Cellular and Molecular Life Sciences

, Volume 71, Issue 18, pp 3523–3535

Colitis-associated neoplasia: molecular basis and clinical translation



Crohn’s disease and ulcerative colitis are both associated with an increased risk of inflammation-associated colorectal carcinoma. Colitis-associated cancer (CAC) is one of the most important causes for morbidity and mortality in patients with inflammatory bowel diseases (IBD). Colitis-associated neoplasia distinctly differs from sporadic colorectal cancer in its biology and the underlying mechanisms. This review discusses the molecular mechanisms of CAC and summarizes the most important genetic alterations and signaling pathways involved in inflammatory carcinogenesis. Then, clinical translation is evaluated by discussing new endoscopic techniques and their contribution to surveillance and early detection of CAC. Last, we briefly address different types of concepts for prevention (i.e., anti-inflammatory therapeutics) and treatment (i.e., surgical intervention) of CAC and give an outlook on this important aspect of IBD.


Inflammatory bowel disease Ulcerative colitis Crohn’s disease Colitis-associated cancer Colorectal carcinoma Endoscopy Chemoprevention 


  1. 1.
    Crohn B, Rosenberg H (1925) The sigmoidoscopic picture of chronic ulcerative colitis (non-specific). Am J Med Sci 170:220–228Google Scholar
  2. 2.
    Ekbom A, Helmick C, Zack M, Adami HO (1990) Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med 323:1228–1233PubMedGoogle Scholar
  3. 3.
    Jess T, Gamborg M, Matzen P et al (2005) Increased risk of intestinal cancer in Crohn’s disease: a meta-analysis of population-based cohort studies. Am J Gastroenterol 100:2724–2729PubMedGoogle Scholar
  4. 4.
    Eaden JA, Abrams KR, Mayberry JF (2001) The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 48:526–535PubMedCentralPubMedGoogle Scholar
  5. 5.
    Rutter MD, Saunders BP, Wilkinson KH et al (2006) Thirty-year analysis of a colonoscopic surveillance program for neoplasia in ulcerative colitis. YGAST 130:1030–1038Google Scholar
  6. 6.
    Soetikno RM, Lin OS, Heidenreich PA et al (2002) Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis. Gastrointest Endosc 56:48–54PubMedGoogle Scholar
  7. 7.
    Velayos FS, Loftus EV, Jess T et al (2006) Predictive and protective factors associated with colorectal cancer in ulcerative colitis: a case-control study. YGAST 130:1941–1949Google Scholar
  8. 8.
    Lashner BA, Turner BC, Bostwick DG et al (1990) Dysplasia and cancer complicating strictures in ulcerative colitis. Dig Dis Sci 35:349–352PubMedGoogle Scholar
  9. 9.
    Lukas M (2010) Inflammatory bowel disease as a risk factor for colorectal cancer. Dig Dis 28:619–624PubMedGoogle Scholar
  10. 10.
    Cho KR, Vogelstein B (1992) Genetic alterations in the adenoma–carcinoma sequence. Cancer 70:1727–1731PubMedGoogle Scholar
  11. 11.
    Vogelstein B, Kinzler KW (2004) Cancer genes and the pathways they control. Nat Med 10:789–799PubMedGoogle Scholar
  12. 12.
    Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87(2):159–170Google Scholar
  13. 13.
    Su LK, Kinzler KW, Vogelstein B et al (1992) Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science (New York, NY) 256:668–670Google Scholar
  14. 14.
    Powell SM, Zilz N, Beazer-Barclay Y et al (1992) APC mutations occur early during colorectal tumorigenesis. Nature 359:235–237. doi:10.1038/359235a0 PubMedGoogle Scholar
  15. 15.
    Foersch S, Waldner MJ, Neurath MF (2012) Colitis and colorectal cancer. Dig Dis 30:469–476PubMedGoogle Scholar
  16. 16.
    Kern SE, Redston M, Seymour AB et al (1994) Molecular genetic profiles of colitis-associated neoplasms. YGAST 107:420–428Google Scholar
  17. 17.
    Lane DP (1992) Cancer. p53, guardian of the genome. Nature 358:15–16. doi:10.1038/358015a0 PubMedGoogle Scholar
  18. 18.
    Gondek LP, Tiu R, O’Keefe CL et al (2008) Chromosomal lesions and uniparental disomy detected by SNP arrays in MDS, MDS/MPD, and MDS-derived AML. Blood 111:1534–1542. doi:10.1182/blood-2007-05-092304 PubMedCentralPubMedGoogle Scholar
  19. 19.
    Burmer GC, Rabinovitch PS, Haggitt RC et al (1992) Neoplastic progression in ulcerative colitis: histology, DNA content, and loss of a p53 allele. YGAST 103:1602–1610Google Scholar
  20. 20.
    Hussain SP, Amstad P, Raja K et al (2000) Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. Cancer Res 60:3333–3337PubMedGoogle Scholar
  21. 21.
