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Inflammatory Bowel Disease: A Model of Chronic Inflammation-Induced Cancer

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Inflammation and Cancer

Part of the book series: Methods in Molecular Biology™ ((MIMB,volume 511))

Summary

Chronic inflammation is a well-recognized risk factor for the development of human cancer. Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a typical longstanding inflammatory disease of the colon with increased risk for the development of colorectal carcinoma. Several molecular events involved in chronic inflammatory process may contribute to multistage progression of human cancer development, including the overproduction of reactive oxygen and nitrogen species, overproduction/activation of key arachidonic acid metabolites and cytokines/growth factors, and immunity system dysfunction. Multiple animal models of IBD have been established, and in general, these models can be mainly categorized into chemically induced, genetically engineered (transgenic or gene knock-out), spontaneous, and adoptive transferring animal models. This chapter mainly focuses on (1) epidemiologic and molecular evidence on IBD and risk of colorectal cancer, (2) molecular pathogen-esis of IBD-induced carcinogenesis, and (3) modeling of IBD-induced carcinogenesis in rodents and its application.

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References

  1. Kirsner, J.B. (2001) Historical origins of current IBD concepts. World J Gastroenterol 7, 175–184

    CAS  PubMed  Google Scholar 

  2. Crohn, B.B., Ginzburg, L., Oppenheimer, G.D. (2000) Regional ileitis: a pathologic and clinical entity. 1932. Mt Sinai J Med 67, 263–268

    CAS  PubMed  Google Scholar 

  3. Balkwill, F., Mantovani, A. (2001) Inflammation and cancer: back to Virchow? Lancet 357, 539–545

    CAS  PubMed  Google Scholar 

  4. Coussens, L.M., Werb, Z. (2002) Inflammation and cancer. Nature 420, 860–867

    CAS  PubMed  Google Scholar 

  5. Fuss, I.J., Heller, F., Boirivant, M., Leon, F., Yoshida, M., Fichtner-Feigl, S., Yang, Z., Exley, M., Kitani A., Blumberg, R.S., Mannon, P., Strober, W. (2004) Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest 113, 1490–1497

    CAS  PubMed  Google Scholar 

  6. Kewenter, J., Ahlman, H., Hulten, L. (1978) Cancer risk in extensive ulcerative colitis. Ann Surg 188, 824–828

    CAS  PubMed  Google Scholar 

  7. Prior, P., Gyde, S.N., Macartney, J.C., Thompson, H., Waterhouse, J.A., Allan, R.N. (1982) Cancer morbidity in ulcerative colitis. Gut 23, 490–497

    CAS  PubMed  Google Scholar 

  8. Brostrom, O., Löfberg, R., Nordenvall, B., Ost, A., Hellers, G. (1987) The risk of colorectal cancer in ulcerative colitis. An epi-demiologic study. Scand J Gastroenterol 22, 1193–1199

    CAS  PubMed  Google Scholar 

  9. Ekbom, A., Helmick, C., Zack, M., Adami, H.O. (1990) Ulcerative colitis and colorec-tal cancer. A population-based study. N Engl J Med 323, 1228–1233

    CAS  PubMed  Google Scholar 

  10. Lashner, B.A., Silverstein, M.D., Hanauer, S.B. (1989) Hazard rates for dysplasia and cancer in ulcerative colitis. Results from a surveillance program. Dig Dis Sci 34, 1536– 1541

    CAS  PubMed  Google Scholar 

  11. Sugita, A., Sachar, D.B., Bodian, C., Ribeiro, M.B., Aufses, A.H., Jr. Greenstein, A.J. (1991) Colorectal cancer in ulcerative colitis. Influence of anatomical extent and age at onset on colitis-cancer interval. Gut 32, 167–169

    CAS  PubMed  Google Scholar 

  12. Eaden, J.A., Abramsb, K.R., Mayberry, J.F. (2001) The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 48, 526–535

    CAS  PubMed  Google Scholar 

  13. Chen, R., Rabinovitch, P.S., Crispin, D.A., Emond, M.J., Koprowicz, K.M., Bronner, M.P., Brentnall, T.A. (2003) DNA fingerprinting abnormalities can distinguish ulcerative colitis patients with dysplasia and cancer from those who are dysplasia/cancer-free. Am J Pathol 162, 665–672

    CAS  PubMed  Google Scholar 

  14. Greenson, J.K. (2002) Dysplasia in inflammatory bowel disease. Semin Diagn Pathol 19, 31–37

    PubMed  Google Scholar 

  15. Sartor, R.B. (1995) Current concepts of the etiology and pathogenesis of ulcerative colitis and Crohn's disease. Gastroenterol Clin North Am 24, 475–507

    CAS  PubMed  Google Scholar 

  16. Fiocchi, C. (1998) Inflammatory bowel disease: etiology and pathogenesis. Gastroen-terology 115, 182–205

    CAS  Google Scholar 

  17. Bouma, G., Strober, W. (2003) The immu-nological and genetic basis of inflammatory bowel disease. Nat Rev Immunol 3, 521– 533

    CAS  PubMed  Google Scholar 

  18. Yang, H., McElree, C., Roth, M.P., Shana-han, F., Targan, S.R., Rotter, J.I. (1993) Familial empirical risks for inflammatory bowel disease: differences between Jews and non-Jews. Gut 34, 517–524

    CAS  PubMed  Google Scholar 

  19. Tysk, C., Lindberg, E., Järnerot, G., Floderus-Myrhed, B. (1988) Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking. Gut 29, 990–996

    CAS  PubMed  Google Scholar 

  20. Hampe, J., Cuthbert, A., Croucher, P.J., Mirza, M.M., Mascheretti, S., Fisher, S., Frenzel, H., King, K., Hasselmeyer, A., MacPherson, A.J., Bridger, S., van Deventer, S., Forbes, A., Nikolaus, S., Lennard-Jones, J.E., Foelsch, U.R., Krawczak, M., Lewis, C., Schreiber, S., Mathew, C.G. (2001) Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet 357, 1925–1928

    CAS  PubMed  Google Scholar 

  21. Hugot, J.P., Chamaillard, M., Zouali, H., Lesage, S., Cezard, J.P., Belaiche, J., Almer, S., Tysk, C., O'Morain, C.A., Gas-sull, M., Binder, V., Finkel, Y., Cortot, A., Modigliani, R., Laurent-Puig, P., Gower-Rousseau, C., Macry, J., Colombel, J.F., Sahbatou, M., Thomas, G. (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603

