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From inflammation to colitis-associated colorectal cancer in inflammatory bowel disease: Pathogenesis and impact of current therapies

Published:February 01, 2021DOI:https://doi.org/10.1016/j.dld.2021.01.012

      Abstract

      The risk of colorectal cancer (CRC) is higher in patients with inflammatory bowel disease (IBD). Population-based data from patients with ulcerative colitis (UC) estimate that the risk of CRC is approximately 2- to 3-fold that of the general population; patients with Crohn's disease appear to have a similar increased risk. However, the true extent of colitis-associated cancer (CAC) in undertreated IBD is unclear. Data suggest that the size (i.e., severity and extent) and persistence of the inflammatory process is largely responsible for the development of CRC in IBD. As patients with IBD and CRC have a worse prognosis than those without a history of IBD, the impact of current therapies for IBD on CAC is of importance. Chronic inflammation of the gut has been shown to increase the risk of developing CAC in both UC and CD. Therefore, control of inflammation is pivotal to the prevention of CAC. This review presents an overview of the current knowledge of CAC in IBD patients, focusing on the role of inflammation in the pathogenesis of CAC and the potential for IBD drugs to interfere with the process of carcinogenesis by reducing the inflammatory process or by modulating pathways directly involved in carcinogenesis.

      Keywords

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      References

        • Munkholm P.
        Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease.
        Aliment Pharmacol Ther. 2003; 18 Suppl 2: 1-5
        • Eaden J.A.
        • Abrams K.R.
        • Mayberry J.F.
        The risk of colorectal cancer in ulcerative colitis: a meta-analysis.
        Gut. 2001; 48: 526-535
        • Hata K.
        • Watanabe T.
        • Kazama S.
        • et al.
        Earlier surveillance colonoscopy programme improves survival in patients with ulcerative colitis associated colorectal cancer: results of a 23-year surveillance programme in the Japanese population.
        Br J Cancer. 2003; 89: 1232-1236
        • Jess T.
        • Loftus Jr., E.V.
        • Velayos F.S.
        • et al.
        Incidence and prognosis of colorectal dysplasia in inflammatory bowel disease: a population-based study from Olmsted County, Minnesota.
        Inflamm Bowel Dis. 2006; 12: 669-676
        • Jess 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: 639-645
        • Rutter M.D.
        • Saunders B.P.
        • Wilkinson K.H.
        • et al.
        Thirty-year analysis of a colonoscopic surveillance program for neoplasia in ulcerative colitis.
        Gastroenterology. 2006; 130: 1030-1038
        • Winther K.V.
        • Jess T.
        • Langholz E.
        • et al.
        Long-term risk of cancer in ulcerative colitis: a population-based cohort study from Copenhagen county.
        Clin Gastroenterol Hepatol. 2004; 2: 1088-1095
        • Dyson J.K.
        • Rutter M.D.
        Colorectal cancer in inflammatory bowel disease: what is the real magnitude of the risk?.
        World J Gastroenterol. 2012; 18: 3839-3848
        • Jess T.
        • Simonsen J.
        • Jorgensen K.T.
        • et al.
        Decreasing risk of colorectal cancer in patients with inflammatory bowel disease over 30 years.
        Gastroenterology. 2012; 143 (e1): 375-381
        • Olen O.
        • Erichsen R.
        • Sachs M.C.
        • et al.
        Colorectal cancer in Crohn's disease: a Scandinavian population-based cohort study.
        Lancet Gastroenterol Hepatol. 2020;
        • Jess T.
        • Gamborg M.
        • Matzen P.
        • et al.
        Increased risk of intestinal cancer in Crohn's disease: a meta-analysis of population-based cohort studies.
        Am J Gastroenterol. 2005; 100: 2724-2729
        • Jess T.
        • Horvath-Puho E.
        • Fallingborg J.
        • et al.
        Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study.
        Am J Gastroenterol. 2013; 108: 1869-1876
        • Lennerz J.K.
        • van der Sloot K.W.J.
        • Le L.P.
        • et al.
        Colorectal cancer in Crohn's colitis is comparable to sporadic colorectal cancer.
        Int J Colorectal Dis. 2016; 31: 973-982
        • Samadder N.J.
