies.World J Gastroenterol. 2008; 14: 3937-3947Crossref PubMed Scopus (282) Google Scholar Together, the cumulative risk for CRC in UC patients has been reported as 1.6% after 10 years, 8.3% after 20 years, and 18.4% after 30 years of disease duration.8Eaden J.A. Abrams K.R. Mayberry J.F. The risk of colorectal cancer in ulcerative colitis: a meta-analysis.Gut. 2001; 48: 526-535Crossref PubMed Scopus (2217) Google Scholar Because these data are based on studies from academic centers, which frequently have patients with more severe disease, true incidence rates may be lower. For instance, Jess et al9Jess T. Rungoe C. Peyrin-Biroulet L. Risk of colorectal cancer in patients with ulcerative colitis: a meta-analysis of population-based cohort studies.Clin Gastroenterol Hepatol. 2012; 10: 639-645Abstract Full Text Full Text PDF PubMed Scopus (562) Google Scholar reported a 2.4-fold increased risk for CRC in UC patients after 15 years of disease in a meta-analysis of population-based cohort studies. In contrast to UC, the influence of CD on CRC risk has been under debate for many decades. Although several cases of CRC were reported in CD patients beginning in the 1950s, subsequent studies could not detect increased incidence rates in comparison with the general population.10Jones J.H. Colonic cancer and Crohn's disease.Gut. 1969; 10: 651-654Crossref PubMed Scopus (52) Google Scholar Recent studies have reported that the risk for CRC in patients with CD patients depends on large-bowel involvement. Similar to UC, the extent and duration of colonic inflammation are the most important risk factors for CRC development in CD patients. In this regard, the cumulative risk for CRC in CD patients has been reported to be 2.9%, 5.6%, and 8.3% after 10, 20, and 30 years of disease, respectively, in a meta-analysis.11Canavan C. Abrams K.R. Mayberry J. Meta-analysis: colorectal and small bowel cancer risk in patients with Crohn's disease.Aliment Pharmacol Ther. 2006; 23: 1097-1104Crossref PubMed Scopus (432) Google Scholar Again, these data are based on studies from academic centers and therefore may overstate the actual incidence rates in patients with CD. Because of the availability of reasonable preclinical models, our knowledge regarding the molecular mechanisms connecting inflammation and cancer development in colitis-associated cancer (CAC) has increased rapidly in recent years. Chronic inflammation has been linked to tumor initiation, in which normal cells acquire genomic alterations that initiate tumorigenesis, as well as promotion driven by the sustained proliferation of initiated cells.12Philip M. Rowley D.A. Schreiber H. Inflammation as a tumor promoter in cancer induction.Semin Cancer Biol. 2004; 14: 433-439Crossref PubMed Scopus (479) Google Scholar This review discusses recent progress in understanding immune signaling pathways involved in these steps during colitis-associated cancer development. For tumor initiation, distinct mutations of oncogenes or tumor-suppressor genes are required to allow subsequent tumor development. These include mutations that result in resistance to apoptosis as well as acquisition of malignant potential. Mutations involved in the initiation of sporadic colorectal carcinoma have been well characterized and accumulate along the individual steps of described adenoma–carcinoma sequence pathways.13Fearon E.R. Vogelstein B. A genetic model for colorectal tumorigenesis.Cell. 1990; 61: 759-767Abstract Full Text PDF PubMed Scopus (9839) Google Scholar, 14Vogelstein B. Fearon E.R. Hamilton S.R. et al.Genetic alterations during colorectal-tumor development.N Engl J Med. 1988; 319: 525-532Crossref PubMed Scopus (5816) Google Scholar Similarly, a sequence of distinct mutations occurs during the stepwise development of colitis-associated cancer. This can be referred to as the inflammation–dysplasia–carcinoma pathway, which describes the development of low-grade dysplasia in a background of intestinal inflammation, with subsequent progression to high-grade dysplasia, and, finally, invasive carcinoma.15Zisman T.L. Rubin D.T. Colorectal cancer and dysplasia in inflammatory bowel disease.World J Gastroenterol. 