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Archives of Toxicology

, Volume 90, Issue 9, pp 2109–2130 | Cite as

Mouse models of intestinal inflammation and cancer

  • Aya M. Westbrook
  • Akos Szakmary
  • Robert H. Schiestl
Review Article

Abstract

Chronic inflammation is strongly associated with approximately one-fifth of all human cancers. Arising from combinations of factors such as environmental exposures, diet, inherited gene polymorphisms, infections, or from dysfunctions of the immune response, chronic inflammation begins as an attempt of the body to remove injurious stimuli; however, over time, this results in continuous tissue destruction and promotion and maintenance of carcinogenesis. Here, we focus on intestinal inflammation and its associated cancers, a group of diseases on the rise and affecting millions of people worldwide. Intestinal inflammation can be widely grouped into inflammatory bowel diseases (ulcerative colitis and Crohn’s disease) and celiac disease. Long-standing intestinal inflammation is associated with colorectal cancer and small-bowel adenocarcinoma, as well as extraintestinal manifestations, including lymphomas and autoimmune diseases. This article highlights potential mechanisms of pathogenesis in inflammatory bowel diseases and celiac disease, as well as those involved in the progression to associated cancers, most of which have been identified from studies utilizing mouse models of intestinal inflammation. Mouse models of intestinal inflammation can be widely grouped into chemically induced models; genetic models, which make up the bulk of the studied models; adoptive transfer models; and spontaneous models. Studies in these models have lead to the understanding that persistent antigen exposure in the intestinal lumen, in combination with loss of epithelial barrier function, and dysfunction and dysregulation of the innate and adaptive immune responses lead to chronic intestinal inflammation. Transcriptional changes in this environment leading to cell survival, hyperplasia, promotion of angiogenesis, persistent DNA damage, or insufficient repair of DNA damage due to an excess of proinflammatory mediators are then thought to lead to sustained malignant transformation. With regard to extraintestinal manifestations such as lymphoma, however, more suitable models are required to further investigate the complex and heterogeneous mechanisms that may be at play.

Keywords

Intestinal inflammation Intestinal cancer Mouse models 

Notes

Acknowledgments

This work was supported in part by NIH Grant ES09519 (RS), the Jonsson Comprehensive Cancer Foundation (RS), a TRP Grant (L618-B11) from the FWF (AS and RS) and a UCLA-NIEHS training grant in Molecular Toxicology (AW).

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.

References

  1. Abu-Shakra M, Guillemin F, Lee P (1993) Cancer in systemic sclerosis. Arthritis Rheum 36(4):460–464PubMedCrossRefGoogle Scholar
  2. Abu-Shakra M, Gladman D, Urowitz M (1996) Malignancy in systemic lupus erythematosus. Arthritis Rheum 39(6):1050–1054PubMedCrossRefGoogle Scholar
  3. Abu-Shakra M et al (2001) Cancer and autoimmunity: autoimmune and rheumatic features in patients with malignancies. Ann Rheum Dis 60(5):433–441PubMedPubMedCentralCrossRefGoogle Scholar
  4. Alex P, Zachos NC, Nguyen T, Gonzales L, Chen TE, Conklin LS, Centola M, Li X (2009) Distinct cytokine patterns identified from multiplex profiles of murine DSS and TNBS-induced colitis. Inflammatory Bowel Diseases 15(3):341–352PubMedCrossRefPubMedCentralGoogle Scholar
  5. Altindag O et al (2007) Increased DNA damage and oxidative stress in patients with rheumatoid arthritis. Clin Biochem 40(3–4):167–171PubMedCrossRefGoogle Scholar
  6. American Cancer Society (2008) Cancer facts and figures 2008. American Cancer Society, AtlantaGoogle Scholar
  7. Ames BN, Gold LS, Willett WC (1995) The causes and prevention of cancer. Proc Natl Acad Sci 92(12):5258–5265PubMedPubMedCentralCrossRefGoogle Scholar
  8. Amos-Landgraf J, Kwong L, Kendziorski C, Reichelderfer M, Torrealba J, Weichert J, Haag J, Chen K, Waller J, Gould M (2007) A target-selected Apc-mutant rat kindred enhances the modeling of familial human colon cancer. Proc Natl Acad Sci USA 104:4036–4041PubMedPubMedCentralCrossRefGoogle Scholar
  9. An G et al (2007) Increased susceptibility to colitis and colorectal tumors in mice lacking core 3-derived O-glycans. J Exp Med 204(6):1417–1429PubMedPubMedCentralCrossRefGoogle Scholar
  10. Aranda R et al (1997) Analysis of intestinal lymphocytes in mouse colitis mediated by transfer of CD4+, CD45RBhigh T cells to SCID recipients. J Immunol 158(7):3464–3473PubMedGoogle Scholar
  11. Arita M et al (2005) Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Proc Natl Acad Sci 102(21):7671–7676PubMedPubMedCentralCrossRefGoogle Scholar
  12. Atreya R, Mudter J, Finotto S, Müllberg J, Jostock T, Wirtz S, Schütz M, Bartsch B, Holtmann M, Becker C (2000) Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in Crohn disease and experimental colitis in vivo. Nat Med 6(5):583–588PubMedCrossRefGoogle Scholar
  13. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357(9255):539–545PubMedCrossRefGoogle Scholar