        • Valentine J.F.
        • Guthery S.
        • et al.
        Family history associates with increased risk of colorectal cancer in patients with inflammatory bowel diseases.
        Clin Gastroenterol Hepatol. 2019; 17 (e1): 1807-1813
        • Canavan 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: 1097-1104
        • Chung I.C.
        • OuYang C.N.
        • Yuan S.N.
        • et al.
        Pretreatment with a heat-killed probiotic modulates the NLRP3 inflammasome and attenuates colitis-associated colorectal cancer in mice.
        Nutrients. 2019; : 11
        • Colman R.J.
        • Rubin D.T.
        Histological inflammation increases the risk of colorectal neoplasia in ulcerative colitis: a systematic review.
        Intest Res. 2016; 14: 202-210
        • Kishikawa J.
        • Hata K.
        • Kazama S.
        • et al.
        Results of a 36-year surveillance program for ulcerative colitis-associated neoplasia in the Japanese population.
        Dig Endosc. 2018; 30: 236-244
        • Rubin 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): 1601-1608
        • Rutter M.
        • Saunders B.
        • Wilkinson K.
        • et al.
        Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis.
        Gastroenterology. 2004; 126: 451-459
        • Scharl S.
        • Barthel C.
        • Rossel J.B.
        • et al.
        Malignancies in inflammatory bowel disease: frequency, incidence and risk factors-results from the Swiss IBD Cohort study.
        Am J Gastroenterol. 2019; 114: 116-126
        • Jess T.
        • Loftus Jr., E.V.
        • Velayos F.S.
        • et al.
        Risk factors for colorectal neoplasia in inflammatory bowel disease: a nested case-control study from Copenhagen county, Denmark and Olmsted county, Minnesota.
        Am J Gastroenterol. 2007; 102: 829-836
        • Dugum M.
        • Lin J.
        • Lopez R.
        • et al.
        Recurrence and survival rates of inflammatory bowel disease-associated colorectal cancer following postoperative chemotherapy: a comparative study.
        Gastroenterol Rep (Oxf). 2017; 5: 57-61
        • Peyrin-Biroulet L.
        • Lepage C.
        • Jooste V.
        • et al.
        Colorectal cancer in inflammatory bowel diseases: a population-based study (1976-2008).
        Inflamm Bowel Dis. 2012; 18: 2247-2251
        • Reynolds I.S.
        • O'Toole A.
        • Deasy J.
        • et al.
        A meta-analysis of the clinicopathological characteristics and survival outcomes of inflammatory bowel disease associated colorectal cancer.
        Int J Colorectal Dis. 2017; 32: 443-451
        • Shaukat A.
        • Salfiti N.I.
        • Virnig D.J.
        • et al.
        Is ulcerative colitis associated with survival among older persons with colorectal cancer in the US? A population-based case-control study.
        Dig Dis Sci. 2012; 57: 1647-1651
        • Adams S.V.
        • Ahnen D.J.
        • Baron J.A.
        • et al.
        Survival after inflammatory bowel disease-associated colorectal cancer in the colon cancer family registry.
        World J Gastroenterol. 2013; 19: 3241-3248
        • Brackmann S.
        • Aamodt G.
        • Andersen S.N.
        • et al.
        Widespread but not localized neoplasia in inflammatory bowel disease worsens the prognosis of colorectal cancer.
        Inflamm Bowel Dis. 2010; 16: 474-481
        • Ording A.G.
        • Horvath-Puho E.
        • Erichsen R.
        • et al.
        Five-year mortality in colorectal cancer patients with ulcerative colitis or Crohn's disease: a nationwide population-based cohort study.
        Inflamm Bowel Dis. 2013; 19: 800-805
        • Renz B.W.
        • Thasler W.E.
        • Preissler G.
        • et al.
        Clinical outcome of IBD-associated versus sporadic colorectal cancer: a matched-pair analysis.
        J Gastrointest Surg. 2013; 17: 981-990
        • Jewel Samadder N.
        • Valentine J.F.
        • Guthery S.
        • et al.
        Colorectal cancer in inflammatory bowel diseases: a population-based study in Utah.
        Dig Dis Sci. 2017; 62: 2126-2132
        • Buchner A.M.