2008; 14: 2662-2669Crossref PubMed Scopus (116) Google Scholar Notably, not all lesions follow this stepwise evolution. Because the tumorigenic pathway and individual genes affected differ between sporadic and colitis-associated CRC, it is reasonable to propose that the mechanisms inducing these mutations also differ. Mutations in sporadic CRC have been attributed to several kinds of genomic and epigenetic instability including chromosomal instability, CpG island methylator phenotype, global hypomethylation, and mutations in mismatch repair genes that lead to microsatellite instability.16Waldner M.J. Neurath M.F. Potential avenues for immunotherapy of colitis-associated neoplasia.Immunotherapy. 2012; 4: 397-405Crossref PubMed Scopus (6) Google Scholar Although these genomic and epigenetic alterations also occur in CAC,17Ullman T.A. Itzkowitz S.H. Intestinal inflammation and cancer.Gastroenterology. 2011; 140: 1807-1816Abstract Full Text Full Text PDF PubMed Scopus (754) Google Scholar growing evidence supports a central role for inflammation-dependent oxidative stress in the induction of mutations that lead to CAC. Oxidative stress occurs as an imbalance of the generation and elimination of reactive oxygen and nitrogen species (RONS).18Gorrini C. Harris I.S. Mak T.W. Modulation of oxidative stress as an anticancer strategy.Nat Rev Drug Discov. 2013; 12: 931-947Crossref PubMed Scopus (2076) Google Scholar Increased oxidative stress is one of the key features of chronic inflammation because cells of the innate immune system release various kinds of RONS including superoxide, hydrogen peroxide, singlet oxygen, hydroxyl radicals, and nitric oxide into the tissue microenvironment on activation. These RONS interact with the DNA of resident cells and induce various forms of DNA damage including single- and double-strand breaks, abasic sites, and nucleotide modification, all of which contribute to tumor initiation when they affect oncogenes or tumor-suppressor genes.19Jackson A.L. Loeb L.A. The contribution of endogenous sources of DNA damage to the multiple mutations in cancer.Mutat Res. 2001; 477: 7-21Crossref PubMed Scopus (505) Google Scholar In human IBD, studies have shown that increased RONS correlates with disease activity, as well as reduced antioxidant levels. For instance, 8-oxo-7,8-dihydro-2,-deoxyguanosine, an oxidative stress–dependent base modification, is common in inflamed and dysplastic tissue, but not in healthy mucosa.20D'Inca R. Cardin R. Benazzato L. et al.Oxidative DNA damage in the mucosa of ulcerative colitis increases with disease duration and dysplasia.Inflamm Bowel Dis. 2004; 10: 23-27Crossref PubMed Scopus (86) Google Scholar Similarly, concentrations of nitric oxide are increased and correlate with oxidative damage in tissue samples of active and even inactive IBD.21Keshavarzian A. Banan A. Farhadi A. et al.Increases in free radicals and cytoskeletal protein oxidation and nitration in the colon of patients with inflammatory bowel disease.Gut. 2003; 52: 720-728Crossref PubMed Scopus (185) Google Scholar To repair reactive oxygen species-induced mutations, the DNA damage response (DDR) is activated, which comprises various mechanisms including direct repair, nucleotide excision repair, and others (see the article by Curtin22Curtin N.J. DNA repair dysregulation from cancer driver to therapeutic target.Nat Rev Cancer. 2012; 12: 801-817Crossref PubMed Scopus (667) Google Scholar for a review). Furthermore, the DDR can regulate cellular proliferation through activation of premature cellular senescence, an irreversible arrest of cell-cycle progression that protects against the amplification of defective DNA and proliferation of mutant clones.23Nardella C. Clohessy J.G. Alimonti A. et al.Pro-senescence therapy for cancer treatment.Nat Rev Cancer. 