    CAS  PubMed  Google Scholar 

  22. Ogura, Y., Bonen, D.K., Inohara, N., Nico-lae, D.L., Chen, F.F., Ramos, R., Britton, H., Moran, T., Karaliuskas, R., Duerr, R.H., Achkar, J.P., Brant, S.R., Bayless, T.M., Kirschner, B.S., Hanauer, S.B., Nunez, G., Cho, J.H. (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606

    CAS  PubMed  Google Scholar 

  23. Ogura, Y., Inohara, N., Benito, A., Chen, F.F., Yamaoka, S., Nunez, G. (2001) Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem 276, 4812–4818

    CAS  PubMed  Google Scholar 

  24. Abreu, M.T., Taylor, K.D., Lin, Y.C., Hang, T., Gaiennie, J., Landers, C.J., Vasiliauskas, E.A., Kam, L.Y., Rojany, M., Papadakis, K.A., Rotter, J.I., Targan, S.R., Yang, H. (2002) Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn's disease. Gastroenterology 123, 679–688

    CAS  PubMed  Google Scholar 

  25. Maeda, S., Hsu, L.C., Liu, H., Bankston, L.A., Iimura, M., Kagnoff, M.F., Eckmann, L., Karin, M. (2005) Nod2 mutation in Crohn's disease potentiates NF-kappaB activity and IL-1beta processing. Science 307, 734–738

    CAS  PubMed  Google Scholar 

  26. Kobayashi, K., Inohara, N., Hernandez, L.D., Galan, J.E., Nunez, G., Janeway, C.A., Medzhitov, R., Flavell, R.A. (2002) RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 416, 194–199

    CAS  PubMed  Google Scholar 

  27. Satsangi, J., Morecroft, J., Shah, N.B., Nimmo, E. (2003) Genetics of inflammatory bowel disease: scientific and clinical implications. Best Pract Res Clin Gastroen-terol 17, 3–18

    CAS  Google Scholar 

  28. Duerr, R.H., Taylor, K.D., Brant, S.R., Rioux, J.D., Silverberg, M.S., Daly, M.J., Steinhart, A.H., Abraham, C., Regueiro, M., Griffiths, A., Dassopoulos, T., Bitton, A., Yang, H., Targan, S., Datta, L.W., Kistner, E.O., Schumm, L.P., Lee, A.T., Gregersen, P.K., Barmada, M.M., Rotter, J.I., Nicolae, D.L., Cho, J.H. (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463

    CAS  PubMed  Google Scholar 

  29. Satsangi, J., Parkes, M., Louis, E., Hashimoto, L., Kato, N., Welsh, K., Terwilliger, J.D., Lathrop, G.M., Bell, J.I., Jewell, D.P. (1996) Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12. Nat Genet 14, 199–202

    CAS  PubMed  Google Scholar 

  30. Peltekova, V.D., Wintle, R.F., Rubin, L.A., Amos, C.I., Huang, Q., Gu, X., Newman, B., Van Oene, M., Cescon, D., Greenberg, G., Griffiths, A.M., St George-Hyslop, P.H., Siminovitch, K.A. (2004) Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat Genet 36, 471–475

    CAS  PubMed  Google Scholar 

  31. Toyoda, H., Wang, S.J., Yang, H.Y., Red-ford, A., Magalong, D., Tyan, D., McElree, C.K., Pressman, S.R., Shanahan, F., Targan, S.R., et al. (1993) Distinct associations of HLA class II genes with inflammatory bowel disease. Gastroenterology 104, 741–748

    CAS  PubMed  Google Scholar 

  32. Asquith, P., Mackintosh, P., Stokes, P.L., Holmes, G.K., Cooke, W.T. (1974) His-tocompatibility antigens in patients with inflammatory-bowel disease. Lancet 1, 113– 115

    CAS  PubMed  Google Scholar 

  33. Strober, W., Fuss, I.J., Blumberg, R.S. (2002) The immunology of mucosal models of inflammation. Annu Rev Immunol 20, 495–549

    CAS  PubMed  Google Scholar 

  34. Savidge, T.C., Newman, P.G., Pan, W.H., Weng, M.Q., Shi, H.N., McCormick, B.A., Quaroni, A., Walker, W.A. (2006) Lipopol-ysaccharide-induced human enterocyte tolerance to cytokine-mediated interleukin-8 production may occur independently of TLR-4/MD-2 signaling. Pediatr Res 59, 89–95

    CAS  PubMed  Google Scholar 

  35. de Baey, A., Memde, I., Baretton, G., Greiner, A., Hartl, W.H., Baeuerle, P.A., Diepolder, H.M. (2003) A subset of human dendritic cells in the T cell area of mucosa-associated lymphoid tissue with a high potential to produce TNF-alpha. J Immunol 170, 5089–5094

    PubMed  Google Scholar 

  36. Parronchi, P., Romagnani, P., Annunziato, F., Sampognaro, S., Becchio, A., Gian-narini, L., Maggi, E., Pupilli, C., Tonelli, F., Romagnani, S. (1997) Type 1 T-helper cell predominance and interleukin-12 expression in the gut of patients with Crohn's disease. Am J Pathol 150, 823–832

    CAS  PubMed  Google Scholar 

  37. Brown, S.J., Mayer, L. (2007) The immune response in inflammatory bowel disease. Am J Gastroenterol, 102, 2058–2069

    CAS  PubMed  Google Scholar 

  38. Nikolaus, S., Bauditz, J., Gionchetti, P., Witt, C., Lochs, H., Schreiber, S. (1998) Increased secretion of pro-inflammatory cytokines by circulating polymorphonuclear neutrophils and regulation by interleukin 10 during intestinal inflammation. Gut 42, 470–476

    CAS  PubMed  Google Scholar 

  39. Tyrer, P., Foxwell, A.R. Cripps, A.W. Api-cella, M.A. Kyd, J.M. (2006) Microbial pattern recognition receptors mediate M-cell uptake of a gram-negative bacterium. Infect Immun 74, 625–631

    CAS  PubMed  Google Scholar 

  40. Lodes, M.J., Cong, Y., Elson, C.O., Mohamath, R., Landers, C.J., Targan, S.R., Fort, M., Hershberg, R.M. (2004) Bacterial flagellin is a dominant antigen in Crohn disease. J Clin Invest 113, 1296–1306