    Brentnall TA, Crispin DA, Rabinovitch PS et al (1994) Mutations in the p53 gene: an early marker of neoplastic progression in ulcerative colitis. YGAST 107:369–378Google Scholar
  22. 22.
    Cooks T, Pateras IS, Tarcic O et al (2013) Mutant p53 prolongs NF-κB activation and promotes chronic inflammation and inflammation-associated colorectal cancer. Cancer Cell 23:634–646. doi:10.1016/j.ccr.2013.03.022 PubMedCentralPubMedGoogle Scholar
  23. 23.
    Tarmin L, Yin J, Harpaz N et al (1995) Adenomatous polyposis coli gene mutations in ulcerative colitis-associated dysplasias and cancers versus sporadic colon neoplasms. Cancer Res 55:2035–2038PubMedGoogle Scholar
  24. 24.
    Fogt F, Vortmeyer AO, Goldman H et al (1998) Comparison of genetic alterations in colonic adenoma and ulcerative colitis-associated dysplasia and carcinoma. Hum Pathol 29:131–136PubMedGoogle Scholar
  25. 25.
    Cooper HS, Everley L, Chang W et al (2001) The role of mutant Apc in the development of dysplasia and cancer in the mouse model of dextran sulfate sodium–induced colitis. Gastroenterology 121:1407–1416. doi:10.1053/gast.2001.29609 PubMedGoogle Scholar
  26. 26.
    Leedham S, Graham T, Oukrif D (2009) Clonality, founder mutations, and field cancerization in human ulcerative colitis-associated neoplasia. Gastroenterology 136(542):550.e6. doi:10.1053/j.gastro.2008.10.086 Google Scholar
  27. 27.
    Brown JB, Lee G, Managlia E et al (2010) Mesalamine inhibits epithelial beta-catenin activation in chronic ulcerative colitis. Gastroenterology 138:595–605, 605.e1–3. doi:10.1053/j.gastro.2009.10.038 PubMedCentralPubMedGoogle Scholar
  28. 28.
    Lee G, Goretsky T, Managlia E et al (2010) Phosphoinositide 3-kinase signaling mediates beta-catenin activation in intestinal epithelial stem and progenitor cells in colitis. Gastroenterology 139:869. doi:10.1053/j.gastro.2010.05.037 PubMedCentralPubMedGoogle Scholar
  29. 29.
    Pozzi A, Yan X, Macias-Perez I et al (2004) Colon carcinoma cell growth is associated with prostaglandin E2/EP4 receptor-evoked ERK activation. J Biol Chem 279:29797–29804. doi:10.1074/jbc.M313989200 PubMedGoogle Scholar
  30. 30.
    Tessner TG, Muhale F, Riehl TE et al (2004) Prostaglandin E2 reduces radiation-induced epithelial apoptosis through a mechanism involving AKT activation and bax translocation. J Clin Invest 114:1676–1685. doi:10.1172/JCI22218 PubMedCentralPubMedGoogle Scholar
  31. 31.
    Rapozo DCM, Grinmann AB, Carvalho ATP et al (2009) Analysis of mutations in TP53, APC, K-ras, and DCC genes in the non-dysplastic mucosa of patients with inflammatory bowel disease. Int J Colorectal Dis 24:1141–1148. doi:10.1007/s00384-009-0748-5 PubMedGoogle Scholar
  32. 32.
    Lang SM, Stratakis DF, Heinzlmann M et al (1999) Molecular screening of patients with long standing extensive ulcerative colitis: detection of p53 and Ki-ras mutations by single strand conformation polymorphism analysis and differential hybridisation in colonic lavage fluid. Gut 44:822–825PubMedCentralPubMedGoogle Scholar
  33. 33.
    Umetani N, Sasaki S, Masaki T et al (2000) Involvement of APC and K-ras mutation in non-polypoid colorectal tumorigenesis. Br J Cancer 82:9–15. doi:10.1054/bjoc.1999.0868 PubMedCentralPubMedGoogle Scholar
  34. 34.
    Itzkowitz SH (2006) Molecular biology of dysplasia and cancer in inflammatory bowel disease. Gastroenterol Clin North Am 35:553–571PubMedGoogle Scholar
  35. 35.
    Rashid A, Hamilton SR (1997) Genetic alterations in sporadic and Crohn’s-associated adenocarcinomas of the small intestine. Gastroenterology 113:127–135PubMedGoogle Scholar
  36. 36.
    Hofseth LJ, Saito S, Hussain SP et al (2003) Nitric oxide-induced cellular stress and p53 activation in chronic inflammation. Proc Natl Acad Sci USA 100:143–148PubMedCentralPubMedGoogle Scholar
  37. 37.
    Hussain SP, Hofseth LJ, Harris CC (2003) Radical causes of cancer. Nat Rev Cancer 3:276–285. doi:10.1038/nrc1046 PubMedGoogle Scholar
  38. 38.