2011; 11: 503-511Crossref PubMed Scopus (333) Google Scholar Senescence occurs in various precancerous lesions, and evasion as a result of mutations in senescence-associated genes has been regarded as a requirement for malignant transformation. In IBD, Sohn et al24Sohn J.J. Schetter A.J. Yfantis H.G. et al.Macrophages, nitric oxide and microRNAs are associated with DNA damage response pathway and senescence in inflammatory bowel disease.PLoS One. 2012; 7: e44156Crossref PubMed Scopus (49) Google Scholar found an increase of DDR (Histon gamma H2A.X, phospho-checkpoint kinase 2) and senescence (Heterochromatin protein 1 gamma) markers in inflamed tissue samples from IBD patients. In UC samples, increased DDR and senescence correlated with infiltration of macrophages as a possible source of RONS. Supporting the activation of senescence as a protective mechanism against malignant transformation in CAC, high levels of senescence markers have been reported in low-grade dysplasia in comparison with nondysplastic inflamed tissues and also high-grade dysplasia of UC patients, proposing an evasion of senescence during the progression from low- to high-grade dysplasia.25Risques R.A. Lai L.A. Brentnall T.A. et al.Ulcerative colitis is a disease of accelerated colon aging: evidence from telomere attrition and DNA damage.Gastroenterology. 2008; 135: 410-418Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 26Risques R.A. Lai L.A. Himmetoglu C. et al.Ulcerative colitis-associated colorectal cancer arises in a field of short telomeres, senescence, and inflammation.Cancer Res. 2011; 71: 1669-1679Crossref PubMed Scopus (96) Google Scholar Evidence for the pathogenic role of oxidative stress and protection afforded by the DDR is provided by preclinical studies using CAC models. Meira et al27Meira L.B. Bugni J.M. Green S.L. et al.DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice.J Clin Invest. 2008; 118: 2516-2525PubMed Google Scholar showed that mice deficient in alkyladenine DNA glycosylase, an enzyme involved in base excision repair, developed more DNA base lesions and higher numbers of tumors in the widely used azoxymethane–dextran sodium sulfate (AOM-DSS) model of CAC. In the same model, mice deficient in the transcription factor nuclear factor-erythroid 2–related factor 2, which regulates genes involved in antioxidant signaling pathways, also had increased numbers of aberrant crypt foci.28Osburn W.O. Karim B. Dolan P.M. et al.Increased colonic inflammatory injury and formation of aberrant crypt foci in Nrf2-deficient mice upon dextran sulfate treatment.Int J Cancer. 2007; 121: 1883-1891Crossref PubMed Scopus (158) Google Scholar Furthermore, mice lacking the glutathione peroxidase Glutathione peroxidase 3, which is regulated by nuclear factor-erythroid 2–related factor 2 and acts as a redox enzyme, develop more tumors with higher grades of dysplasia in the AOM-DSS model.29Barrett C.W. Ning W. Chen X. et al.Tumor suppressor function of the plasma glutathione peroxidase gpx3 in colitis-associated carcinoma.Cancer Res. 2013; 73: 1245-1255Crossref PubMed Scopus (117) Google Scholar GPX3-deficient mice even developed polyps after DSS treatment without AOM, indicating that increased oxidative stress without an effective DDR is sufficient for tumor initiation. After tumor initiation, the proinflammatory microenvironment also contributes to tumor promotion. Inflammation occurring as a response to infection or tissue damage removes dead cells and promotes restoration of tissue integrity via stem cell and myofibroblast activation, cell proliferation, angiogenesis, and other processes. Because of the overlap between mechanisms involved in wound healing and tumorigenesis, tumors have been described as "wounds that do not heal."30Dvorak H.F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing.N Engl J Med. 1986; 315: 1650-1659Crossref PubMed Scopus (3442) Google Scholar In fact, chronic inflammation can result in excessive tissue regeneration and thereby enhance the promotion and progression of initiated tumor cells.31Kuraishy A. Karin M. Grivennikov S.I. Tumor promotion via injury- and death-induced inflammation.Immunity. 