    CAS  PubMed  Google Scholar 

  41. Rakoff-Nahoum, S., Paglino, J., Eslami-Var-zaneh, F., Edberg, S., Medzhitov, R. (2004) Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241

    CAS  PubMed  Google Scholar 

  42. Fukata, M., Michelsen, K.S., Eri, R., Thomas, L.S., Hu, B., Lukasek, K., Nast, C.C., Lechago, J., Xu, R., Naiki, Y., Soliman, A., Arditi, M., Abreu, M.T. (2005) Tolllike receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis. Am J Physiol Gastrointest Liver Physiol 288, G1055–1065

    CAS  PubMed  Google Scholar 

  43. Doering, J., Begue, B., Lentze, M.J., Rieux-Laucat, F., Goulet, O., Schmitz, J. Cerf-Bensussan, N., Ruemmele, F.M. (2004) Induction of T lymphocyte apoptosis by sul-phasalazine in patients with Crohn's disease. Gut 53, 1632–1638

    CAS  PubMed  Google Scholar 

  44. Mosmann, T.R., Cher winski, H., Bond, M.W., Giedlin, M.A., Coffman, R.L. (1986) Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136, 2348–2357

    CAS  PubMed  Google Scholar 

  45. Mannon, P.J., Fuss, I.J. Mayer, L., Elson, C.O., Sandborn, W.J., Present, D., Dolin, B., Goodman, N., Groden, C., Hornung, R.L., Quezado, M., Yang, Z., Neurath, M.F., Salfeld, J., Veldman, G.M., Schwertschlag, U., Strober, W. (2004) Anti-interleukin-12 antibody for active Crohn's disease. N Engl J Med 351, 2069–2079

    CAS  PubMed  Google Scholar 

  46. Fujino, S., Andoh, A., Bamba, S., Ogawa, A., Hata, K., Araki, Y., Bamba, T., Fujiyama, Y. (2003) Increased expression of interleukin 17 in inflammatory bowel disease. Gut 52, 65–70

    CAS  PubMed  Google Scholar 

  47. Niessner, M., Volk, B.A. (1995) Altered Th1/Th2 cytokine profiles in the intestinal mucosa of patients with inflammatory bowel disease as assessed by quantitative reversed transcribed polymerase chain reaction (RT-PCR). Clin Exp Immunol 101, 428–435

    CAS  PubMed  Google Scholar 

  48. MacDonald, T.T., Pender, S.L. (1998) Lamina propria T cells. Chem Immunol 71, 103–117

    CAS  PubMed  Google Scholar 

  49. Fuss, I.J., Neurath, M., Boirivant, M., Klein, J.S., de la Motte, C., Strong, S.A., Fiocchi, C., Strober, W. (1996) Disparate CD4 + lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol 157, 1261–1270

    CAS  PubMed  Google Scholar 

  50. Harrington, L.E., Hatton, R.D., Mangan, P.R., Turner, H., Murphy, T.L., Murphy, K.M., Weaver, C.T. (2005) Interleukin 17-producing CD4 + effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6, 1123–1132

    CAS  PubMed  Google Scholar 

  51. Trinchieri, G. (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3, 133–146

    CAS  PubMed  Google Scholar 

  52. Davidson, N.J., Hudak, S.A., Lesley, R.E., Menon, S., Leach, M.W., Rennick, D.M. (1998) IL-12, but not IFN-gamma, plays a major role in sustaining the chronic phase of colitis in IL-10-deficient mice. J Immunol 161, 3143–3149

    CAS  PubMed  Google Scholar 

  53. Fuss, I.J., Becker, C., Yang, Z., Groden, C., Hornung, R.L., Heller, F., Neurath, M.F., Strober, W., Mannon, P.J. (2006) Both IL-12p70 and IL-23 are synthesized during active Crohn's disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody. Inflamm Bowel Dis 12, 9–15

    PubMed  Google Scholar 

  54. Yen, D., Cheung, J., Scheerens, H., Poulet, F., McClanahan, T., McKenzie, B., Klein-schek, M.A., Owyang, A., Mattson, J., Blu-menschein, W., Murphy, E., Sathe, M., Cua, D.J., Kastelein, R.A., Rennick, D. (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

    CAS  PubMed  Google Scholar 

  55. Rutgeerts, P., Sandborn, W.J., Feagan, B.G., Reinisch, W., Olson, A., Johanns, J., Travers, S., Rachmilewitz, D., Hanauer, S.B., Lichtenstein, G.R., de Villiers, W.J., Present, D., Sands, B.E., Colombel, J.F. (2005) Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 353, 2462–2476

    CAS  PubMed  Google Scholar 

  56. Katz, S. (2005) Update in medical therapy of ulcerative colitis: newer concepts and therapies. J Clin Gastroenterol 39, 557–569

    PubMed  Google Scholar 

  57. Olson, T.S., Bamias, G., Naganuma, M., Rivera-Nieves, J., Burcin, T.L., Ross, W., Morris, M.A., Pizarro, T.T., Ernst, P.B., Cominelli, F., Ley, K. (2004) Expanded B cell population blocks regulatory T cells and exacerbates ileitis in a murine model of Crohn disease. J Clin Invest 114, 389–398

    CAS  PubMed  Google Scholar 

  58. Kawamura, T., Kanai, T., Dohi, T., Uraushi-hara, K., Totsuka, T., Iiyama, R., Taneda, C., Yamazaki, M., Nakamura, T., Higuchi, T., Aiba, Y., Tsubata, T., Watanabe, M. (2004) Ectopic CD40 ligand expression on B cells triggers intestinal inflammation. J Immunol 172, 6388–6397

    CAS  PubMed  Google Scholar 

  59. Lee, J.C., Cevallos, A.M., Naeem, A., Len-nard-Jones, J.E., Farthing, M.J. (1999) Detection of anti-colon antibodies in inflammatory bowel disease using human cultured colonic cells. Gut 44, 196–202

    CAS  PubMed  Google Scholar 

  60. Das, K.M., Squillante, L., Chitayet, D., Kalousek, D.K. (1992) Simultaneous appearance of a unique common epitope in fetal colon, skin, and biliary epithelial cells. A possible link for extracolonic manifestations in ulcerative colitis. J Clin Gastroen-terol 15, 311–316