  14. Baribault H et al (1994) Colorectal hyperplasia and inflammation in keratin 8-deficient FVB/N mice. Genes Dev 8(24):2964–2973PubMedCrossRefGoogle Scholar
  15. Barrett J et al (2008) Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet 40(8):955–962PubMedPubMedCentralCrossRefGoogle Scholar
  16. Beatty PL et al (2007) Cutting edge: transgenic expression of human MUC1 in IL-10−/− mice accelerates inflammatory bowel disease and progression to colon cancer. J Immunol 179(2):735–739PubMedCrossRefGoogle Scholar
  17. Bensinger SJ et al (2008) LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell 134(1):97–111PubMedPubMedCentralCrossRefGoogle Scholar
  18. Bettelli E et al (2004) Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. J Exp Med 200(1):79–87PubMedPubMedCentralCrossRefGoogle Scholar
  19. Bibiloni R et al (2006) The bacteriology of biopsies differs between newly diagnosed, untreated, Crohn’s disease and ulcerative colitis patients. J Med Microbiol 55(8):1141–1149PubMedCrossRefGoogle Scholar
  20. Black KE, Murray JA, David CS (2002) HLA-DQ determines the response to exogenous wheat proteins: a model of gluten sensitivity in transgenic knockout mice. J Immunol 169:5595–600PubMedCrossRefGoogle Scholar
  21. Boirivant M et al (1998) Oxazolone colitis: a murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4. J Exp Med 188(10):1929–1939PubMedPubMedCentralCrossRefGoogle Scholar
  22. Boone DL et al (2004) The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol 5(10):1052–1060PubMedCrossRefGoogle Scholar
  23. Brandwein S et al (1997) Spontaneously colitic C3H/HeJBir mice demonstrate selective antibody reactivity to antigens of the enteric bacterial flora. J Immunol 159(1):44–52PubMedGoogle Scholar
  24. Brimnes J et al (2001) Enteric bacterial antigens activate CD4+ T cells from scid mice with inflammatory bowel disease. Eur J Immunol 31(1):23–31PubMedCrossRefGoogle Scholar
  25. Brimnes J et al (2005) Defects in CD8+ regulatory T cells in the lamina propria of patients with inflammatory bowel disease. J Immunol 174(9):5814–5822PubMedCrossRefGoogle Scholar
  26. Camoglio L et al (2000) Hapten-induced colitis associated with maintained Th1 and inflammatory responses in IFN-receptor-deficient mice. Eur J Immunol 30(5):1486–1495PubMedCrossRefGoogle Scholar
  27. Canavan C, Abrams KR, Mayberry J (2006) Meta-analysis: colorectal and small bowel cancer risk in patients with Crohn’s disease. Aliment Pharmacol Ther 23(8):1097–1104PubMedCrossRefGoogle Scholar
  28. Catassi C, Bearzi I, Holmes GKT (2005) Association of celiac disease and intestinal lymphomas and other cancers. Gastroenterology 128(4, Supplement 1):S79–S86PubMedCrossRefGoogle Scholar
  29. Chan RCF et al (2006) Small bowel adenocarcinoma with high levels of microsatellite instability in Crohn’s disease. Hum Pathol 37(5):631–634PubMedCrossRefGoogle Scholar
  30. Chaux P et al (1996) Inflammatory cells infiltrating human colorectal carcinomas express HLA class II but not B7-1 and B7-2 costimulatory molecules of the T-cell activation. Lab Invest 74(5):975–984PubMedGoogle Scholar
  31. Chu FF et al (2004) Bacteria-induced intestinal cancer in mice with disrupted Gpx1 and Gpx2 genes. Cancer Res 64(3):962–968PubMedCrossRefGoogle Scholar
  32. Clegg C et al (1997) Thymus dysfunction and chronic inflammatory disease in gp39 transgenic mice. Int Immunol 9(8):1111–1122PubMedCrossRefGoogle Scholar
  33. Colussi C et al (2001) 1, 2-Dimethylhydrazine-induced colon carcinoma and lymphoma in msh2(−/−) mice. J Natl Cancer Inst 93(20):1534–1540PubMedCrossRefGoogle Scholar
  34. Coombes J, Maloy K (2007) Control of intestinal homeostasis by regulatory T cells and dendritic cells. Elsevier, AmsterdamGoogle Scholar
  35. Cooper HS et al (1993) Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest 69(2):238–249PubMedGoogle Scholar
  36. Cooper HS et al (2000) Dysplasia and cancer in the dextran sulfate sodium mouse colitis model. Relevance to colitis-associated neoplasia in the human: a study of histopathology, B-catenin and p53 expression and the role of inflammation. Carcinogenesis 21(4):757–768PubMedCrossRefGoogle Scholar
  37. Cotran RS, Kumar V, Collins T (1999) Robbins pathological basis of disease, 6th edn. WB Saunders, Philadelphia, pp 50–458Google Scholar
  38. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420(6917):860–867PubMedPubMedCentralCrossRefGoogle Scholar
  39. Coussens LM et al (1999) Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev 13(11):1382–1397PubMedPubMedCentralCrossRefGoogle Scholar
  40. De Giorgi V et al (2009) In vivo characterization of the inflammatory infiltrate and apoptotic status in imiquimod-treated basal cell carcinoma. Int J Dermatol 48:312–321PubMedCrossRefGoogle Scholar
  41. de Kauwe AL et al (2009) Resistance to celiac disease in humanized HLA-DR3-DQ2-transgenic mice expressing specific anti-gliadin CD4+ T cells. J Immunol 182(12):7440–7450PubMedCrossRefGoogle Scholar
  42. De Marzo AM et al (2007) Inflammation in prostate carcinogenesis. Nat Rev Cancer 7(4):256–269PubMedPubMedCentralCrossRefGoogle Scholar
  43. Delaunoit T et al (2005) Pathogenesis and risk factors of small bowel adenocarcinoma: a colorectal cancer sibling? Am J Gastroenterol 100(3):703–710PubMedCrossRefGoogle Scholar