    Westbrook AM, Wei B, Braun J, Schiestl RH (2009) Intestinal mucosal inflammation leads to systemic genotoxicity in mice. Cancer Res 69:4827–4834. doi:10.1158/0008-5472.CAN-08-4416 PubMedCentralPubMedGoogle Scholar
  39. 39.
    Ferguson LR (2010) Chronic inflammation and mutagenesis. Mutat Res 690:3–11. doi:10.1016/j.mrfmmm.2010.03.007 PubMedGoogle Scholar
  40. 40.
    Cook PJ, Ju BG, Telese F et al (2009) Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions. Nature 458:591–596. doi:10.1038/nature07849 PubMedCentralPubMedGoogle Scholar
  41. 41.
    Shaked H, Hofseth LJ, Chumanevich A et al (2012) Chronic epithelial NF-κB activation accelerates APC loss and intestinal tumor initiation through iNOS up-regulation. Proc Natl Acad Sci USA 109:14007–14012. doi:10.1073/pnas.1211509109 PubMedCentralPubMedGoogle Scholar
  42. 42.
    Erdman SE, Rao VP, Poutahidis T et al (2009) Nitric oxide and TNF-alpha trigger colonic inflammation and carcinogenesis in Helicobacter hepaticus-infected, Rag2-deficient mice. Proc Natl Acad Sci USA 106:1027–1032. doi:10.1073/pnas.0812347106 PubMedCentralPubMedGoogle Scholar
  43. 43.
    Goodman JE, Hofseth LJ, Hussain SP, Harris CC (2004) Nitric oxide and p53 in cancer-prone chronic inflammation and oxyradical overload disease. Environ Mol Mutagen 44:3–9. doi:10.1002/em.20024 PubMedGoogle Scholar
  44. 44.
    Bonner WM, Redon CE, Dickey JS et al (2008) GammaH2AX and cancer. Nat Rev Cancer 8:957–967. doi:10.1038/nrc2523 PubMedCentralPubMedGoogle Scholar
  45. 45.
    Risques RA, Lai La, Brentnall Ta et al (2008) Ulcerative colitis is a disease of accelerated colon aging: evidence from telomere attrition and DNA damage. Gastroenterology 135:410–418. doi:10.1053/j.gastro.2008.04.008 PubMedCentralPubMedGoogle Scholar
  46. 46.
    O’Sullivan JN, Bronner MP, Brentnall Ta et al (2002) Chromosomal instability in ulcerative colitis is related to telomere shortening. Nat Genet 32:280–284. doi:10.1038/ng989 PubMedGoogle Scholar
  47. 47.
    O’Sullivan J, Risques RA, Mandelson MT et al (2006) Telomere length in the colon declines with age: a relation to colorectal cancer? Cancer Epidemiol Biomarkers Prev 15:573–577. doi:10.1158/1055-9965.EPI-05-0542 PubMedGoogle Scholar
  48. 48.
    Wirtz S, Neufert C, Weigmann B, Neurath MF (2007) Chemically induced mouse models of intestinal inflammation. Nat Protoc 2:541–546PubMedGoogle Scholar
  49. 49.
    Neurath MF, Finotto S (2009) Translating inflammatory bowel disease research into clinical medicine. Immunity 31:357–361. doi:10.1016/j.immuni.2009.08.016 PubMedGoogle Scholar
  50. 50.
    Amit S, Ben-Neriah Y (2003) NF-kappaB activation in cancer: a challenge for ubiquitination- and proteasome-based therapeutic approach. Semin Cancer Biol 13:15–28PubMedGoogle Scholar
  51. 51.
    Greten FR, Eckmann L, Greten TF et al (2004) IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118:285–296. doi:10.1016/j.cell.2004.07.013 PubMedGoogle Scholar
  52. 52.
    Greten FR, Arkan MC, Bollrath J et al (2007) NF-kappaB is a negative regulator of IL-1beta secretion as revealed by genetic and pharmacological inhibition of IKKbeta. Cell 130:918–931PubMedCentralPubMedGoogle Scholar
  53. 53.
    Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F et al (2004) Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118:229–241PubMedGoogle Scholar
  54. 54.
    Waldner MJ, Foersch S, Neurath MF (2012) Interleukin-6—a key regulator of colorectal cancer development. Int J Biol Sci 8:1248–1253PubMedCentralPubMedGoogle Scholar
  55. 55.
    Yamamoto K, Rose-John S (2012) Therapeutic blockade of interleukin-6 in chronic inflammatory disease. Clin Pharmacol Ther 91:574–576. doi:10.1038/clpt.2012.11 PubMedGoogle Scholar
  56. 56.
    Neurath MF, Finotto S (2011) IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer. Cytokine Growth Factor Rev 22:83–89. doi:10.1016/j.cytogfr.2011.02.003 PubMedGoogle Scholar
  57. 57.
    Jarnicki A, Putoczki T, Ernst M (2010) Stat3: linking inflammation to epithelial cancer—more than a “gut” feeling? Cell Div 5:14. doi:10.1186/1747-1028-5-14 PubMedCentralPubMedGoogle Scholar
  58. 58.
    Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798–809. doi:10.1038/nrc2734 PubMedGoogle Scholar
  59. 59.
    Waldner MJ, Wirtz S, Jefremow A et al (2010) VEGF receptor signaling links inflammation and tumorigenesis in colitis-associated cancer. J Exp Med 207:2855–2868PubMedCentralPubMedGoogle Scholar
  60. 60.
    Grivennikov S, Karin E, Terzic J et al (2009) IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15:103–113. doi:10.1016/j.ccr.2009.01.001 PubMedCentralPubMedGoogle Scholar
  61. 61.
    Grivennikov S, Karin M (2008) Autocrine IL-6 signaling: a key event in tumorigenesis? Cancer Cell 13:7–9. doi:10.1016/j.ccr.2007.12.020 PubMedGoogle Scholar
  62. 62.
    Putoczki TL, Thiem S, Loving A et al (2013) Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically. Cancer Cell 24:257–271. doi:10.1016/j.ccr.2013.06.017 PubMedGoogle Scholar
  63. 63.
    Chung Y-C, Chang Y-F (2003) Significance of inflammatory cytokines in the progression of colorectal cancer. Hepatogastroenterology 50:1910–1913PubMedGoogle Scholar
  64. 64.
    Tanaka T, Narazaki M, Kishimoto T (2012) Therapeutic targeting of the interleukin-6 receptor. Annu Rev Pharmacol Toxicol 52:199–219. doi:10.1146/annurev-pharmtox-010611-134715 PubMedGoogle Scholar
  65. 65.
    Rutgeerts P, Sandborn WJ, Feagan BG et al (2005) Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 353:2462–2476. doi:10.1056/NEJMoa050516 PubMedGoogle Scholar
  66. 66.
    Popivanova BK, Kitamura K, Wu Y et al (2008) Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. J Clin Invest 118:560–570PubMedCentralPubMedGoogle Scholar
  67. 67.
    Kim YJ, Hong KS, Chung JW et al (2010) Prevention of colitis-associated carcinogenesis with infliximab. Cancer Prev Res (Phila) 3:1314–1333. doi:10.1158/1940-6207.CAPR-09-0272 Google Scholar
  68. 68.
    Berg DJ, Davidson N, Kühn R et al (1996) Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. J Clin Invest 98:1010–1020. doi:10.1172/JCI118861 PubMedCentralPubMedGoogle Scholar
  69. 69.
    Rennick DM, Fort MM, Davidson NJ (1997) Studies with IL-10-/- mice: an overview. J Leukoc Biol 61:389–396PubMedGoogle Scholar
  70. 70.
    Kühn R, Löhler J, Rennick D et al (1993) Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75:263–274PubMedGoogle Scholar
  71. 71.
    Grütz G (2005) New insights into the molecular mechanism of interleukin-10-mediated immunosuppression. J Leukoc Biol 77:3–15. doi:10.1189/jlb.0904484 PubMedGoogle Scholar
  72. 72.
    Franke A, Balschun T, Karlsen TH et al (2008) Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat Genet 40:1319–1323. doi:10.1038/ng.221 PubMedGoogle Scholar
  73. 73.
    Danese S (2012) New therapies for inflammatory bowel disease: from the bench to the bedside. Gut 61:918–932. doi:10.1136/gutjnl-2011-300904 PubMedGoogle Scholar
  74. 74.
    Sturlan S, Oberhuber G, Beinhauer BG et al (2001) Interleukin-10-deficient mice and inflammatory bowel disease associated cancer development. Carcinogenesis 22:665–671PubMedGoogle Scholar
  75. 75.
    Buonocore S, Ahern PP, Uhlig HH et al (2010) Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464:1371–1375. doi:10.1038/nature08949 PubMedCentralPubMedGoogle Scholar
  76. 76.
    Yen D, Cheung J, Scheerens H et al (2006) IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest 116:1310–1316. doi:10.1172/JCI21404 PubMedCentralPubMedGoogle Scholar
  77. 77.
    Grivennikov SI, Wang K, Mucida D et al (2012) Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491:254–258. doi:10.1038/nature11465 PubMedCentralPubMedGoogle Scholar
  78. 78.
    Langowski JL, Zhang X, Wu L et al (2006) IL-23 promotes tumour incidence and growth. Nature 442:461–465. doi:10.1038/nature04808 PubMedGoogle Scholar
  79. 79.
    Hinoi T, Akyol A, Theisen BK et al (2007) Mouse model of colonic adenoma-carcinoma progression based on somatic Apc inactivation. Cancer Res 67:9721–9730. doi:10.1158/0008-5472.CAN-07-2735 PubMedGoogle Scholar
  80. 80.
    Hurwitz HI, Yi J, Ince W et al (2009) The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. Oncologist 14:22–28PubMedGoogle Scholar
  81. 81.