    CAS  Google Scholar 

  61. Cohavy, O., Bruckner, D., Gordon, L.K., Misra, R., Wei, B., Eggena, M.E., Targan, S.R., Braun, J. (2000) Colonic bacteria express an ulcerative colitis pANCA-related protein epitope. Infect Immun 68, 1542– 1548

    CAS  PubMed  Google Scholar 

  62. Mow, W.S., Vasiliauskas, E.A., Lin, Y.C., Fleshner, P.R., Papadakis, K.A., Taylor, K.D., Landers, C.J., Abreu-Martin, M.T., Rotter, J.I., Yang, H., Targan, S.R. (2004) Association of antibody responses to micro-bial antigens and complications of small bowel Crohn's disease. Gastroenterology 126, 414–424

    CAS  PubMed  Google Scholar 

  63. Arnott, I.D., Landers, C.J., Nimmo, E.J., Drummond, H.E., Smith, B.K., Targan, S.R., Satsangi, J. (2004) Sero-reactivity to microbial components in Crohn's disease is associated with disease severity and progression, but not NOD2/CARD15 genotype. Am J Gastroenterol 99, 2376–2384

    PubMed  Google Scholar 

  64. Lih-Brody, L., Powell, S.R., Collier, K.P., Reddy, G.M., Cerchia, R., Kahn, E., Weiss-man, G.S., Katz, S., Floyd, R.A., McKinley, M.J., Fisher, S.E., Mullin, G.E. (1996) Increased oxidative stress and decreased anti-oxidant defenses in mucosa of inflammatory bowel disease. Dig Dis Sci 41, 2078–2086

    CAS  PubMed  Google Scholar 

  65. Simmonds, N.J., Allen, R.E. Stevens, T.R., Van Someren, R.N., Blake, D.R., Ramp-ton, D.S. (1992) Chemiluminescence assay of mucosal reactive oxygen metabolites in inflammatory bowel disease. Gastroenterol-ogy 103, 186–196

    CAS  Google Scholar 

  66. McKenzie, S.J., Baker, M.S., Buffinton, G.D., Doe, W.F. (1996) Evidence of oxi-dant-induced injury to epithelial cells during inflammatory bowel disease. J Clin Invest 98, 136–141

    CAS  PubMed  Google Scholar 

  67. Mahida, Y.R., Wu, K.C. Jewell, D.P. (1989) Respiratory burst activity of intestinal macrophages in normal and inflammatory bowel disease. Gut 30, 1362–1370

    CAS  PubMed  Google Scholar 

  68. Schreiber, S., MacDermott, R.P., Raedler, A., Pinnau, R., Bertovich, M.J., and Nash, G.S. (1991) Increased activation of isolated intestinal lamina propria mononuclear cells in inflammatory bowel disease. Gastroenter-ology 101, 1020–1030

    CAS  Google Scholar 

  69. Babbs, C.F. (1992) Oxygen radicals in ulcerative colitis. Free Radic Biol Med 13, 169–181

    CAS  PubMed  Google Scholar 

  70. Grisham, M.B. (1994) Oxidants and free radicals in inflammatory bowel disease. Lancet 344, 859–861

    CAS  PubMed  Google Scholar 

  71. Hussain, S.P., Amstad, P., Raja, K., Ambs, S., Nagashima, M., Bennett, W.P., Shields, P.G., Ham, A.J., Swenberg, J.A., Marrogi, A.J., Harris, C.C. (2000) Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. Cancer Res 60, 3333–3337

    CAS  PubMed  Google Scholar 

  72. Hisamatsu, T., Watanabe, M., Ogata, H., Ezaki, T., Hozawa, S., Ishii, H., Kanai, T., Hibi, T. (1999) Interferon-inducible gene family 1–8U expression in colitis-associated colon cancer and severely inflamed mucosa in ulcerative colitis. Cancer Res 59, 5927–5931

    CAS  PubMed  Google Scholar 

  73. Oudkerk Pool, M., Bouma, G., Visser, J.J., Kolkman, J.J., Tran, D.D., Meuwissen, S.G., Pena, A.S. (1995) Serum nitrate levels in ulcerative colitis and Crohn's disease. Scand J Gastroenterol 30, 784–788

    CAS  PubMed  Google Scholar 

  74. Rachmilewitz, D., Stamler, J.S., Bachwich, D., Karmeli, F., Ackerman, Z., Podolsky, D.K. (1995) Enhanced colonic nitric oxide generation and nitric oxide synthase activity in ulcerative colitis and Crohn's disease. Gut 36, 718–723

    CAS  PubMed  Google Scholar 

  75. Hofseth, L.J., Shinichi, S., Hussain, S.P., Espey, M.G., Miranda, K.M., Araki, Y., Jhappan, C., Higashimoto, Y., He, P., Linke, S.P., Quezado, M.M., Zurer, I., Rotter, V., Wink, D.A., Appella, E., Harris, C.C. (2003) Nitric oxide-induced cellular stress and p53 activation in chronic inflammation. Proc Natl Acad Sci USA 100, 143–148

    CAS  PubMed  Google Scholar 

  76. Kimura, H., Hokari, R., Miura, S., Shige-matsu, T., Hirokawa, M., Akiba, Y., Kurose, I., Higuchi, H., Fujimori, H., Tsuzuki, Y., Serizawa, H., Ishii, H. (1998) Increased expression of an inducible isoform of nitric oxide synthase and the formation of perox-ynitrite in colonic mucosa of patients with active ulcerative colitis. Gut 42, 180–187

    CAS  PubMed  Google Scholar 

  77. Kimura, H., Miura, S., Shigematsu, T., Ohkubo, N., Tsuzuki, Y., Kurose, I., Higuchi, H., Akiba, Y., Hokari, R., Hirokawa, M., Serizawa, H., Ishii, H. (1997) Increased nitric oxide production and inducible nitric oxide synthase activity in colonic mucosa of patients with active ulcerative colitis and Crohn's disease. Dig Dis Sci 42, 1047–1054

    CAS  PubMed  Google Scholar 

  78. Hokari, R., Kato, S., Matsuzaki, K., Kuroki, M., Iwai, A., Kawaguchi, A., Nagao, S., Miyahara, T., Itoh, K., Sekizuka, E., Nagata, H., Ishii, H., Miura, S. (2001) Reduced sensitivity of inducible nitric oxide synthase-deficient mice to chronic colitis. Free Radic Biol Med 31, 153–163