  44. D’Haens G et al (1998) Early lesions of recurrent Crohn’s disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology 114(2):262–267PubMedCrossRefGoogle Scholar
  45. Dieleman LA et al (1994) Dextran sulfate sodium-induced colitis occurs in severe combined immunodeficient mice. Gastroenterology 107(6):1643–1652PubMedCrossRefGoogle Scholar
  46. Dominici F et al (2006) Fine particulate air pollution and hospital admission for cardiovascular and respiratory diseases. J Am Med Assoc 295(10):1127–1134CrossRefGoogle Scholar
  47. Dotan I (2007) Serologic markers in inflammatory bowel disease: tools for better diagnosis and disease stratification. Expert Rev Gastroenterol Hepatol 1(2):265–274PubMedCrossRefGoogle Scholar
  48. Eckburg P, Relman DA (2007) The role of microbes in Crohn’s disease. Clin Infect Dis 44:256–262PubMedCrossRefGoogle Scholar
  49. Elder D, Paraskeva C (1999) Induced apoptosis in the prevention of colorectal cancer by non-steroidal anti-inflammatory drugs. Apoptosis 4(5):365–372PubMedCrossRefGoogle Scholar
  50. Elgbratt K et al (2007) Aberrant T-cell ontogeny and defective thymocyte and colonic T-cell chemotactic migration in colitis-prone Gai2-deficient mice. Immunology 122(2):199–209PubMedPubMedCentralCrossRefGoogle Scholar
  51. Elson C et al (2005) Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota. Immunol Rev 206(1):260–276PubMedCrossRefGoogle Scholar
  52. Engle SJ et al (2002) Elimination of colon cancer in germ-free transforming growth factor beta 1-deficient mice. Cancer Res 62(22):6362–6366PubMedGoogle Scholar
  53. Erdman SE et al (2001) Cutting edge: typhlocolitis in NF-{{kappa}}B-deficient mice. J Immunol 166(3):1443–1447PubMedCrossRefGoogle Scholar
  54. Erdman SE et al (2003) CD4+ CD25+ regulatory T lymphocytes inhibit microbially induced colon cancer in Rag2-deficient mice. Am J Pathol 162(2):691–702PubMedPubMedCentralCrossRefGoogle Scholar
  55. Esensten JH et al (2009) T-bet-deficient NOD mice are protected from diabetes due to defects in both T cell and innate immune system function. J Immunol 183(1):75–82PubMedPubMedCentralCrossRefGoogle Scholar
  56. Farrell R, LaMont J (2002) Microbial factors in inflammatory bowel disease. Gastroenterol Clin North Am 31(1):41–62PubMedCrossRefGoogle Scholar
  57. Festen EA et al (2009) Inflammatory bowel disease and celiac disease: overlaps in the pathology and genetics, and their potential drug targets. Endocr Metab Immune Disord Drug Targets 9(2):199–218PubMedCrossRefGoogle Scholar
  58. Fichtner-Feigl S et al (2005) Treatment of murine Th1-and Th2-mediated inflammatory bowel disease with NF-B decoy oligonucleotides. J Clin Invest 115(11):3057–3071PubMedPubMedCentralCrossRefGoogle Scholar
  59. Fina D et al (2008) Interleukin 21 contributes to the mucosal T helper cell type 1 response in coeliac disease. Gut 57(7):887–892PubMedCrossRefGoogle Scholar
  60. Frank D et al (2007) Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci 104(34):13780–13785PubMedPubMedCentralCrossRefGoogle Scholar
  61. Funabashi H et al (2001) Establishment of a Tcrb and Trp53 genes deficient mouse strain as an animal model for spontaneous colorectal cancer. Exp Anim 50(1):41–47CrossRefPubMedGoogle Scholar
  62. Garlanda C et al (2004) Intestinal inflammation in mice deficient in Tir8, an inhibitory member of the IL-1 receptor family. Proc Natl Acad Sci USA 101(10):3522–3526PubMedPubMedCentralCrossRefGoogle Scholar
  63. Garrett WS et al (2007) Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131(1):33–45PubMedPubMedCentralCrossRefGoogle Scholar
  64. Garrett WS et al (2009) Colitis-associated colorectal cancer driven by T-bet deficiency in dendritic cells. Cancer Cell 16(3):208–219PubMedPubMedCentralCrossRefGoogle Scholar
  65. Gorelik L, Flavell RA (2000) Abrogation of TGF[beta] signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12(2):171–181PubMedCrossRefGoogle Scholar
  66. Green PHR, Jabri B (2003a) Celiac disease and other precursors to small-bowel malignancy. Hematol Oncol Clin North Am 17(2):611–624CrossRefGoogle Scholar
  67. Green PHR, Jabri B (2003b) Coeliac disease. Lancet 362(9381):383–391PubMedCrossRefGoogle Scholar
  68. Greenstein AJ et al (1985) Extraintestinal cancers in inflammatory bowel disease. Cancer 56(12):2914–2921PubMedCrossRefGoogle Scholar
  69. Gryfe R, Kim H, Hsieh ETK, Aronson MD, Holowaty EJ, Bull SB, Redston M, Gallinger S (2000) Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 342:69–77PubMedCrossRefGoogle Scholar
  70. Guldenschuh I, Hurlimann R, Muller A, Ammann R, Mullhaupt B, Dobbie Z, Zala G, Flury R, Seelentag W, Roth J (2001) Relationship between APC genotype, polyp distribution, and oral sulindac treatment in the colon and rectum of patients with familial adenomatous polyposis. Dis Colon Rectum 44:1090–1097PubMedCrossRefGoogle Scholar
  71. Hanada T et al (2006) IFN{gamma}-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice. J Exp Med 203(6):1391–1397PubMedPubMedCentralCrossRefGoogle Scholar
  72. Hecht S (1997) Tobacco and cancer: approaches using carcinogen biomarkers and chemoprevention. Ann N Y Acad Sci 833(1 Cancer: Genetics and the Environment): 91–111Google Scholar
  73. Heller F et al (2002) Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 17(5):629–638PubMedCrossRefGoogle Scholar