        • Lichtenstein G.R.
        Evaluation and detection of dysplasia in IBD: the role of chromoendoscopy and enhanced imaging techniques.
        Curr Treat Options Gastroenterol. 2016; 14: 73-82
        • Gui X.
        • Kobel M.
        • Ferraz J.G.
        • et al.
        Histological and molecular diversity and heterogeneity of precancerous lesions associated with inflammatory bowel diseases.
        J Clin Pathol. 2020; 73: 391-402
        • Hata K.
        • Kishikawa J.
        • Anzai H.
        • et al.
        Surveillance colonoscopy for colitis-associated dysplasia and cancer in ulcerative colitis patients.
        Dig Endosc. 2016; 28: 260-265
        • Mark-Christensen A.
        • Laurberg S.
        • Haboubi N.
        Dysplasia in inflammatory bowel disease: historical review, critical histopathological analysis, and clinical implications.
        Inflamm Bowel Dis. 2018; 24 ([Epub ahead of print]): 1895-1903
        • Neumann H.
        • Vieth M.
        • Langner C.
        • et al.
        Cancer risk in IBD: how to diagnose and how to manage DALM and ALM.
        World J Gastroenterol. 2011; 17: 3184-3191
        • Ullman T.
        • Odze R.
        • Farraye F.A.
        Diagnosis and management of dysplasia in patients with ulcerative colitis and Crohn's disease of the colon.
        Inflamm Bowel Dis. 2009; 15: 630-638
        • Riddell R.H.
        • Goldman H.
        • Ransohoff D.F.
        • et al.
        Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications.
        Hum Pathol. 1983; 14: 931-968
        • Baker A.M.
        • Cross W.
        • Curtius K.
        • et al.
        Evolutionary history of human colitis-associated colorectal cancer.
        Gut. 2019; 68: 985-995
        • Baker K.T.
        • Salk J.J.
        • Brentnall T.A.
        • et al.
        Precancer in ulcerative colitis: the role of the field effect and its clinical implications.
        Carcinogenesis. 2018; 39: 11-20
        • Karin M.
        NF-kappaB and cancer: mechanisms and targets.
        Mol Carcinog. 2006; 45: 355-361
        • Waldner M.J.
        • Neurath M.F.
        Mechanisms of immune signaling in colitis-associated cancer.
        Cell Mol Gastroenterol Hepatol. 2015; 1: 6-16
        • Kay J.
        • Thadhani E.
        • Samson L.
        • et al.
        Inflammation-induced DNA damage, mutations and cancer.
        DNA Repair (Amst). 2019; 83102673
        • Arthur J.C.
        • Jobin C.
        The struggle within: microbial influences on colorectal cancer.
        Inflamm Bowel Dis. 2011; 17: 396-409
        • DuPont A.W.
        • DuPont H.L.
        The intestinal microbiota and chronic disorders of the gut.
        Nat Rev Gastroenterol Hepatol. 2011; 8: 523-531
        • Choi C.R.
        • Bakir I.A.
        • Hart A.L.
        • et al.
        Clonal evolution of colorectal cancer in IBD.
        Nat Rev Gastroenterol Hepatol. 2017; 14: 218-229
        • Dulai P.S.
        • Sandborn W.J.
        • Gupta S.
        Colorectal cancer and dysplasia in inflammatory bowel disease: a review of disease epidemiology, pathophysiology, and management.
        Cancer Prev Res (Phila). 2016; 9: 887-894
        • Fujiwara I.
        • Yashiro M.
        • Kubo N.
        • et al.
        Ulcerative colitis-associated colorectal cancer is frequently associated with the microsatellite instability pathway.
        Dis Colon Rectum. 2008; 51: 1387-1394
        • Kameyama H.
        • Nagahashi M.
        • Shimada Y.
        • et al.
        Genomic characterization of colitis-associated colorectal cancer.
        World J Surg Oncol. 2018; 16: 121
        • Fujita M.
        • Matsubara N.
        • Matsuda I.
        • et al.
        Genomic landscape of colitis-associated cancer indicates the impact of chronic inflammation and its stratification by mutations in the Wnt signaling.
        Oncotarget. 2018; 9: 969-981
        • Robles A.I.
        • Traverso G.