    CAS  PubMed  Google Scholar 

  79. Singer, II, Kawka, D.W., Scott, S., Weidner, J.R., Mumford, R.A., Riehl, T.E., Stenson, W.F. (1996) Expression of inducible nitric oxide synthase and nitrotyrosine in colonic epithelium in inflammatory bowel disease. Gastroenterology 111, 871–885

    CAS  PubMed  Google Scholar 

  80. Rachmilewitz, D., Stamler, J.S., Karmeli, F., Mullins, M.E., Singel, D.J., Loscalzo, J., Xavier, R.J., Podolsky, D.K. (1993) Perox-ynitrite-induced rat colitis–a new model of colonic inflammation. Gastroenterology 105, 1681–1688

    CAS  PubMed  Google Scholar 

  81. Rogler, G., Brand, K., Vogl, D., Page, S., Hofmeister, R., Andus, T., Knuechel, R., Baeuerle, P.A., Scholmerich, J., Gross, V. (1998) Nuclear factor kappaB is activated in macrophages and epithelial cells of inflamed intestinal mucosa. Gastroenterology 115, 357–369

    CAS  PubMed  Google Scholar 

  82. Yamamoto, Y., Gaynor, R.B. (2001) Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. J Clin Invest 107, 135–142

    CAS  PubMed  Google Scholar 

  83. Dubuquoy, L., Jansson, E.A., Deeb, S., Rakotobe, S., Karoui, M., Colombel, J.F., Auwerx, J., Pettersson, S., Desreumaux, P. (2003) Impaired expression of peroxi-some proliferator-activated receptor gamma in ulcerative colitis. Gastroenterology 124, 1265–1276

    CAS  PubMed  Google Scholar 

  84. Su, C.G., Wen, X., Bailey, S.T., Jiang, W., Rangwala, S.M., Keilbaugh, S.A., Flani-gan, A., Murthy, S., Lazar, M.A., Wu, G.D. (1999) A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response. J Clin Invest 104, 383–389

    CAS  PubMed  Google Scholar 

  85. Dull, B.J., Salata, K., Van Langenhove, A., Goldman, P. (1987) 5-Aminosalicylate: oxidation by activated leukocytes and protection of cultured cells from oxidative damage. Biochem Pharmacol 36, 2467–2472

    CAS  PubMed  Google Scholar 

  86. Craven, P.A., Pfanstiel, J., Saito, R., DeRu-bertis, F.R. (1987) Actions of sulfasalazine and 5-aminosalicylic acid as reactive oxygen scavengers in the suppression of bile acid-induced increases in colonic epithelial cell loss and proliferative activity. Gastroenterol-ogy 92, 1998–2008

    CAS  Google Scholar 

  87. Gionchetti, P., Gionchetti, C., Campieri, M., Belluzzi, A., Brignola, C., Iannone, P., Miglioli, M., Barbara, L. (1991) Scavenger effect of sulfasalazine, 5-aminosalicylic acid, and olsalazine on superoxide radical generation. Dig Dis Sci 36, 174–178

    CAS  PubMed  Google Scholar 

  88. Seril, D.N., Liao, J., Ho, K.L., Warsi, A., Yang, C.S., Yang, G.Y. (2002) Dietary iron supplementation enhances DSS-induced colitis and associated colorectal carcinoma development in mice. Dig Dis Sci 47, 1266– 1278

    CAS  PubMed  Google Scholar 

  89. Keshavarzian, A., Morgan, G., Sedghi, S., Gordon, J.H., Doria, M. (1990) Role of reactive oxygen metabolites in experimental colitis. Gut 31, 786–790

    CAS  PubMed  Google Scholar 

  90. Keshavarzian, A., Haydek, J., Zabihi, R., Doria, M., D'Astice, M., Sorenson, J.R. (1992) Agents capable of eliminating reactive oxygen species. Catalase, WR-2721, or Cu(II)2(3,5-DIPS)4 decrease experimental colitis. Dig Dis Sci 37, 1866–1873

    CAS  PubMed  Google Scholar 

  91. Rachmilewitz, D., Karmeli, F., Okon, E., Bursztyn, M. (1995) Experimental colitis is ameliorated by inhibition of nitric oxide synthase activity. Gut 37, 247–255

    CAS  PubMed  Google Scholar 

  92. Naito, Y., Takagi, T. Ishikawa, T. Handa, O. Matsumoto, N. Yagi, N. Matsuyama, K. Yoshida, N. Yoshikawa, T. (2001) The inducible nitric oxide synthase inhibitor ONO-1714 blunts dextran sulfate sodium colitis in mice. Eur J Pharmacol 412, 91–99

    CAS  PubMed  Google Scholar 

  93. Seril, D.N., Liao, J., Yang, G.Y., Yang, C.S. (2003) Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models. Carcinogenesis 24, 353–362

    CAS  PubMed  Google Scholar 

  94. Chu, F.F., Esworthy, R.S., Chu, P.G., Long-mate, J.A., Huycke, M.M., Wilczynski, S., Doroshow, J.H. (2004) Bacteria-induced intestinal cancer in mice with disrupted Gpx1 and Gpx2 genes. Cancer Res 64, 962– 968

    CAS  PubMed  Google Scholar 

  95. Buffinton, G.D., Doe, W.F. (1995) Depleted mucosal antioxidant defences in inflammatory bowel disease. Free Radic Biol Med 19, 911–918

    CAS  PubMed  Google Scholar 

  96. Holmes, E.W., Yong, S.L., Eiznhamer, D., Keshavarzian, A. (1998) Glutathione content of colonic mucosa: evidence for oxida-tive damage in active ulcerative colitis. Dig Dis Sci 43, 1088–1095

    CAS  PubMed  Google Scholar 

  97. Ekbom, A., Adami, H.O., Helmick, C.G., Jonzon, A., Zack, M.M. (1990) Perinatal risk factors for inflammatory bowel disease: a case-control study. Am J Epidemiol 132, 1111–1119

    CAS  PubMed  Google Scholar 

  98. Russel, M.G., Stockbrugger, R.W. (1996) Epidemiology of inflammatory bowel disease: an update. Scand J Gastroenterol 31, 417–427