  74. Heller F et al (2005) Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 129(2):550–564PubMedCrossRefGoogle Scholar
  75. Hermiston M, Gordon J (1995) Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin. Science 270(5239):1203–1237PubMedCrossRefGoogle Scholar
  76. Hoffmann J, Pawlowski N, Kühl A, Höhne W, Zeitz M (2000) Animal models of inflammatory bowel disease: an overview. Pathobiology 70:121–130CrossRefGoogle Scholar
  77. Hollander GA, Simpson SJ, Mizoguchi E, Nichogiannopoulou A, She J, Gutierrez-Ramos JC, Bhan AK, Burakoff SJ, Wang B, Terhorst C (1995) Severe colitis in mice with aberrant thymic selection. Immunity 3(1):27–38PubMedCrossRefGoogle Scholar
  78. Hovhannisyan Z, Weiss A, Martin A, Wiesner M, Tollefsen S, Yoshida K, Ciszewski C, Curran SA, Murray JA, David CS, Sollid LM, Koning F, Teyton L, Jabri B (2008) The role of HLA-DQ8 β57 polymorphism in the anti-gluten T-cell response in coeliac disease. Nature 456:534–538PubMedPubMedCentralCrossRefGoogle Scholar
  79. Huang TT et al (2003) TCR-mediated hyper-responsiveness of autoimmune Galphai2(−/−) mice is an intrinsic naive CD4(+) T cell disorder selective for the Galphai2 subunit. Int Immunol 15(11):1359–1367PubMedCrossRefGoogle Scholar
  80. Hugot J et al (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411(6837):599–603PubMedCrossRefGoogle Scholar
  81. Iijima H et al (2004) Specific regulation of T helper cell 1—mediated murine colitis by CEACAM1. J Exp Med 199(4):471–482PubMedPubMedCentralCrossRefGoogle Scholar
  82. Iqbal N, Oliver J, Wagner F, Lazenby A, Elson C, Weaver C (2002) T helper 1 and T helper 2 cells are pathogenic in an antigen-specific model of colitis. J Exp Med 195(1):71–84PubMedCentralCrossRefPubMedGoogle Scholar
  83. Issa J et al (2001) Accelerated age-related CpG Island methylation in ulcerative colitis 1. Cancer Res 61(9):3573–3577PubMedGoogle Scholar
  84. Itzkowitz SH, Yio X (2004) Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Liver Physiol 287(1):G7–G17PubMedCrossRefGoogle Scholar
  85. Jess T et al (2005) Increased risk of intestinal cancer in Crohn’s disease: a meta-analysis of population-based cohort studies. Am J Gastroenterol 100(12):2724–2729PubMedCrossRefGoogle Scholar
  86. Kado S et al (2001) 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 61(6):2395–2398PubMedGoogle Scholar
  87. Kakazu T et al (1999) Type 1 T-helper cell predominance in granulomas of Crohn’s disease. Am J Gastroenterol 94(8):2149–2155PubMedCrossRefGoogle Scholar
  88. Kanagarajan N et al (2008) Disease modifying effect of statins in dextran sulfate sodium model of mouse colitis. Inflamm Res 57(1):34–38PubMedCrossRefGoogle Scholar
  89. Kang S et al (2008) An antibiotic-responsive mouse model of fulminant ulcerative colitis. PLoS Med 5(3):e41PubMedPubMedCentralCrossRefGoogle Scholar
  90. Kaser A et al (2008) XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134(5):743–756PubMedPubMedCentralCrossRefGoogle Scholar
  91. Kastenbauer S, Ziegler-Heitbrock H (1999) NF-kappaB1 (p50) is upregulated in lipopolysaccharide tolerance and can block tumor necrosis factor gene expression. Infect Immun 67(4):1553–1559PubMedCentralPubMedGoogle Scholar
  92. Kobayashi M et al (2003) Toll-like receptor-dependent production of IL-12p40 causes chronic enterocolitis in myeloid cell-specific Stat3-deficient mice. J Clin Invest 111(9):1297–1308PubMedPubMedCentralCrossRefGoogle Scholar
  93. Kobayashi KS et al (2005) Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307(5710):731–734PubMedCrossRefGoogle Scholar
  94. Kohno H, Suzuki R, Sugie S, Tanaka T (2005) Beta-Catenin mutations in a mouse model of inflammation-related colon carcinogenesis induced by 1,2-dimethylhydrazine and dextran sodium sulfate. Cancer Sci 96(2):69–76PubMedCrossRefGoogle Scholar
  95. Kontoyiannis D et al (1999) Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 10:387–398PubMedCrossRefGoogle Scholar
  96. Kruis W et al (2004) Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut 53(11):1617–1623PubMedPubMedCentralCrossRefGoogle Scholar
  97. Kühn R et al (1993) Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75(2):263–274PubMedCrossRefGoogle Scholar
  98. Kühnel D, Taugner F, Scholtka B, Steinberg P (2009) Inflammation does not precede or accompany the induction of preneoplastic lesions in the colon of 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine-fed rats. Arch Toxicol 83:763–768PubMedCrossRefGoogle Scholar
  99. Kulkarni AB et al (1995) Transforming growth factor-beta 1 null mice. An animal model for inflammatory disorders. Am J Pathol 146(1):264–275PubMedPubMedCentralGoogle Scholar
  100. Kullberg M, Andersen J, Gorelick P, Caspar P, Suerbaum S, Fox J, Cheever A, Jankovic D, Sher A (2003) Induction of colitis by a CD4+ T cell clone specific for a bacterial epitope. Proc Natl Acad Sci USA 100(26):15830–15835PubMedPubMedCentralCrossRefGoogle Scholar
  101. Kuper H, Adami HO, Trichopoulos D (2000) Infections as a major preventable cause of human cancer. J Intern Med 248:171–183PubMedCrossRefGoogle Scholar
  102. Laden F et al (2007) Cause-specific mortality in the unionized US trucking industry. Environ Health Perspect 115(8):1192PubMedPubMedCentralCrossRefGoogle Scholar