        • Zhang M.
        • et al.
        Whole-exome sequencing analyses of inflammatory bowel disease-associated colorectal cancers.
        Gastroenterology. 2016; 150: 931-943
        • Alpert L.
        • Yassan L.
        • Poon R.
        • et al.
        Targeted mutational analysis of inflammatory bowel disease-associated colorectal cancers.
        Hum Pathol. 2019; 89: 44-50
        • Schulmann K.
        • Mori Y.
        • Croog V.
        • et al.
        Molecular phenotype of inflammatory bowel disease-associated neoplasms with microsatellite instability.
        Gastroenterology. 2005; 129: 74-85
        • Wanders L.K.
        • Cordes M.
        • Voorham Q.
        • et al.
        IBD-associated dysplastic lesions show more chromosomal instability than sporadic adenomas.
        Inflamm Bowel Dis. 2020; 26: 167-180
        • Du L.
        • Kim J.J.
        • Shen J.
        • et al.
        KRAS and TP53 mutations in inflammatory bowel disease-associated colorectal cancer: a meta-analysis.
        Oncotarget. 2017; 8: 22175-22186
        • Bozec D.
        • Iuga A.C.
        • Roda G.
        • et al.
        Critical function of the necroptosis adaptor RIPK3 in protecting from intestinal tumorigenesis.
        Oncotarget. 2016; 7: 46384-46400
        • Feagins L.A.
        Role of transforming growth factor-beta in inflammatory bowel disease and colitis-associated colon cancer.
        Inflamm Bowel Dis. 2010; 16: 1963-1968
        • Luo C.
        • Zhang H.
        The role of proinflammatory pathways in the pathogenesis of colitis-associated colorectal cancer.
        Mediat Inflamm. 2017; 20175126048
        • Erreni M.
        • Mantovani A.
        • Allavena P.
        Tumor-associated macrophages (TAM) and inflammation in colorectal cancer.
        Cancer Microenviron. 2011; 4: 141-154
        • Hayakawa Y.
        • Hirata Y.
        • Nakagawa H.
        • et al.
        Apoptosis signal-regulating kinase 1 regulates colitis and colitis-associated tumorigenesis by the innate immune responses.
        Gastroenterology. 2010; 138 (e1-4): 1055-1067
        • Rizzo A.
        • Waldner M.J.
        • Stolfi C.
        • et al.
        Smad7 expression in T cells prevents colitis-associated cancer.
        Cancer Res. 2011; 71: 7423-7432
        • McLoughlin R.M.
        • Witowski J.
        • Robson R.L.
        • et al.
        Interplay between IFN-gamma and IL-6 signaling governs neutrophil trafficking and apoptosis during acute inflammation.
        J Clin Invest. 2003; 112: 598-607
        • Ren W.
        • Shen S.
        • Sun Z.
        • et al.
        Jak-STAT3 pathway triggers DICER1 for proteasomal degradation by ubiquitin ligase complex of CUL4A(DCAF1) to promote colon cancer development.
        Cancer Lett. 2016; 375: 209-220
        • Zhang X.
        • Wei L.
        • Wang J.
        • et al.
        Suppression colitis and colitis-associated colon cancer by anti-S100a9 antibody in mice.
        Front Immunol. 2017; 8: 1774
        • Zhang X.
        • Ai F.
        • Li X.
        • et al.
        Inflammation-induced S100A8 activates Id3 and promotes colorectal tumorigenesis.
        Int J Cancer. 2015; 137: 2803-2814
        • Grivennikov S.I.
        • Karin M.
        Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer.
        Cytokine Growth Factor Rev. 2010; 21: 11-19
        • Moriasi C.
        • Subramaniam D.
        • Awasthi S.
        • et al.
        Prevention of colitis-associated cancer: natural compounds that target the IL-6 soluble receptor.
        Anticancer Agents Med Chem. 2012; 12: 1221-1238
        • Welte T.
        • Zhang S.S.
        • Wang T.
        • et al.
        STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity.
        Proc Natl Acad Sci U S A. 2003; 100: 1879-1884
        • Greten 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: 285-296
        • Luo J.L.
        • Maeda S.
        • Hsu L.C.
        • et al.