    CAS  PubMed  Google Scholar 

  99. Dejaco, C., Harrer, M., Waldhoer, T., Miehsler, W., Vogelsang, H., Reinisch, W. (2003) Antibiotics and azathioprine for the treatment of perianal fistulas in Crohn's disease. Aliment Pharmacol Ther 18, 1113– 1120

    CAS  PubMed  Google Scholar 

  100. Wild, G.E. (2004) The role of antibiotics in the management of Crohn's disease. Inflamm Bowel Dis 10, 321–323

    PubMed  Google Scholar 

  101. Rutgeerts, P., Hiele, M., Geboes, K., Peeters, M., Penninckx, F., Aerts, R., Kerremans, R. (1995) Controlled trial of metronidazole treatment for prevention of Crohn's recurrence after ileal resection. Gastroenterology 108, 1617–1621

    CAS  PubMed  Google Scholar 

  102. Rutgeerts, P., Van Assche, G., Vermeire, S., D'Haens, G., Baert, F., Noman, M., Aer-den, I., De Hertogh, G., Geboes, K., Hiele, M., D'Hoore, A., Penninckx, F. (2005) Ornidazole for prophylaxis of postoperative Crohn's disease recurrence: a randomized, double-blind, placebo-controlled trial. Gas-troenterology 128, 856–861

    CAS  Google Scholar 

  103. Auer, I.O., Roder, A., Wensinck, F., van de Merwe, J.P., Schmidt, H. (1983) Selected bacterial antibodies in Crohn's disease and ulcerative colitis. Scand J Gastroenterol 18, 217–223

    CAS  PubMed  Google Scholar 

  104. Duchmann, R., Schmitt, E., Knolle, P., Meyer zum Buschenfelde, K.H., Neurath, M. (1996) Tolerance towards resident intestinal flora in mice is abrogated in experimental colitis and restored by treatment with interleukin-10 or antibodies to inter-leukin-12. Eur J Immunol 26, 934–938

    CAS  PubMed  Google Scholar 

  105. Burke, D.A., Axon, A.T. (1987) Ulcerative colitis and Escherichia coli with adhesive properties. J Clin Pathol 40, 782–786

    CAS  PubMed  Google Scholar 

  106. Roediger, W.E., Moore, J., Babidge, W. (1997) Colonic sulfide in pathogenesis and treatment of ulcerative colitis. Dig Dis Sci 42, 1571–1579

    CAS  PubMed  Google Scholar 

  107. Levine, J., Ellis, C.J., Furne, J.K., Springfield, J., Levitt, M.D. (1998) Fecal hydrogen sulfide production in ulcerative colitis. Am J Gastroenterol 93, 83–87

    CAS  PubMed  Google Scholar 

  108. Farmer, G.W., Vincent, M.M., Fuccillo, D.A., Horta-Barbosa, L., Ritman, S., Sever, J.L., Gitnick, G.L. (1973) Viral investigations in ulcerative colitis and regional enteritis. Gastroenterology 65, 8–18

    CAS  PubMed  Google Scholar 

  109. Wakefield, A.J., Fox, J.D., Sawyerr, A.M., Taylor, J.E., Sweenie, C.H., Smith, M., Emery, V.C., Hudson, M., Tedder, R.S., Pounder, R.E. (1992) Detection of herpes-virus DNA in the large intestine of patients with ulcerative colitis and Crohn's disease using the nested polymerase chain reaction. J Med Virol 38, 183–190

    CAS  PubMed  Google Scholar 

  110. Hermon-Taylor, J., Bull, T. (2002) Crohn's disease caused by Mycobacterium avium subspecies paratuberculosis: a public health tragedy whose resolution is long overdue. J Med Microbiol 51, 3–6

    PubMed  Google Scholar 

  111. van der Wiel-Korstanje, J.A. Winkler, K.C. (1975) The faecal flora in ulcerative colitis. J Med Microbiol 8, 491–501

    PubMed  Google Scholar 

  112. Prindiville, T., Cantrell, M., Wilson, K.H. (2004) Ribosomal DNA sequence analysis of mucosa-associated bacteria in Crohn's disease. Inflamm Bowel Dis 10, 824–833

    PubMed  Google Scholar 

  113. Sartor, R.B. (2004) Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics. Gastroenterology 126, 1620– 1633

    PubMed  Google Scholar 

  114. Ricciardiello, L., Baglioni, M., Giovan-nini, C., Pariali, M., Cenacchi, G., Ripalti, A., Landini, M.P., Sawa, H., Nagashima, K., Frisque, R.J., Goel, A., Boland, C.R. Tognon, M., Roda, E., Bazzoli, F. (2003) Induction of chromosomal instability in colonic cells by the human polyomavirus JC virus. Cancer Res 63, 7256–7262

    CAS  PubMed  Google Scholar 

  115. Ho, G.T., Soranzo, N., Nimmo, E.R., Ten-esa, A., Goldstein, D.B., Satsangi, J. (2006) ABCB1/MDR1 gene determines susceptibility and phenotype in ulcerative colitis: discrimination of critical variants using a gene-wide haplotype tagging approach. Hum Mol Genet 15, 797–805

    CAS  PubMed  Google Scholar 

  116. Newman, B., Gu, X., Wintle, R., Cescon, D., Yazdanpanah, M., Liu, X., Peltekova, V., Van Oene, M., Amos, C.I., Siminovitch, K.A. (2005) A risk haplotype in the Solute Carrier Family 22A4/22A5 gene cluster influences phenotypic expression of Crohn's disease. Gastroenterology 128, 260–269

    CAS  PubMed  Google Scholar 

  117. Panwala, C.M., Jones, J.C., Viney, J.L. (1998) A novel model of inflammatory bowel disease: mice deficient for the multiple drug resistance gene, mdr1a, spontaneously develop colitis. J Immunol 161, 5733–5744

    CAS  PubMed  Google Scholar 

  118. Papadakis, K.A., Targan, S.R. (2000) Role of cytokines in the pathogenesis of inflammatory bowel disease. Annu Rev Med 51, 289–298

    CAS  PubMed  Google Scholar 

  119. Podolsky, D.K. (2002) Inflammatory bowel disease. N Engl J Med 347, 417–429

    CAS  PubMed  Google Scholar 

  120. Karlen, P., Löfberg, R., Brostrom, O., Lei-jonmarck, C.E., Hellers, G., Persson, P.G. (1999) Increased risk of cancer in ulcerative colitis: a population-based cohort study. Am J Gastroenterol 94, 1047–1052