  103. Laubitz D et al (2008) Colonic gene expression profile in NHE3-deficient mice: evidence for spontaneous distal colitis. Am J Physiol Gastrointest Liver Physiol 295(1):G63–G77PubMedPubMedCentralCrossRefGoogle Scholar
  104. Lazarus MN et al (2006) Incidence of cancer in a cohort of patients with primary Sjogren’s syndrome. Rheumatology 45(8):1012–1015PubMedCrossRefGoogle Scholar
  105. Lee EG et al (2000) Failure to regulate TNF-induced NF-kappa B and cell death responses in A20-deficient mice. Science 289(5488):2350–2354PubMedPubMedCentralCrossRefGoogle Scholar
  106. Lee S-H et al (2003) Microsatellite instability and suppressed DNA repair enzyme expression in rheumatoid arthritis. J Immunol 170(4):2214–2220PubMedCrossRefGoogle Scholar
  107. Leeds JS et al (2007) Is there an association between coeliac disease and inflammatory bowel diseases? A study of relative prevalence in comparison with population controls. Scand J Gastroenterol 42(10):1214–1220PubMedCrossRefGoogle Scholar
  108. Liao J et al (2008) Increased susceptibility of chronic ulcerative colitis-induced carcinoma development in DNA repair enzyme Ogg1 deficient mice J. Liao and DN Seril contributed equally to this study. Mol Carcinog 47(8):638–646PubMedPubMedCentralCrossRefGoogle Scholar
  109. Prisciandaro L et al (2009) Probiotics and their derivatives as treatments for inflammatory bowel disease. Inflamm Bowel Dis 15(12):1906–1914PubMedCrossRefGoogle Scholar
  110. Mahmud S, Franco E, Aprikian A (2004) Prostate cancer and use of nonsteroidal anti-inflammatory drugs: systematic review and **meta-analysis. Br J Cancer. 90(1):93–99PubMedPubMedCentralCrossRefGoogle Scholar
  111. Marchesi J et al (2007) Rapid and noninvasive metabonomic characterization of inflammatory bowel disease. J Proteome Res 6(2):546–551PubMedCrossRefGoogle Scholar
  112. Marine JC et al (1999) SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality. Cell 98:609–616PubMedCrossRefGoogle Scholar
  113. Mashimo H et al (1996) Impaired defense of intestinal mucosa in mice lacking intestinal trefoil factor. Science 274(5285):262–265PubMedCrossRefGoogle Scholar
  114. Matsumoto S et al (1998) Inflammatory bowel disease-like enteritis and caecitis in a senescence accelerated mouse P1/Yit strain. Gut 43(1):71–78PubMedPubMedCentralCrossRefGoogle Scholar
  115. Matteson E et al (1991) Occurrence of neoplasia in patients with rheumatoid arthritis enrolled in a DMARD Registry. Rheumatoid Arthritis Azathioprine Registry Steering Committee. J Rheumatol 18(6):809–814PubMedGoogle Scholar
  116. McCafferty D-M et al (2000) Spontaneously developing chronic colitis in IL-10/iNOS double-deficient mice. Am J Physiol Gastrointest Liver Physiol 279(1):G90–G99PubMedGoogle Scholar
  117. McGhee JR et al (1998) Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect Immun 66(11):5224–5231Google Scholar
  118. McGovern D, Powrie F (2007) The IL23 axis plays a key role in the pathogenesis of IBD. Gut 56(10):1333PubMedPubMedCentralCrossRefGoogle Scholar
  119. McPherson M et al (2008) Colitis immunoregulation by CD8+ T cell requires T cell cytotoxicity and B cell peptide antigen presentation. Am J Physiol Gastrointest Liver Physiol 295(3):G485–G492. doi: 10.1152/ajpgi.90221.2008 PubMedPubMedCentralCrossRefGoogle Scholar
  120. Meira LB et al (2008) DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice. J Clin Invest 118(7):2516PubMedPubMedCentralGoogle Scholar
  121. Merritt MA et al (2008) Talcum powder, chronic pelvic inflammation and NSAIDs in relation to risk of epithelial ovarian cancer. Int J Cancer 122(1):170–176PubMedCrossRefGoogle Scholar
  122. Mizoguchi A, Mizoguchi E, Bhan A (1999) The critical role of interleukin 4 but not interferon gamma in the pathogenesis of colitis in T-cell receptor alpha mutant mice. Gastroenterology 116(2):320–326PubMedCrossRefGoogle Scholar
  123. Mombaerts P et al (1993) Spontaneous development of inflammatory bowel disease in T cell receptor mutant mice. Cell 75(2):274–282PubMedCrossRefGoogle Scholar
  124. Monteleone G et al (2001) Blocking Smad7 restores TGF- 1 signaling in chronic inflammatory bowel disease. J Clin Invest 108(4):601–609PubMedPubMedCentralCrossRefGoogle Scholar
  125. Mori H et al (1984) Absence of genotoxicity of the carcinogenic sulfated polysaccharides carrageenan and dextran sulfate in mammalian DNA repair and bacterial mutagenicity assays. Nutr Cancer 6(2):92–97PubMedCrossRefGoogle Scholar
  126. Morrissey P et al (1993) CD4+ T cells that express high levels of CD45RB induce wasting disease when transferred into congenic severe combined immunodeficient mice. Disease development is prevented by cotransfer of purified CD4+ T cells. J Exp Med 178(1):237–244PubMedCrossRefGoogle Scholar
  127. Moser A, Pitot H, Dove W (1990) A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247:322–324PubMedCrossRefGoogle Scholar
  128. Munkholm P et al (1994) Intestinal permeability in patients with Crohn’s disease and ulcerative colitis and their first degree relatives. Gut 35(1):68–72PubMedPubMedCentralCrossRefGoogle Scholar
  129. Mylonaki M et al (2005) Molecular characterization of rectal mucosa-associated bacterial flora in inflammatory bowel disease. Inflamm Bowel Dis 11(5):481–487PubMedCrossRefGoogle Scholar