    Costa C, Incio J, Soares R (2007) Angiogenesis and chronic inflammation: cause or consequence? Angiogenesis 10:149–166PubMedGoogle Scholar
  82. 82.
    Yoo S-A, Kwok S-K, Kim W-U (2008) Proinflammatory role of vascular endothelial growth factor in the pathogenesis of rheumatoid arthritis: prospects for therapeutic intervention. Mediators Inflamm 2008:129873PubMedCentralPubMedGoogle Scholar
  83. 83.
    Scaldaferri F, Vetrano S, Sans M et al (2009) VEGF-A links angiogenesis and inflammation in inflammatory bowel disease pathogenesis. Gastroenterology 136(585):595.e5Google Scholar
  84. 84.
    Jänne PA, Mayer RJ (2000) Chemoprevention of colorectal cancer. N Engl J Med 342:1960–1968PubMedGoogle Scholar
  85. 85.
    Gupta RA, Dubois RN (2001) Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer 1:11–21. doi:10.1038/35094017 PubMedGoogle Scholar
  86. 86.
    Raju R, Cruz-Correa M (2006) Chemoprevention of colorectal cancer. Dis Colon Rectum 49:113–115PubMedGoogle Scholar
  87. 87.
    Velayos FS, Terdiman JP, Walsh JM (2005) Effect of 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and metaanalysis of observational studies. Am J Gastroenterol 100(6):1345–1353 (Division of Gastroenterology and UCSF Center for Colitis and Crohn’s Disease, University of California, San Francisco, California 94143, USA)PubMedGoogle Scholar
  88. 88.
    Rubin DT, Cruz-Correa MR, Gasche C et al (2008) Colorectal cancer prevention in inflammatory bowel disease and the role of 5-aminosalicylic acid: a clinical review and update. Inflamm Bowel Dis 14:265–274. doi:10.1002/ibd.20297 PubMedGoogle Scholar
  89. 89.
    Ishikawa T-O, Herschman HR (2010) Tumor formation in a mouse model of colitis-associated colon cancer does not require COX-1 or COX-2 expression. Carcinogenesis 31:729–736. doi:10.1093/carcin/bgq002 PubMedCentralPubMedGoogle Scholar
  90. 90.
    Waldner MJ, Neurath MF (2009) Colitis-associated cancer: the role of T cells in tumor development. Semin Immunopathol 31:249–256. doi:10.1007/s00281-009-0161-8 PubMedGoogle Scholar
  91. 91.
    Mangerich A, Knutson CG, Parry NM, et al. (2012) Infection-induced colitis in mice causes dynamic and tissue-specific changes in stress response and DNA damage leading to colon cancer. http://www.pnas.org/cgi/doi/10.1073/pnas.1207829109
  92. 92.
    Podolsky DK (2002) Inflammatory bowel disease. N Engl J Med 347:417–429. doi:10.1056/NEJMra020831 PubMedGoogle Scholar
  93. 93.
    Shibata M, Nezu T, Kanou H et al (2002) Decreased production of interleukin-12 and type 2 immune responses are marked in cachectic patients with colorectal and gastric cancer. J Clin Gastroenterol 34:416–420PubMedGoogle Scholar
  94. 94.
    Pagès F, Berger A, Camus M et al (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353:2654–2666. doi:10.1056/NEJMoa051424 PubMedGoogle Scholar
  95. 95.
    Kettunen HL, Kettunen ASL, Rautonen NE (2003) Intestinal immune responses in wild-type and Apcmin/+ mouse, a model for colon cancer. Cancer Res 63:5136–5142PubMedGoogle Scholar
  96. 96.
    Wolf D, Wolf AM, Rumpold H et al (2005) The expression of the regulatory T cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer. Clin Cancer Res 11:8326–8331. doi:10.1158/1078-0432.CCR-05-1244 PubMedGoogle Scholar
  97. 97.
    Erdman SE, Sohn JJ, Rao VP et al (2005) CD4+ CD25+ regulatory lymphocytes induce regression of intestinal tumors in ApcMin/+ mice. Cancer Res 65:3998–4004. doi:10.1158/0008-5472.CAN-04-3104 PubMedGoogle Scholar
  98. 98.
    Erdman SE, Poutahidis T (2010) Roles for inflammation and regulatory T cells in colon cancer. Toxicol Pathol 38:76–87. doi:10.1177/0192623309354110 PubMedCentralPubMedGoogle Scholar
  99. 99.
    Műzes G, Molnár B, Sipos F (2012) Regulatory T cells in inflammatory bowel diseases and colorectal cancer. World J Gastroenterol 18:5688–5694. doi:10.3748/wjg.v18.i40.5688 PubMedCentralPubMedGoogle Scholar
  100. 100.
    Clevers H (2004) At the crossroads of inflammation and cancer. Cell 118:671–674PubMedGoogle Scholar
  101. 101.
    Barker N, van Es JH, Kuipers J et al (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449:1003–1007PubMedGoogle Scholar
  102. 102.