    CAS  PubMed  Google Scholar 

  121. Rutter, M., Saunders, B., Wilkinson, K., Rumbles, S., Schofield, G., Kamm, M., Williams, C., Price, A., Talbot, I., Forbes, A. (2004) Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 126, 451–459

    PubMed  Google Scholar 

  122. Madsen, K.L., Malfair, D., Gray, D., Doyle, J.S., Jewell, L.D., Fedorak, R.N. (1999) Interleukin-10 gene-deficient mice develop a primary intestinal permeability defect in response to enteric microflora. Inflamm Bowel Dis 5, 262–270

    CAS  PubMed  Google Scholar 

  123. Pullan, R.D., Thomas, G.A., Rhodes, M., Newcombe, R.G., Williams, G.T., Allen, A., Rhodes, J. (1994) Thickness of adherent mucus gel on colonic mucosa in humans and its relevance to colitis. Gut 35, 353–359

    CAS  PubMed  Google Scholar 

  124. Podolsky, D.K., Isselbacher, K.J. (1984) Glycoprotein composition of colonic mucosa. Specific alterations in ulcerative colitis. Gastroenterology 87, 991–998

    CAS  PubMed  Google Scholar 

  125. Rhodes, J.M. (1989) Colonic mucus and mucosal glycoproteins: the key to colitis and cancer? Gut 30, 1660–1666

    CAS  PubMed  Google Scholar 

  126. Kim, Y.I. (1998) Short-chain fatty acids in ulcerative colitis. Nutr Rev 56, 17–24

    CAS  PubMed  Google Scholar 

  127. Finnie, I.A., Dwarakanath, A.D., Taylor, B.A., Rhodes, J.M. (1995) Colonic mucin synthesis is increased by sodium butyrate. Gut 36, 93–99

    CAS  PubMed  Google Scholar 

  128. Sandborn, W.J. (2003) Strategies for targeting tumour necrosis factor in IBD. Best Pract Res Clin Gastroenterol 17, 105–117

    CAS  PubMed  Google Scholar 

  129. Vogelstein, B., Fearon, E.R., Hamilton, S.R., Kern, S.E., Preisinger, A.C., Leppert, M., Nakamura, Y., White, R., Smits, A.M., Bos, J.L. (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319, 525–532

    CAS  PubMed  Google Scholar 

  130. Sato, T., Tanigami, A., Yamakawa, K., Aki-yama, F., Kasumi, F., Sakamoto, G., Naka-mura, Y. (1990) Allelotype of breast cancer: cumulative allele losses promote tumor progression in primary breast cancer. Cancer Res 50, 7184–7189

    CAS  PubMed  Google Scholar 

  131. Presti, J.C., Jr. Reuter, V.E., Galan, T., Fair, W.R., Cordon-Cardo, C. (1991) Molecular genetic alterations in superficial and locally advanced human bladder cancer. Cancer Res 51, 5405–5409

    PubMed  Google Scholar 

  132. Itzkowitz, S.H. (2002) Cancer prevention in patients with inflammatory bowel disease. Gastroenterol Clin North Am 31, 1133– 1144

    PubMed  Google Scholar 

  133. Eaden, J.A., Abrams, K., Ekbom, A., Jackson, E., Mayberry, J. (2000) Colorectal cancer prevention in ulcerative colitis: a case-control study. Aliment Pharmacol Ther 14, 145–153

    CAS  PubMed  Google Scholar 

  134. Pinczowski, D., Ekbom, A., Baron, J., Yuen, J., Adami, H.O. (1994) Risk factors for colorectal cancer in patients with ulcerative colitis: a case-control study. Gastroenterology 107, 117–120

    CAS  PubMed  Google Scholar 

  135. Mathy, C., Schneider, K., Chen, Y.Y., Varma, M., Terdiman, J.P., Mahadevan, U. (2003) Gross versus microscopic pancolitis and the occurrence of neoplasia in ulcerative colitis. Inflamm Bowel Dis 9, 351–355

    PubMed  Google Scholar 

  136. Itzkowitz, S.H., Yio, X. (2004) Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Liver Physiol 287, G7–G17

    CAS  PubMed  Google Scholar 

  137. Boland, C.R., Thibodeau, S.N., Hamilton, S.R., Sidransky, D., Eshleman, J.R., Burt, R.W., Meltzer, S.J., Rodriguez-Bigas, M.A., Fodde, R., Ranzani, G.N., Srivastava, S. (1998) A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58, 5248– 5257

    CAS  PubMed  Google Scholar 

  138. Jass, J.R., Whitehall, V.L., Young, J., Leg-gett, B.A. (2002) Emerging concepts in colorectal neoplasia. Gastroenterology 123, 862–876

    CAS  PubMed  Google Scholar 

  139. Willenbucher, R.F., Zelman, S.J., Ferrell, L.D., Moore, D.H., II, Waldman, F.M. (1997) Chromosomal alterations in ulcera-tive colitis-related neoplastic progression. Gastroenterology 113, 791–801

    CAS  PubMed  Google Scholar 

  140. Willenbucher, R.F., Aust, D.E., Chang, C.G., Zelman, S.J., Ferrell, L.D., Moore, D.H., II, Waldman, F.M. (1999) Genomic instability is an early event during the progression pathway of ulcerative-colitis-related neoplasia. Am J Pathol 154, 1825–1830

    CAS  PubMed  Google Scholar 

  141. Rabinovitch, P.S., Dziadon, S., Brentnall, T.A., Emond, M.J., Crispin, D.A., Haggitt, R.C., Bronner, M.P. (1999) Pancolonic chromosomal instability precedes dysplasia and cancer in ulcerative colitis. Cancer Res 59, 5148–5153

    CAS  PubMed  Google Scholar 

  142. Hammarberg, C., Slezak, P., Tribukait, B. (1984) Early detection of malignancy in ulcerative colitis. A flow-cytometric DNA study. Cancer 53, 291–295

    CAS  PubMed  Google Scholar 

  143. Rubin, C., Haggitt, R.C., Burmer, G.C., Brentnall, T.A., Stevens, A.C., Levine, D.S., Dean, P.J., Kimmey, M., Perera, D.R., Rab-inovitch, P.S. (1992) DNA aneuploidy in colonic biopsies predicts future development of dysplasia in ulcerative colitis. Gas-troenterology 103, 1611–1620