  130. Nemetz N et al (2008) Induction of colitis and rapid development of colorectal tumors in mice deficient in the neuropeptide PACAP. Int J Cancer 122(8):1803–1809PubMedPubMedCentralCrossRefGoogle Scholar
  131. Nenci A et al (2007) Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446(7135):557–561PubMedCrossRefGoogle Scholar
  132. Neurath MF et al (1996) Effects of IL-12 and antibodies to IL-12 on established granulomatous colitis in mice. Ann N Y Acad Sci 795(Interleukin 12 Cellular and Molecular Immunology of an Important Regulatory Cytokine):368–370Google Scholar
  133. Neurath MF et al (2002) The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn’s disease. J Exp Med 195(9):1129–1143PubMedPubMedCentralCrossRefGoogle Scholar
  134. O’Connor W Jr et al (2009) A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat Immunol 10(6):603–609PubMedPubMedCentralCrossRefGoogle Scholar
  135. Ohman L et al (2000) Immune activation in the intestinal mucosa before the onset of colitis in Galphai2-deficient mice. Scand J Immunol 52(1):80–90PubMedCrossRefGoogle Scholar
  136. Okayasu I et al (1990) A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 98(3):694–702PubMedGoogle Scholar
  137. Okuda Y et al (2003) Development of colitis in signal transducers and activators of transcription 6-deficient T-cell receptor -deficient mice a potential role of signal transducers and activators of transcription 6-independent interleukin-4 signaling for the generation of Th2-biased pathological CD4+ T Cells. Am J Pathol 162(1):263–271PubMedPubMedCentralCrossRefGoogle Scholar
  138. O’Sullivan JN et al (2002) Chromosomal instability in ulcerative colitis is related to telomere shortening. Nat Genet 32(2):280–284PubMedCrossRefGoogle Scholar
  139. Panwala CM, Jones JC, Viney JL (1998) A novel model of inflammatory bowel disease: mice deficient for the multiple drug resistance gene, mdr1a, spontaneously develop colitis. J Immunol 161(10):5733–5744PubMedGoogle Scholar
  140. Park JW et al (2009) Restoration of T-box-containing protein expressed in T cells protects against allergen-induced asthma. J Allergy Clin Immunol 123(2):479–485PubMedCrossRefGoogle Scholar
  141. Parke D, Sapota A (1996) Chemical toxicity and reactive oxygen species. Int J Occup Med Environ Health 9:331–340PubMedGoogle Scholar
  142. Peebles K et al (2007) Inflammation and lung carcinogenesis: applying findings in prevention and treatment. Expert Rev Anticancer Ther 7(10):1405–1421PubMedCrossRefGoogle Scholar
  143. Peltekova V et al (2004) Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat Genet 36(5):471–475PubMedCrossRefGoogle Scholar
  144. Popivanova BK et al (2008) Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. J Clin Invest 118(2):560–570PubMedPubMedCentralGoogle Scholar
  145. Potter D et al (2004) The role of defective mismatch repair in small bowel adenocarcinoma in celiac disease. Cancer Res 64(19):7073–7077PubMedCrossRefGoogle Scholar
  146. Powrie F et al (1993) Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int Immunol 5(11):1461–1471PubMedCrossRefGoogle Scholar
  147. Prantera C, Scribano ML (2009) Antibiotics and probiotics in inflammatory bowel disease: why, when, and how. Curr Opin Gastroenterol 25(4):329–333PubMedCrossRefGoogle Scholar
  148. Qiu B et al (1999) The role of CD4+ lymphocytes in the susceptibility of mice to stress-induced reactivation of experimental colitis. Nat Med 5(10):1178–1182PubMedCrossRefGoogle Scholar
  149. Rakoff-Nahoum S (2006) Cancer issue: why cancer and inflammation? Yale J Biol Med 79(3–4):123–130PubMedGoogle Scholar
  150. Rakoff-Nahoum S, Medzhitov R (2007) Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science 317(5834):124–127PubMedCrossRefGoogle Scholar
  151. Rakoff-Nahoum S et al (2004) Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118(2):229–241PubMedCrossRefGoogle Scholar
  152. Rashid A, Hamilton S (1997) Genetic alterations in sporadic and Crohn’s-associated adenocarcinomas of the small intestine. Gastroenterology 113(1):127–135PubMedCrossRefGoogle Scholar
  153. Read S, Malmstrom V, Powrie F (2000) Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+ CD4+ regulatory cells that control intestinal inflammation. J Exp Med 192(2):295–302PubMedCentralCrossRefPubMedGoogle Scholar
  154. Rennick DM, Fort MM (2000) Lessons from genetically engineered animal models: XII. IL-10-deficient (IL-10−/−) mice and intestinal inflammation. Am J Physiol Gastrointest Liver Physiol 278(6):G829–G833PubMedGoogle Scholar
  155. Reuter B, Zhang X-J, Miller M (2002) Therapeutic utility of aspirin in the ApcMin/+ murine model of colon carcinogenesis. BMC Cancer 2:19–27PubMedPubMedCentralCrossRefGoogle Scholar
  156. Ritland S, Gendler S (1999) Chemoprevention of intestinal adenomas in the ApcMin mouse by piroxicam: kinetics, strain effects and resistance to chemosuppression. Carcinogenesis 20:51–58PubMedCrossRefGoogle Scholar
  157. Rudolph U et al (1995) Ulcerative colitis and adenocarcinoma of the colon in G alpha i2-deficient mice. Nat Genet 10(2):143–150PubMedCrossRefGoogle Scholar
  158. Sadlack B et al (1993) Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75:253–261PubMedCrossRefGoogle Scholar