    Sato T, Vries RG, Snippert HJ et al (2009) Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459:262–265PubMedGoogle Scholar
  103. 103.
    Barker N, Ridgway RA, van Es JH et al (2009) Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457:608–611PubMedGoogle Scholar
  104. 104.
    Schwitalla S, Fingerle Aa, Cammareri P et al (2013) Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152:25–38. doi:10.1016/j.cell.2012.12.012 PubMedGoogle Scholar
  105. 105.
    Neufert C, Becker C, Türeci Ö et al (2013) Tumor fibroblast-derived epiregulin promotes growth of colitis-associated neoplasms through ERK. J Clin Invest 123:1428–1443. doi:10.1172/JCI63748 PubMedCentralPubMedGoogle Scholar
  106. 106.
    Guarner F, Malagelada J-R (2003) Gut flora in health and disease. Lancet 361:512–519. doi:10.1016/S0140-6736(03)12489-0 PubMedGoogle Scholar
  107. 107.
    Cho I, Blaser MJ (2012) The human microbiome: at the interface of health and disease. Nat Rev Genet 13:260–270. doi:10.1038/nrg3182 PubMedCentralPubMedGoogle Scholar
  108. 108.
    Rous P, Beard JW (1935) The progression to carcinoma of virus-induced rabbit papillomas (SHOPE). J Exp Med 62:523–548PubMedCentralPubMedGoogle Scholar
  109. 109.
    Schwabe RF, Jobin C (2013) The microbiome and cancer. Nat Rev Cancer 13:800–812. doi:10.1038/nrc3610 PubMedCentralPubMedGoogle Scholar
  110. 110.
    Li Y, Kundu P, Seow SW et al (2012) Gut microbiota accelerate tumor growth via c-jun and STAT3 phosphorylation in APCMin/+ mice. Carcinogenesis 33:1231–1238. doi:10.1093/carcin/bgs137 PubMedGoogle Scholar
  111. 111.
    Strober W, Fuss IJ (2006) Experimental models of mucosal inflammation. Adv Exp Med Biol 579:55–97. doi:10.1007/0-387-33778-4_5 PubMedGoogle Scholar
  112. 112.
    Arthur JC, Perez-Chanona E, Mühlbauer M et al (2012) Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 338:120–123. doi:10.1126/science.1224820 PubMedCentralPubMedGoogle Scholar
  113. 113.
    Wu S, Rhee K-J, Albesiano E et al (2009) A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med 15:1016–1022. doi:10.1038/nm.2015 PubMedCentralPubMedGoogle Scholar
  114. 114.
    Chichlowski M, Sharp JM, Vanderford DA et al (2008) Helicobacter typhlonius and Helicobacter rodentium differentially affect the severity of colon inflammation and inflammation-associated neoplasia in IL10-deficient mice. Comp Med 58:534–541PubMedCentralPubMedGoogle Scholar
  115. 115.
    Iliev ID, Funari VA, Taylor KD et al (2012) Interactions between commensal fungi and the C-type lectin receptor dectin-1 influence colitis. Science 336:1314–1317. doi:10.1126/science.1221789 PubMedCentralPubMedGoogle Scholar
  116. 116.
    Relton CL, Smith GD (2010) Epigenetic epidemiology of common complex disease: prospects for prediction, prevention, and treatment. PLoS Med. doi:10.1371/journal.pmed.1000356 PubMedCentralPubMedGoogle Scholar
  117. 117.
    Ventham NT, Kennedy Na, Nimmo ER, Satsangi J (2013) Beyond gene discovery in inflammatory bowel disease: the emerging role of epigenetics. Gastroenterology 145:293–308. doi:10.1053/j.gastro.2013.05.050 PubMedCentralPubMedGoogle Scholar
  118. 118.
    Saito S, Kato J, Hiraoka S et al (2011) DNA methylation of colon mucosa in ulcerative colitis patients: correlation with inflammatory status. Inflamm Bowel Dis 17:1955–1965. doi:10.1002/ibd.21573 PubMedGoogle Scholar
  119. 119.
    Dhir M, Montgomery EA, Glöckner SC et al (2008) Epigenetic regulation of WNT signaling pathway genes in inflammatory bowel disease (IBD) associated neoplasia. J Gastrointest Surg 12:1745–1753. doi:10.1007/s11605-008-0633-5 PubMedCentralPubMedGoogle Scholar
  120. 120.
    Issa JP, Ahuja N, Toyota M et al (2001) Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res 61:3573–3577PubMedGoogle Scholar
  121. 121.
    Tao R, de Zoeten EF, Ozkaynak E et al (2007) Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med 13:1299–1307. doi:10.1038/nm1652 PubMedGoogle Scholar
  122. 122.
    Rosen MJ, Frey MR, Washington MK et al (2011) STAT6 activation in ulcerative colitis: a new target for prevention of IL-13-induced colon epithelial cell dysfunction. Inflamm Bowel Dis 17:2224–2234. doi:10.1002/ibd.21628 PubMedCentralPubMedGoogle Scholar
  123. 123.