2011; 35: 467-477Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar During recent years, major proinflammatory pathways have been implicated in inflammation-associated tumor development. Among these, the group of nuclear factor-κB (NF-κB) transcription factors takes center stage. NF-κB transcription factors comprise dimers of the subunits RelA (p65), c-Rel, RelB, p50/NF-κB1, and p52/NF-κB2.32Karin M. Nuclear factor-kappaB in cancer development and progression.Nature. 2006; 441: 431-436Crossref PubMed Scopus (2913) Google Scholar In a resting state, NF-κB dimers are bound to specific inhibitors (Iκ) within the cytoplasm. Two signaling pathways leading to NF-κB activation have been reported. In the classic pathway, proinflammatory stimuli including tumor necrosis factor α (TNFα), interleukin 1 (IL1), lipopolysaccharide (LPS), and CD40 ligand lead to activation of the IκB kinase (IKK) subunits IKK-α, IKK-β, and IKK-γ (NF-kappa-B essential modulator), which together target IκB proteins for proteosomal degradation. Subsequently, unbound NF-κB dimers (primarily RelA/p50) translocate to the nucleus and initiate transcription of target genes. The alternative pathway largely is dependent on activation by lymphotoxin α/β and CD40L, but not TNFα, IL1, or LPS. Alternative pathway activation leads to the conversion of p100 to p52 via IKK-α–dependent phosphorylation and subsequent proteosomal cleavage. The resulting p52/RelB heterodimers translocate to the nucleus and lead to target gene transcription (for review see the article by Karin et al33Karin M. Yamamoto Y. Wang Q.M. The IKK NF-kappa B system: a treasure trove for drug development.Nat Rev Drug Discov. 2004; 3: 17-26Crossref PubMed Scopus (1214) Google Scholar). Both pathways of NF-κB activation lead to increased expression of genes involved in the regulation of cell-cycle progression, apoptosis, and other cancer-relevant signaling pathways. In CAC, the initial evidence for the functional relevance of NF-κB signaling was provided in a preclinical study by Greten et al,34Greten F.R. Eckmann L. Greten T.F. et al.IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer.Cell. 2004; 118: 285-296Abstract Full Text Full Text PDF PubMed Scopus (2048) Google Scholar which showed that deletion of IKK-β in intestinal epithelial cells resulted in decreased numbers of tumors, increased apoptosis, and defective Bcl-Xl signaling. In contrast, deletion of IKK-β in myeloid cells led to diminished tumor size along with reduced expression of proinflammatory cytokines including IL1β, TNFα, and IL6 in the AOM-DSS model. These data suggest that tumor cell–specific NF-κB activation is required for inflammation-associated tumor initiation, and NF-κB activation in myeloid cells contributes to tumor promotion and progression. In line with these data, mice with constitutive activation of IKK-β in intestinal epithelial cells and germline deletion of the tumor-suppressor gene adenomatous polyposis coli (APC) show enhanced tumor development with marked DNA damage and DDR activation.35Shaked H. Hofseth L.J. Chumanevich A. et al.Chronic epithelial NF-kappaB activation accelerates APC loss and intestinal tumor initiation through iNOS up-regulation.Proc Natl Acad Sci U S A. 2012; 109: 14007-14012Crossref PubMed Scopus (112) Google Scholar Because differences in tumor load were largely dependent on tumor numbers, and tumors even developed spontaneously in mice with constitutively active IKK-β (even without APC loss), these data again highlight the central roles of epithelial NF-κB activation and oxidative stress in tumor initiation. Interestingly, a study by Cooks et al36Cooks T. Pateras I.S. Tarcic O. et al.Mutant p53 prolongs NF-kappaB activation and promotes chronic inflammation and inflammation-associated colorectal cancer.Cancer Cell. 2013; 23: 634-646Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar found increased NF-κB signaling in mice with a gain-of-function mutation of TP53. The p53 protein generally acts as a mediator of cellular senescence by triggering cell-cycle arrest. Mutations affecting TP53 occur at late stages of sporadic CRC, usually resulting in loss of p53 function, bypass of senescence, and infiltrative and metastatic tumor growth.37Collado M. Serrano M. Senescence in tumours: evidence from mice and humans.Nat Rev Cancer. 