  159. Saftig P et al (1995) Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells. EMBO J 14(15):3599–3608PubMedPubMedCentralGoogle Scholar
  160. Sartor B (2007) Bacteria in Crohn’s disease: mechanisms of inflammation and therapeutic implications. J Clin Gastroenterol 41:S37–S43CrossRefGoogle Scholar
  161. Saurer L, Mueller C (2009) T cell-mediated immunoregulation in the gastrointestinal tract. Allergy 64(4):505–519PubMedCrossRefGoogle Scholar
  162. Scanlan P et al (2006) Culture-independent analyses of temporal variation of the dominant fecal microbiota and targeted bacterial subgroups in Crohn’s disease. J Clin Microbiol 44(11):3980–3988PubMedPubMedCentralCrossRefGoogle Scholar
  163. Schuppler M et al (2004) An abundance of Escherichia coli is harbored by the mucosa-associated bacterial flora of interleukin-2-deficient mice. Infect Immun 72(4):1983–1990PubMedPubMedCentralCrossRefGoogle Scholar
  164. Seril DN et al (2003) Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models. Carcinogenesis 24(3):353–362PubMedCrossRefGoogle Scholar
  165. Shekhawat PS et al (2007) Spontaneous development of intestinal and colonic atrophy and inflammation in the carnitine-deficient jvs (OCTN2/) mice. Mol Genet Metab 92(4):315–324PubMedPubMedCentralCrossRefGoogle Scholar
  166. Shintani N et al (1997) Proliferative effect of dextran sulfate sodium (DSS)-pulsed macrophages on T cells from mice with DSS-induced colitis and inhibition of effect by IgG. Scand J Immunol 46(6):581–586PubMedCrossRefGoogle Scholar
  167. Shoenfeld Y, Gershwin M (2000) Cancer and autoimmunity. In: Shoenfeld Y, Gershwin M (eds) Cancer and autoimmunity. Elsevier, Amsterdam, pp 1–446Google Scholar
  168. Shull M et al (1992) Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359(6397):693–699PubMedPubMedCentralCrossRefGoogle Scholar
  169. Siegmund B et al (2004) Development of intestinal inflammation in double IL-10-and leptin-deficient mice. J Leukoc Biol 76(4):782–786PubMedCrossRefGoogle Scholar
  170. Siemes C et al (2006) C-reactive protein levels, variation in the C-reactive protein gene, and cancer risk: the Rotterdam Study. J Clin Oncol 24(33):5216–5222PubMedCrossRefGoogle Scholar
  171. Slattery ML et al (2004) Aspirin, NSAIDs, and colorectal cancer: possible involvement in an insulin-related pathway. Cancer Epidemiol Biomarkers Prev 13(4):538–545PubMedGoogle Scholar
  172. Snapper S et al (1998) Wiskott-Aldrich syndrome protein-deficient mice reveal a role for WASP in T but not B cell activation. Immunity 9(1):81–91PubMedCrossRefGoogle Scholar
  173. Soderstrom K et al (1996) Increased frequency of abnormal gamma delta T cells in blood of patients with inflammatory bowel diseases. J Immunol 156(6):2331–2339PubMedGoogle Scholar
  174. Spencer SD et al (1998) The orphan receptor CRF2-4 is an essential subunit of the interleukin 10 receptor. J Exp Med 187(4):571–578PubMedPubMedCentralCrossRefGoogle Scholar
  175. Spurzem J et al (1991) Chronic inflammation is associated with an increased proportion of goblet cells recovered by bronchial lavage. Chest 100(2):389–393PubMedCrossRefGoogle Scholar
  176. Steidler L et al (2000) Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 289(5483):1352–1355PubMedCrossRefGoogle Scholar
  177. Steinhoff U, Brinkmann V, Klemm U, Aichele P, Seiler P, Brandt U, Bland PW, Prinz I, Zügel U, Kaufmann SH (1999) Autoimmune intestinal pathology induced by hsp60-specific CD8 T cells. Immunity 11(3):349–358PubMedCrossRefGoogle Scholar
  178. Stewart BW, Kleihues P (2003) World cancer report. Iarc, Lyon, pp 56–66Google Scholar
  179. Stoicov C et al (2009) T-bet knockout prevents Helicobacter felis-induced gastric cancer. J Immunol 183(1):642–649PubMedPubMedCentralCrossRefGoogle Scholar
  180. Stoll M et al (2004) Genetic variation in DLG5 is associated with inflammatory bowel disease. Nat Genet 36(5):476–480PubMedCrossRefGoogle Scholar
  181. Strauch UG et al (2007) Calcitriol analog ZK191784 ameliorates acute and chronic dextran sodium sulfate-induced colitis by modulation of intestinal dendritic cell numbers and phenotype. World J Gastroenterol 13(48):6529–6537PubMedPubMedCentralCrossRefGoogle Scholar
  182. Sugawara K et al (2005) Linkage to peroxisome proliferator-activated receptor- in SAMP1/YitFc mice and in human Crohn’s disease. Gastroenterology 128(2):351–360PubMedCrossRefGoogle Scholar
  183. Sundberg J et al (1994) Spontaneous, heritable colitis in a new substrain of C3H/HeJ mice. Gastroenterology 107(6):1726–1735PubMedCrossRefGoogle Scholar
  184. Suzuki R et al (2007) Global gene expression analysis of the mouse colonic mucosa treated with azoxymethane and dextran sodium sulfate. BMC Cancer 7:84PubMedPubMedCentralCrossRefGoogle Scholar
  185. Swidsinski A et al (2002) Mucosal flora in inflammatory bowel disease. Gastroenterology 122(1):44–54PubMedCrossRefGoogle Scholar
  186. Takaki K et al (2006) Attenuation of experimental colonic injury by thiazolidinedione agents. Inflamm Res 55(1):10–15PubMedCrossRefGoogle Scholar
  187. Takeda K et al (1996) Essential role of Stat6 in IL-4 signalling. Nature 380(6575):627–630PubMedCrossRefGoogle Scholar
  188. Takeda K et al (1999) Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10:39–50PubMedCrossRefGoogle Scholar