        Inhibition of NF-kappaB in cancer cells converts inflammation-induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression.
        Cancer Cell. 2004; 6: 297-305
        • Monteleone G.
        • Mann J.
        • Monteleone I.
        • et al.
        A failure of transforming growth factor-beta1 negative regulation maintains sustained NF-kappaB activation in gut inflammation.
        J Biol Chem. 2004; 279: 3925-3932
        • Popivanova 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: 560-570
        • Khare V.
        • Paul G.
        • Movadat O.
        • et al.
        IL10R2 overexpression promotes IL22/STAT3 signaling in colorectal carcinogenesis.
        Cancer Immunol Res. 2015; 3: 1227-1235
        • Taniguchi K.
        • Wu L.W.
        • Grivennikov S.I.
        • et al.
        A gp130-Src-YAP module links inflammation to epithelial regeneration.
        Nature. 2015; 519: 57-62
        • Li Y.
        • de Haar C.
        • Peppelenbosch M.P.
        • et al.
        SOCS3 in immune regulation of inflammatory bowel disease and inflammatory bowel disease-related cancer.
        Cytokine Growth Factor Rev. 2012; 23: 127-138
        • Li Y.
        • de Haar C.
        • Chen M.
        • et al.
        Disease-related expression of the IL6/STAT3/SOCS3 signalling pathway in ulcerative colitis and ulcerative colitis-related carcinogenesis.
        Gut. 2010; 59: 227-235
        • Rigby R.J.
        • Simmons J.G.
        • Greenhalgh C.J.
        • et al.
        Suppressor of cytokine signaling 3 (SOCS3) limits damage-induced crypt hyper-proliferation and inflammation-associated tumorigenesis in the colon.
        Oncogene. 2007; 26: 4833-4841
        • Becker C.
        • Fantini M.C.
        • Schramm C.
        • et al.
        TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling.
        Immunity. 2004; 21: 491-501
        • Means A.L.
        • Freeman T.J.
        • Zhu J.
        • et al.
        Epithelial Smad4 deletion up-regulates inflammation and promotes inflammation-associated cancer.
        Cell Mol Gastroenterol Hepatol. 2018; 6: 257-276
        • Principe D.R.
        • DeCant B.
        • Staudacher J.
        • et al.
        Loss of TGFbeta signaling promotes colon cancer progression and tumor-associated inflammation.
        Oncotarget. 2017; 8: 3826-3839
      1. Cui G. TH9, TH17, and TH22 cell subsets and their main cytokine products in the pathogenesis of colorectal cancer.
        Front Oncol. 2019; 9: 1002
        • Kempski J.
        • Brockmann L.
        • Gagliani N.
        • et al.
        TH17 cell and epithelial cell crosstalk during inflammatory bowel disease and carcinogenesis.
        Front Immunol. 2017; 8: 1373
        • Wang C.
        • Gong G.
        • Sheh A.
        • et al.
        Interleukin-22 drives nitric oxide-dependent DNA damage and dysplasia in a murine model of colitis-associated cancer.
        Mucosal Immunol. 2017; 10: 1504-1517
        • Vyas S.P.
        • Goswami R.
        A decade of Th9 Cells: role of Th9 cells in inflammatory bowel disease.
        Front Immunol. 2018; 9: 1139
        • Krzystek-Korpacka M.
        • Zawadzki M.
        • Kapturkiewicz B.
        • et al.
        Subsite heterogeneity in the profiles of circulating cytokines in colorectal cancer.
        Cytokine. 2018; 110: 435-441
        • Tian L.
        • Li Y.
        • Chang R.
        • et al.
        Lentiviral vector-mediated IL-9 overexpression stimulates cell proliferation by targeting c-myc and cyclin D1 in colitis-associated cancer.
        Oncol Lett. 2019; 17: 175-182
        • Hardbower D.M.
        • Coburn L.A.
        • Asim M.
        • et al.
        EGFR-mediated macrophage activation promotes colitis-associated tumorigenesis.
        Oncogene. 2017; 36: 3807-3819
        • Murray P.J.
        • Wynn T.A.
        Protective and pathogenic functions of macrophage subsets.
        Nat Rev Immunol. 2011; 11: 723-737
        • Wang W.