    Bian Z, Li L, Cui J et al (2011) Role of miR-150-targeting c-Myb in colonic epithelial disruption during dextran sulphate sodium-induced murine experimental colitis and human ulcerative colitis. J Pathol 225:544–553. doi:10.1002/path.2907 PubMedGoogle Scholar
  124. 124.
    Wu F, Zikusoka M, Trindade A et al (2008) MicroRNAs are differentially expressed in ulcerative colitis and alter expression of macrophage inflammatory peptide-2α. Gastroenterology. doi:10.1053/j.gastro.2008.07.068 Google Scholar
  125. 125.
    McKenna LB, Schug J, Vourekas A et al (2010) MicroRNAs control intestinal epithelial differentiation, architecture, and barrier function. Gastroenterology. doi:10.1053/j.gastro.2010.07.040 PubMedCentralGoogle Scholar
  126. 126.
    Bernstein CN, Shanahan F, Weinstein WM (1994) Are we telling patients the truth about surveillance colonoscopy in ulcerative colitis? Lancet 343:71–74PubMedGoogle Scholar
  127. 127.
    Rutter MD, Saunders BP, Wilkinson KH et al (2004) Cancer surveillance in longstanding ulcerative colitis: endoscopic appearances help predict cancer risk. Gut 53:1813–1816PubMedCentralPubMedGoogle Scholar
  128. 128.
    Rubin CE, Haggitt RC, Burmer GC et al (1992) DNA aneuploidy in colonic biopsies predicts future development of dysplasia in ulcerative colitis. YGAST 103:1611–1620Google Scholar
  129. 129.
    Hoffman A, Kagel C, Goetz M et al (2008) High definition colonoscopy (HD plus) with I-scan function allows to recognize and characterize flat neoplastic changes as precisely as chromoendoscopy. Gastrointest Endosc 67:AB125Google Scholar
  130. 130.
    Wu L, Li P, Wu J et al (2012) The diagnostic accuracy of chromoendoscopy for dysplasia in ulcerative colitis: meta-analysis of six randomized controlled trials. Colorectal Dis 14:416–420PubMedGoogle Scholar
  131. 131.
    Neumann H, Mönkemüller K, Günther C et al (2012) Advanced endoscopic imaging for diagnosis of Crohn’s disease. Gastroenterol Res Pract 2012:301541PubMedCentralPubMedGoogle Scholar
  132. 132.
    Kiesslich R, Fritsch J, Holtmann M et al (2003) Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 124:880–888PubMedGoogle Scholar
  133. 133.
    Rutter MD, Saunders BP, Schofield G et al (2004) Pancolonic indigo carmine dye spraying for the detection of dysplasia in ulcerative colitis. Gut 53:256–260PubMedCentralPubMedGoogle Scholar
  134. 134.
    Kiesslich R, Burg J, Vieth M et al (2004) Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo. Gastroenterology 127:706–713PubMedGoogle Scholar
  135. 135.
    Kiesslich R, Goetz M, Lammersdorf K et al (2007) Chromoscopy-guided endomicroscopy increases the diagnostic yield of intraepithelial neoplasia in ulcerative colitis. Gastroenterology 132:874–882PubMedGoogle Scholar
  136. 136.
    Hurlstone DP, Thomson M, Brown S et al (2007) Confocal endomicroscopy in ulcerative colitis: differentiating dysplasia-associated lesional mass and adenoma-like mass. Clin Gastroenterol Hepatol 5:1235–1241PubMedGoogle Scholar
  137. 137.
    Hurlstone DP, Kiesslich R, Thomson M et al (2007) Confocal chromoscopic endomicroscopy is superior to chromoscopy alone for the detection and characterisation of intraepithelial neoplasia in chronic ulcerative colitis. Gut 57:196–204Google Scholar
  138. 138.
    Goetz M, Ziebart A, Foersch S et al (2010) In vivo molecular imaging of colorectal cancer with confocal endomicroscopy by targeting epidermal growth factor receptor. Gastroenterology 138:435–446PubMedGoogle Scholar
  139. 139.
    Foersch S, Kiesslich R, Waldner MJ et al (2010) Molecular imaging of VEGF in gastrointestinal cancer in vivo using confocal laser endomicroscopy. Gut 59:1046–1055PubMedGoogle Scholar
  140. 140.
    Foersch S, Neufert C, Neurath MF, Waldner MJ (2013) Endomicroscopic imaging of COX-2 activity in murine sporadic and colitis-associated colorectal cancer. Diagn Ther Endosc 2013:250641. doi:10.1155/2013/250641 PubMedCentralPubMedGoogle Scholar
  141. 141.
    Atreya R, Neumann H, Neufert C et al (2014) In vivo imaging using fluorescent antibodies to tumor necrosis factor predicts therapeutic response in Crohn’s disease. Nat Med 20:313–318. doi:10.1038/nm.3462 PubMedGoogle Scholar
  142. 142.