  189. Tanaka T, Kohno H, Suzuki R, Yamada Y, Sugie S, Mori H (2003) A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate. Cancer Sci 94(11):965–973PubMedCrossRefGoogle Scholar
  190. te Velde AA, Verstege MI, Hommes DW (2006) Critical appraisal of the current practice in murine TNBS-induced colitis. Inflamm Bowel Dis 12(10):995–999CrossRefGoogle Scholar
  191. Tlaskalova H et al (2000) Malignancy in coeliac disease and dermatitis herpetiformis. In: Shoenfeld Y, Gershwin M (eds) Cancer and autoimmunity. Elsevier, Amsterdam, pp 105–110CrossRefGoogle Scholar
  192. Turer EE et al (2008) Homeostatic MyD88-dependent signals cause lethal inflammation in the absence of A20. J Exp Med 205(2):451–464PubMedPubMedCentralCrossRefGoogle Scholar
  193. Uhlig HH et al (2006) Characterization of Foxp3+ CD4+ CD25+ and IL-10-secreting CD4+ CD25+ T cells during cure of colitis. J Immunol 177(9):5852–5860PubMedCrossRefGoogle Scholar
  194. Uronis J, Threadgill D (2009) Murine models of colorectal cancer. Mamm Genome 20:261–268PubMedPubMedCentralCrossRefGoogle Scholar
  195. Van der Sluis M et al (2006) Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131(1):117–129PubMedCrossRefGoogle Scholar
  196. van Meeteren ME, Meijssen MAC, Zijlstra FJ (2000) The effect of dexamethasone treatment on murine colitis. Scand J Gastroenterol 35(5):517–521CrossRefPubMedGoogle Scholar
  197. Verdu EF, Huang X, Natividad J, Lu J, Blennerhassett PA, David CS, McKay DM, Murray JA (2008) Gliadin-dependent neuromuscular and epithelial secretory responses in gluten-sensitive HLA-DQ8 transgenic mice. Am J Physiol Gastrointest Liver Physiol 294:G217–25PubMedCrossRefGoogle Scholar
  198. Vogelsang H, Schwarzenhofer M, Oberhuber G (1998) Changes in gastrointestinal permeability in celiac disease. Dig Dis 16:333–336PubMedCrossRefGoogle Scholar
  199. Watanabe M et al (1998) Interleukin 7 transgenic mice develop chronic colitis with decreased interleukin 7 protein accumulation in the colonic mucosa. J Exp Med 187(3):389–402PubMedPubMedCentralCrossRefGoogle Scholar
  200. Welte T et al (2003) STAT3 deletion during hematopoiesis causes Crohn’s disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity. Proc Natl Acad Sci 100(4):1879–1884PubMedPubMedCentralCrossRefGoogle Scholar
  201. Westbrook A, Schiestl RH (2010) Atm deficient mice exhibit increased sensitivity to dextran sulfate sodium-induced colitis characterized by elevated DNA damage and persistent immune activation damage and persistent immune activation. Cancer Res 70(5):1875–1884. doi: 10.1158/0008-5472.CAN-09-2584 PubMedPubMedCentralCrossRefGoogle Scholar
  202. Westbrook A et al (2009a) More damaging than we think: systemic effects of intestinal inflammation. Cell Cycle 8(16):2482–2483PubMedPubMedCentralCrossRefGoogle Scholar
  203. Westbrook AM et al (2009b) Intestinal mucosal inflammation leads to systemic genotoxicity in mice. Cancer Res 69(11):4827–4834PubMedPubMedCentralCrossRefGoogle Scholar
  204. Westbrook AM, Szakmary A, Schiestl RH (2010) Mechanisms of intestinal inflammation and development of associated cancers: lessons learned from mouse models. Mutat Res 705(1):40–59PubMedPubMedCentralCrossRefGoogle Scholar
  205. Wheeler JMD et al (2002) An insight into the genetic pathway of adenocarcinoma of the small intestine. Gut 50(2):218–223PubMedPubMedCentralCrossRefGoogle Scholar
  206. Willerford DM et al (1995) Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3(4):521–530PubMedCrossRefGoogle Scholar
  207. Wirtz S, Neurath MF (2007) Mouse models of inflammatory bowel disease. Adv Drug Deliv Rev 59(11):1073–1083PubMedCrossRefGoogle Scholar
  208. Wirtz S et al (1999) Cutting edge: chronic intestinal inflammation in STAT-4 transgenic mice: characterization of disease and adoptive transfer by TNF-plus IFN-gamma-producing CD4- T cells that respond to bacterial antigens. J Immunol 162(4):1884PubMedGoogle Scholar
  209. Xie J, Itzkowitz SH (2008) Cancer in inflammatory bowel disease. World J Gastroenterol 14(3):378–389PubMedPubMedCentralCrossRefGoogle Scholar
  210. Yang X et al (1999) Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta. EMBO J 18(5):1280–1291PubMedPubMedCentralCrossRefGoogle Scholar
  211. Yang Y et al (2009) T-bet is essential for encephalitogenicity of both Th1 and Th17 cells. J Exp Med 206(7):1549–1564PubMedPubMedCentralCrossRefGoogle Scholar
  212. Zaph C et al (2007) Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis. Nature 446(7135):552–556CrossRefPubMedGoogle Scholar
  213. Zhang MQ, Chen ZME, Wang HL (2006) Immunohistochemical investigation of tumorigenic pathways in small intestinal adenocarcinoma: a comparison with colorectal adenocarcinoma. Mod Pathol 19(4):573–580PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Aya M. Westbrook
    • 1
    • 2
  • Akos Szakmary
    • 3
  • Robert H. Schiestl
    • 1
    • 2
  1. 1.Molecular Toxicology Interdepartmental Program, UCLA School of Medicine and School of Public HealthUniversity of California at Los AngelesLos AngelesUSA
  2. 2.Department of Pathology and Lab Medicine, UCLA School of Medicine and School of Public HealthUniversity of California at Los AngelesLos AngelesUSA
  3. 3.Institute for Cancer ResearchMedical University of ViennaViennaAustria

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