        • Li X.
        • Zheng D.
        • et al.
        Dynamic changes and functions of macrophages and M1/M2 subpopulations during ulcerative colitis-associated carcinogenesis in an AOM/DSS mouse model.
        Mol Med Rep. 2015; 11: 2397-2406
        • Singh K.
        • Coburn L.A.
        • Asim M.
        • et al.
        Ornithine decarboxylase in macrophages exacerbates colitis and promotes colitis-associated colon carcinogenesis by impairing M1 immune responses.
        Cancer Res. 2018; 78: 4303-4315
        • Wang W.
        • Li X.
        • Zheng D.
        • et al.
        Dynamic changes of peritoneal macrophages and subpopulations during ulcerative colitis to metastasis of colorectal carcinoma in a mouse model.
        Inflamm Res. 2013; 62: 669-680
        • Zhang W.
        • Chen L.
        • Ma K.
        • et al.
        Polarization of macrophages in the tumor microenvironment is influenced by EGFR signaling within colon cancer cells.
        Oncotarget. 2016; 7: 75366-75378
        • Castillo E.F.
        • Ray A.L.
        • Beswick E.J.
        MK2: an unrecognized regulator of tumor promoting macrophages in colorectal cancer?.
        Macrophage (Houst). 2016; : 3
        • Geremia A.
        • Arancibia-Carcamo C.V.
        Innate lymphoid cells in intestinal inflammation.
        Front Immunol. 2017; 8: 1296
        • Yoshioka K.
        • Ueno Y.
        • Tanaka S.
        • et al.
        Role of natural killer T cells in the mouse colitis-associated colon cancer model.
        Scand J Immunol. 2012; 75: 16-26
        • Ward-Hartstonge K.A.
        • Kemp R.A.
        Regulatory T-cell heterogeneity and the cancer immune response.
        Clin Transl Immunol. 2017; 6: e154
        • Saito T.
        • Nishikawa H.
        • Wada H.
        • et al.
        Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers.
        Nat Med. 2016; 22: 679-684
        • Blatner N.R.
        • Mulcahy M.F.
        • Dennis K.L.
        • et al.
        Expression of RORγt marks a pathogenic regulatory T cell subset in human colon cancer.
        Sci Transl Med. 2012; 4: 164ra59
        • Rizzo A.
        • Di Giovangiulio M.
        • Stolfi C.
        • et al.
        RORgammat-expressing Tregs drive the growth of colitis-associated colorectal cancer by controlling IL6 in dendritic cells.
        Cancer Immunol Res. 2018; 6: 1082-1092
        • Di Giovangiulio M.
        • Rizzo A.
        • Franze E.
        • et al.
        Tbet expression in regulatory T cells is required to initiate Th1-mediated colitis.
        Front Immunol. 2019; 10: 2158
        • Uronis J.M.
        • Muhlbauer M.
        • Herfarth H.H.
        • et al.
        Modulation of the intestinal microbiota alters colitis-associated colorectal cancer susceptibility.
        PLoS ONE. 2009; 4: e6026
        • Kado S.
        • Uchida K.
        • Funabashi H.
        • et al.
        Intestinal microflora are necessary for development of spontaneous adenocarcinoma of the large intestine in T-cell receptor beta chain and p53 double-knockout mice.
        Cancer Res. 2001; 61: 2395-2398
        • Fukata M.
        • Chen A.
        • Vamadevan A.S.
        • et al.
        Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors.
        Gastroenterology. 2007; 133: 1869-1881
        • Rakoff-Nahoum S.
        • Medzhitov R.
        Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88.
        Science. 2007; 317: 124-127
        • Richard M.L.
        • Liguori G.
        • Lamas B.
        • et al.
        Mucosa-associated microbiota dysbiosis in colitis associated cancer.
        Gut Microbes. 2018; 9: 131-142
        • Brennan C.A.
        • Garrett W.S.
        Fusobacterium nucleatum - symbiont, opportunist and oncobacterium.
        Nat Rev Microbiol. 2019; 17: 156-166
        • Yu M.R.
        • Kim H.J.
        • Park H.R.
        Fusobacterium nucleatum accelerates the progression of colitis-associated colorectal cancer by promoting EMT.