    Schürmann S, Foersch S, Atreya R et al (2013) Label-free imaging of inflammatory bowel disease using multiphoton microscopy. Gastroenterology 145:514–516. doi:10.1053/j.gastro.2013.06.054 PubMedGoogle Scholar
  143. 143.
    Eaden J, Abrams K, Ekbom A et al (2000) Colorectal cancer prevention in ulcerative colitis: a case-control study. Aliment Pharmacol Ther 14:145–153PubMedGoogle Scholar
  144. 144.
    Eaden J (2003) Review article: the data supporting a role for aminosalicylates in the chemoprevention of colorectal cancer in patients with inflammatory bowel disease. Aliment Pharmacol Ther 18(Suppl 2):15–21PubMedGoogle Scholar
  145. 145.
    Bernstein CN, Eaden J, Steinhart AH et al (2002) Cancer prevention in inflammatory bowel disease and the chemoprophylactic potential of 5-aminosalicylic acid. Inflamm Bowel Dis 8:356–361PubMedGoogle Scholar
  146. 146.
    Brown WA, Farmer KC, Skinner SA et al (2000) 5-aminosalicyclic acid and olsalazine inhibit tumor growth in a rodent model of colorectal cancer. Dig Dis Sci 45:1578–1584PubMedGoogle Scholar
  147. 147.
    MacGregor DJ, Kim YS, Sleisenger MH, Johnson LK (2000) Chemoprevention of colon cancer carcinogenesis by balsalazide: inhibition of azoxymethane-induced aberrant crypt formation in the rat colon and intestinal tumor formation in the B6-Min/+ mouse. Int J Oncol 17:173–179PubMedGoogle Scholar
  148. 148.
    Lindberg B, Persson B, Veress B et al (1996) Twenty years’ colonoscopic surveillance of patients with ulcerative colitis. Detection of dysplastic and malignant transformation. Scand J Gastroenterol 31:1195–1204PubMedGoogle Scholar
  149. 149.
    Herfarth H (2012) The role of chemoprevention of colorectal cancer with 5-aminosalicylates in ulcerative colitis. Dig Dis 30(Suppl 2):55–59. doi:10.1159/000341894 PubMedGoogle Scholar
  150. 150.
    Tung BY, Emond MJ, Haggitt RC et al (2001) Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Ann Intern Med 134:89–95PubMedGoogle Scholar
  151. 151.
    Pardi DS, Loftus EV, Kremers WK et al (2003) Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis. YGAST 124:889–893Google Scholar
  152. 152.
    Ikegami T, Matsuzaki Y (2008) Ursodeoxycholic acid: mechanism of action and novel clinical applications. Hepatol Res 38:123–131PubMedGoogle Scholar
  153. 153.
    Eaton JE, Silveira MG, Pardi DS et al (2011) High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Am J Gastroenterol 106:1638–1645PubMedCentralPubMedGoogle Scholar
  154. 154.
    Van Staa TP, Card T, Logan RF, Leufkens HGM (2005) 5-Aminosalicylate use and colorectal cancer risk in inflammatory bowel disease: a large epidemiological study. Gut 54:1573–1578. doi:10.1136/gut.2005.070896 PubMedCentralPubMedGoogle Scholar
  155. 155.
    Chan EP, Lichtenstein GR (2006) Chemoprevention: risk reduction with medical therapy of inflammatory bowel disease. Gastroenterol Clin North Am 35:675–712. doi:10.1016/j.gtc.2006.07.003 PubMedGoogle Scholar
  156. 156.
    Biancone L, Petruzziello C, Calabrese E et al (2009) Long-term safety of Infliximab for the treatment of inflammatory bowel disease: does blocking TNFalpha reduce colitis-associated colorectal carcinogenesis? Gut 58:1703. doi:10.1136/gut.2008.176461 PubMedGoogle Scholar
  157. 157.
    Fidder H, Schnitzler F, Ferrante M et al (2009) Long-term safety of infliximab for the treatment of inflammatory bowel disease: a single-centre cohort study. Gut 58:501–508. doi:10.1136/gut.2008.163642 PubMedGoogle Scholar
  158. 158.
    Caspersen S, Elkjaer M, Riis L et al (2008) Infliximab for inflammatory bowel disease in Denmark 1999–2005: clinical outcome and follow-up evaluation of malignancy and mortality. Clin Gastroenterol Hepatol 6:1212–1217 (quiz 1176)PubMedGoogle Scholar
  159. 159.
    Ullman TA, Itzkowitz SH (2011) Intestinal inflammation and cancer. Gastroenterology 140:1807–1816PubMedGoogle Scholar
  160. 160.
    Farraye FA, Odze RD, Eaden J, Itzkowitz SH (2010) AGA technical review on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology 138:746–774 (774.e1–4; quiz e12–3)PubMedGoogle Scholar

Copyright information

© Springer Basel 2014

Authors and Affiliations

  1. 1.Department of Medicine 1FAU Erlangen-NürnbergErlangenGermany

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