2010; 10: 51-57Crossref PubMed Scopus (761) Google Scholar, 38Schwitalla S. Ziegler P.K. Horst D. et al.Loss of p53 in enterocytes generates an inflammatory microenvironment enabling invasion and lymph node metastasis of carcinogen-induced colorectal tumors.Cancer Cell. 2013; 23: 93-106Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar In contrast to sporadic CRC, TP53 mutations occur at early steps of CAC, before infiltrative or metastatic tumor growth. Therefore, the functional role of TP53 mutations at early steps of CAC has been controversial. The data discussed earlier suggest that gain-of-function mutations in TP53 at early steps of CAC development enhance NF-κB signaling in tumor cells.36Cooks T. Pateras I.S. Tarcic O. et al.Mutant p53 prolongs NF-kappaB activation and promotes chronic inflammation and inflammation-associated colorectal cancer.Cancer Cell. 2013; 23: 634-646Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar Despite these advances, very few studies have analyzed NF-κB signaling in human CAC.39Andresen L. Jorgensen V.L. Perner A. et al.Activation of nuclear factor kappaB in colonic mucosa from patients with collagenous and ulcerative colitis.Gut. 2005; 54: 503-509Crossref PubMed Scopus (149) Google Scholar, 40Kojima M. Morisaki T. Sasaki N. et al.Increased nuclear factor-kB activation in human colorectal carcinoma and its correlation with tumor progression.Anticancer Res. 2004; 24: 675-681PubMed Google Scholar Because of its central role in maintaining chronic inflammation in IBD, TNFα signaling has been proposed as a tumor-promoting mechanism in CAC. The contribution of TNFα to IBD is highlighted by the efficacy of anti-TNFα therapeutics that now routinely are used to treat IBD patients.41Bradley J.R. TNF-mediated inflammatory disease.J Pathol. 2008; 214: 149-160Crossref PubMed Scopus (1258) Google Scholar TNFα, which is expressed as pro-TNF on the plasma membrane of myeloid and T cells, is released after cleavage by converting enzymes such as ADAM-17. Soluble TNFα then binds to 1 of 2 receptors: TNF-Rp55 (TNFR1) or TNF-Rp75 (TNFR2).41Bradley J.R. TNF-mediated inflammatory disease.J Pathol. 2008; 214: 149-160Crossref PubMed Scopus (1258) Google Scholar Although activation of TNFR1 results in apoptosis via caspase-3 activation, activation of TNFR2 promotes cell survival via activation of NF-κB and other signaling pathways.42Faustman D. Davis M. TNF receptor 2 pathway: drug target for autoimmune diseases.Nat Rev Drug Discov. 2010; 9: 482-493Crossref PubMed Scopus (302) Google Scholar Although TNF initially was discovered and named as a factor that induces tumor necrosis, it now has been implicated in the pathogenesis of inflammation-associated cancer, likely as a consequence of proinflammatory signaling. Functional evidence for this concept has been provided by preclinical studies using the AOM-DSS CAC model. TNFR2 expression is up-regulated on intestinal epithelial cells in adoptive transfer and DSS colitis,43Onizawa M. Nagaishi T. Kanai T. et al.Signaling pathway via TNF-alpha/NF-kappaB in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis.Am J Physiol Gastrointest Liver Physiol. 2009; 296: G850-G859Crossref PubMed Scopus (124) Google Scholar, 44Su L. Nalle S.C. Shen L. et al.TNFR2 activates MLCK-dependent tight junction dysregulation to cause apoptosis-mediated barrier loss and experimental colitis.Gastroenterology. 2013; 145: 407-415Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar and increased NF-κB signaling after TNFR2 activation in the AOM-DSS model.43Onizawa M. Nagaishi T. Kanai T. et al.Signaling pathway via TNF-alpha/NF-kappaB in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis.Am J Physiol Gastrointest Liver Physiol. 