        Cancers (Basel). 2020; : 12
        • Wu S.
        • Rhee K.J.
        • Albesiano E.
        • et al.
        A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses.
        Nat Med. 2009; 15: 1016-1022
        • Hwang S.
        • Lee C.G.
        • Jo M.
        • et al.
        Enterotoxigenic Bacteroides fragilis infection exacerbates tumorigenesis in AOM/DSS mouse model.
        Int J Med Sci. 2020; 17: 145-152
        • Lee Y.K.
        • Mehrabian P.
        • Boyajian S.
        • et al.
        The protective role of Bacteroides fragilis in a murine model of colitis-associated colorectal cancer.
        mSphere. 2018; 3
        • Tian Y.
        • Xu Q.
        • Sun L.
        • et al.
        Short-chain fatty acids administration is protective in colitis-associated colorectal cancer development.
        J Nutr Biochem. 2018; 57: 103-109
        • Bezzio C.
        • Festa S.
        • Saibeni S.
        • et al.
        Chemoprevention of colorectal cancer in ulcerative colitis: digging deep in current evidence.
        Expert Rev Gastroenterol Hepatol. 2017; 11: 339-347
        • Lopez A.
        • Pouillon L.
        • Beaugerie L.
        • et al.
        Colorectal cancer prevention in patients with ulcerative colitis.
        Best Pract Res Clin Gastroenterol. 2018; 32-33: 103-109
        • Waldner M.J.
        • Neurath M.F.
        Cytokines in colitis associated cancer: potential drug targets?.
        Inflamm Allergy Drug Targets. 2008; 7: 187-194
        • Actis G.C.
        • Pellicano R.
        • David E.
        • et al.
        Azathioprine, mucosal healing in ulcerative colitis, and the chemoprevention of colitic cancer: a clinical-practice-based forecast.
        Inflamm Allergy Drug Targets. 2010; 9: 6-9
        • Baars J.E.
        • Looman C.W.
        • Steyerberg E.W.
        • et al.
        The risk of inflammatory bowel disease-related colorectal carcinoma is limited: results from a nationwide nested case-control study.
        Am J Gastroenterol. 2011; 106: 319-328
        • Velayos F.S.
        • Loftus Jr., E.V.
        • Jess T.
        • et al.
        Predictive and protective factors associated with colorectal cancer in ulcerative colitis: a case-control study.
        Gastroenterology. 2006; 130: 1941-1949
        • Singh S.
        Preventing colorectal cancer in patients with inflammatory bowel diseases: chemopreventive and surgical approaches.
        in: Feuerstein J.D. Cheifetz A.S. Cancer screening in inflammatory bowel disease. Springer Nature, Cham, Switzerland2019: 109-118
        • Jess T.
        • Lopez A.
        • Andersson M.
        • et al.
        Thiopurines and risk of colorectal neoplasia in patients with inflammatory bowel disease: a meta-analysis.
        Clin Gastroenterol Hepatol. 2014; 12 (e1): 1793-1800
        • Khare V.
        • Lyakhovich A.
        • Dammann K.
        • et al.
        Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1.
        Biochem Pharmacol. 2013; 85: 234-244
        • Stolfi C.
        • Pallone F.
        • Monteleone G.
        Colorectal cancer chemoprevention by mesalazine and its derivatives.
        J Biomed Biotechnol. 2012; 2012980458
        • Wielenga M.C.
        • de Jeude JFvL
        • Rosekrans S.L.
        • et al.
        Azathioprine does not reduce adenoma formation in a mouse model of sporadic intestinal tumorigenesis.
        World J Gastroenterol WJG. 2014; 20: 16683
        • Lamb C.A.
        • Kennedy N.A.
        • Raine T.
        • et al.
        British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults.
        Gut. 2019; 68: s1-s106
        • Koelink P.J.
        • Robanus-Maandag E.C.
        • Devilee P.
        • et al.
        5-Aminosalicylic acid inhibits colitis-associated but not sporadic colorectal neoplasia in a novel conditional Apc mouse model.
        Carcinogenesis. 2009; 30: 1217-1224
        • Stolfi C.
        • Fina D.
        • Caruso R.
        • et al.
        Mesalazine negatively regulates CDC25A protein expression and promotes accumulation of colon cancer cells in S phase.