2009; 296: G850-G859Crossref PubMed Scopus (124) Google Scholar Treatment of mice with an anti-TNF antibody reduced tumor number and size. TNFR2 activation in intestinal epithelial cells also leads to myosin light chain kinase up-regulation with subsequent release of pro-tumorigenic cytokines and breakdown of tight junctions.44Su L. Nalle S.C. Shen L. et al.TNFR2 activates MLCK-dependent tight junction dysregulation to cause apoptosis-mediated barrier loss and experimental colitis.Gastroenterology. 2013; 145: 407-415Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar, 45Suzuki M. Nagaishi T. Yamazaki M. et al.Myosin light chain kinase expression induced via tumor necrosis factor receptor 2 signaling in the epithelial cells regulates the development of colitis-associated carcinogenesis.PLoS One. 2014; 9: e88369Crossref PubMed Scopus (32) Google Scholar, 46Wang F. Schwarz B.T. Graham W.V. et al.IFN-gamma-induced TNFR2 expression is required for TNF-dependent intestinal epithelial barrier dysfunction.Gastroenterology. 2006; 131: 1153-1163Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar Similar to TNFR2, tumor growth was reduced in TNFR1-deficient mice as well as in wild-type mice treated with the anti-TNF inhibitor entanercept in the AOM-DSS model.47Popivanova B.K. Kitamura K. Wu Y. et al.Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis.J Clin Invest. 2008; 118: 560-570PubMed Google Scholar The effectiveness of entanercept is somewhat surprising because this anti-TNF biologic is not effective in human IBD. Nevertheless, reduced TNF signaling is accompanied by decreased colonic infiltration by neutrophils and macrophages. Bone marrow chimera mice also were used to show that the effects of TNFR1 on tumor growth were caused by expression on bone marrow–derived rather than stromal and parenchymal cell types. Thus, TNFR1 activation in infiltrating immune cells seems to be important for tumor-promoting effects of chronic inflammation, whereas TNFR2 activation seems to be important for NF-κB–dependent tumor cell survival, tight junction barrier loss, and tumor-promoting cytokine release (Figure 1). Importantly, these data on TNF signaling in CAC were derived from preclinical studies, whereas data from human CAC are rare. Moreover, despite the widespread use of anti-TNF therapeutics in IBD treatment, there are currently no data available that clearly show a preventive effect on CAC development. Another cytokine implicated in the pathogenesis of CAC is IL6. On activation of proinflammatory signaling pathways involving NF-κB or nuclear factor of activated T-cells, cytoplasmic 2, IL6 is released by monocytes, macrophages, fibroblasts, endothelial cells, lymphocytes, and cancer cells. This IL6 binds to membrane-bound IL6-receptor (IL6R) on target cells, and the complex then binds to a homodimer of glycoprotein 130 (gp130), which mediates further downstream signaling.48Rose-John S. IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6.Int J Biol Sci. 2012; 8: 1237-1247Crossref PubMed Scopus (571) Google Scholar In addition, IL6 can act on cells that do not express IL6R. In this trans-signaling, IL6 binds to a soluble form of IL6R and the complex binds to membrane-bound gp130 on target cells to activate downstream signaling. Initially, a role for IL6 in cancer development was suggested by in vitro studies of growth-promoting effects on colon cancer cell lines.49Schneider M.R. Hoeflich A. Fischer J.R. et al.Interleukin-6 stimulates clonogenic growth of primary and metastatic human colon carcinoma cells.Cancer Lett. 2000; 151: 31-38Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 50Lahm H. Petral-Malec D. Yilmaz-Ceyhan A. et al.Growth stimulation of a human colorectal carcinoma cell line by interleukin-1 and -6 and antagonistic effects of transforming growth factor beta 1.Eur J Cancer. 1992; 28A: 1894-1899Abstract Full Text PDF PubMed Scopus (51) Google Scholar Because these cells do not express membrane-bound IL6R, it was argued that IL6 signaling might act through trans-signaling.50Lahm H. Petral-Malec D. Yilmaz-Ceyhan A. et al.Growth stimulation of a human colorectal carcinoma cell line by interleukin-1 and -6 and antagonistic effects of transforming growth fact