        Carcinogenesis. 2008; 29: 1258-1266
        • Gasche C.
        • Goel A.
        • Natarajan L.
        • et al.
        Mesalazine improves replication fidelity in cultured colorectal cells.
        Cancer Res. 2005; 65: 3993-3997
        • Bos C.L.
        • Diks S.H.
        • Hardwick J.C.
        • et al.
        Protein phosphatase 2A is required for mesalazine-dependent inhibition of Wnt/beta-catenin pathway activity.
        Carcinogenesis. 2006; 27: 2371-2382
        • Monteleone G.
        • Franchi L.
        • Fina D.
        • et al.
        Silencing of SH-PTP2 defines a crucial role in the inactivation of epidermal growth factor receptor by 5-aminosalicylic acid in colon cancer cells.
        Cell Death Differ. 2006; 13: 202-211
        • Rousseaux C.
        • Lefebvre B.
        • Dubuquoy L.
        • et al.
        Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-gamma.
        J Exp Med. 2005; 201: 1205-1215
        • Desreumaux P.
        • Ghosh S.
        Review article: mode of action and delivery of 5-aminosalicylic acid - new evidence.
        Aliment Pharmacol Ther. 2006; 24 Suppl 1: 2-9
        • Carrat F.
        • Seksik P.
        • Colombel J.F.
        • et al.
        The effects of aminosalicylates or thiopurines on the risk of colorectal cancer in inflammatory bowel disease.
        Aliment Pharmacol Ther. 2017; 45: 533-541
        • Bernstein C.N.
        • Nugent Z.
        • Blanchard J.F.
        5-aminosalicylate is not chemoprophylactic for colorectal cancer in IBD: a population based study.
        Am J Gastroenterol. 2011; 106: 731-736
        • Nguyen G.C.
        • Gulamhusein A.
        • Bernstein C.N.
        5-Aminosalicylic acid is not protective against colorectal cancer in inflammatory bowel disease: a meta-analysis of non-referral populations.
        Am J Gastroenterol. 2012; 107: 1298-1304
        • Velayos F.S.
        • Terdiman J.P.
        • Walsh J.M.
        Effect of 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and metaanalysis of observational studies.
        Am J Gastroenterol. 2005; 100: 1345-1353
        • Xu X.
        • Xu X.
        • Ciren Y.
        • et al.
        Chemopreventive effects of 5-amino salicylic acids on inflammatory bowel disease-associated colonic cancer and colonic dysplasia: a meta-analysis.
        Int J Clin Exp Med. 2015; 8: 2212-2218
        • Zhao L.N.
        • Li J.Y.
        • Yu T.
        • et al.
        5-Aminosalicylates reduce the risk of colorectal neoplasia in patients with ulcerative colitis: an updated meta-analysis.
        PLoS ONE. 2014; 9: e94208
        • Beaugerie L.
        • Svrcek M.
        • Seksik P.
        • et al.
        Risk of colorectal high-grade dysplasia and cancer in a prospective observational cohort of patients with inflammatory bowel disease.
        Gastroenterology. 2013; 145 (e8): 166-175
        • Lu M.J.
        • Qiu X.Y.
        • Mao X.Q.
        • et al.
        Systematic review with meta-analysis: thiopurines decrease the risk of colorectal neoplasia in patients with inflammatory bowel disease.
        Aliment Pharmacol Ther. 2018; 47: 318-331
        • Biancone L.
        • Petruzziello C.
        • Calabrese E.
        • et al.
        Long-term safety of Infliximab for the treatment of inflammatory bowel disease: does blocking TNFα reduce colitis-associated colorectal carcinogenesis?.
        Gut. 2009; 58: 1703
        • Kim Y.J.
        • Hong K.S.
        • Chung J.W.
        • et al.
        Prevention of colitis-associated carcinogenesis with infliximab.
        Cancer Prev Res (Phila). 2010; 3: 1314-1333
        • Lopetuso L.R.
        • Petito V.
        • Zinicola T.
        • et al.
        Infliximab does not increase colonic cancer risk associated to murine chronic colitis.
        World J Gastroenterol. 2016; 22: 9727-9733
        • Onizawa 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-G859