    CAS  Google Scholar 

  144. O'Sullivan, J.N., Bronner, M.P., Brentnall, T.A., Finley, J.C., Shen, W.T., Emerson, S., Emond, M.J., Gollahon, K.A., Moskovitz, A.H., Crispin, D.A., Potter, J.D., Rabino-vitch, P.S. (2002) Chromosomal instability in ulcerative colitis is related to telomere shortening. Nat Genet 32, 280–284

    PubMed  Google Scholar 

  145. Levine, A.J. (1997) p53, the cellular gatekeeper for growth and division. Cell 88, 323–331

    CAS  PubMed  Google Scholar 

  146. Burmer, G.C., Rabinovitch, P.S., Haggitt, R.C., Crispin, D.A., Brentnall, T.A., Kolli, V.R., Stevens, A.C., Rubin, C.E. (1992) Neoplastic progression in ulcerative colitis: histology, DNA content, and loss of a p53 allele. Gastroenterology 103, 1602–1610

    CAS  PubMed  Google Scholar 

  147. Yin, J., Harpaz, N., Tong, Y., Huang, Y., Laurin, J., Greenwald, B.D., Hontanosas, M., Newkirk, C., Meltzer, S.J. (1993) p53 point mutations in dysplastic and cancerous ulcerative colitis lesions. Gastroenterology 104, 1633–1639

    CAS  PubMed  Google Scholar 

  148. Chaubert, P., Benhattar, J., Saraga, E., Costa, J. (1994) K-ras mutations and p53 alterations in neoplastic and nonneoplastic lesions associated with longstanding ulcera-tive colitis. Am J Pathol 144, 767–775

    CAS  PubMed  Google Scholar 

  149. Kern, S.E., Redston, M., Seymour, A.B., Caldas, C., Powell, S.M., Kornacki, S., Kin-zler, K.W. (1994) Molecular genetic profiles of colitis-associated neoplasms. Gastroenter-ology 107, 420–428

    CAS  Google Scholar 

  150. Brentnall, T.A., Crispin, D.A., Rabinovitch, P.S., Haggitt, R.C., Rubin, C.E., Stevens, A.C., Burmer, G.C. (1994) Mutations in the p53 gene: an early marker of neoplastic progression in ulcerative colitis. Gastroenter-ology 107, 369–378

    CAS  Google Scholar 

  151. Holzmann, K., Klump, B., Borchard, F., Hsieh, C.J., Kuhn, A., Gaco, V., Gregor, M., Porschen, R. (1998) Comparative analysis of histology, DNA content, p53 and Ki-ras mutations in colectomy specimens with long-standing ulcerative colitis. Int J Cancer 76, 1–6

    CAS  PubMed  Google Scholar 

  152. Lashner, B.A., Shapiro, B.D., Husain, A., Goldblum, J.R. (1999) Evaluation of the usefulness of testing for p53 mutations in colorectal cancer surveillance for ulcerative colitis. Am J Gastroenterol 94, 456–462

    CAS  PubMed  Google Scholar 

  153. Harpaz, N., Peck, A.L., Yin, J., Fiel, I., Hon-tanosas, M., Tong, T.R., Laurin, J.N., Abraham, J.M., Greenwald, B.D., Meltzer, S.J. (1994) p53 protein expression in ulcerative colitis-associated colorectal dysplasia and carcinoma. Hum Pathol 25, 1069–1074

    CAS  PubMed  Google Scholar 

  154. Greenblatt, M.S., Bennett, W.P., Hollstein, M., Harris, C.C. (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54, 4855–4878

    CAS  PubMed  Google Scholar 

  155. Tornaletti, S., Pfeifer, G.P. (1995) Complete and tissue-independent methylation of CpG sites in the p53 gene: implications for mutations in human cancers. Oncogene 10, 1493–1499

    CAS  PubMed  Google Scholar 

  156. Aust, D.E., Terdiman, J.P., Willenbucher, R.F., Chang, C.G., Molinaro-Clark, A., Baretton, G.B., Loehrs, U., Waldman, F.M. (2002) The APC/beta-catenin pathway in ulcerative colitis-related colorectal carcinomas: a mutational analysis. Cancer 94, 1421–1427

    CAS  PubMed  Google Scholar 

  157. Redston, M.S., Papadopoulos, N., Cal-das, C., Kinzler, K.W., Kern, S.E. (1995) Common occurrence of APC and K-ras gene mutations in the spectrum of colitis-associated neoplasias. Gastroenterology 108, 383–392

    CAS  PubMed  Google Scholar 

  158. Tarmin, L., Yin, J., Harpaz, N., Kozam, M., Noordzij, J., Antonio, L.B., Jiang, H.Y., Chan, O., Cymes, K., Meltzer, S.J. (1995) Adenomatous polyposis coli gene mutations in ulcerative colitis-associated dysplasias and cancers versus sporadic colon neoplasms. Cancer Res 55, 2035–2038

    CAS  PubMed  Google Scholar 

  159. Umetani, N., Sasaki, S., Watanabe, T., Shi-nozaki, M., Matsuda, K., Ishigami, H., Ueda, E., Muto, T. (1999) Genetic alterations in ulcerative colitis-associated neo-plasia focusing on APC, K-ras gene and microsatellite instability. Jpn J Cancer Res 90, 1081–1087

    CAS  PubMed  Google Scholar 

  160. Greenwald, B.D., Harpaz, N., Yin, J., Huang, Y., Tong, Y., Brown, V.L., McDan-iel, T., Newkirk, C., Resau, J.H., Meltzer, S.J. (1992) Loss of heterozygosity affecting the p53, Rb, and mcc/apc tumor suppressor gene loci in dysplastic and cancerous ulcera-tive colitis. Cancer Res 52, 741–745

    CAS  PubMed  Google Scholar 

  161. Fogt, F., Vortmeyer, A.O., Goldman, H., Giordano, T.J., Merino, M.J., Zhuang, Z. (1998) Comparison of genetic alterations in colonic adenoma and ulcerative colitis-associated dysplasia and carcinoma. Hum Pathol 29, 131–136

    CAS  PubMed  Google Scholar 

  162. Benedict, W.F., Xu, H.J. Takahashi, R. (1990) The retinoblastoma gene: its role in human malignancies. Cancer Invest 8, 535– 540

    CAS  PubMed  Google Scholar 

  163. Carnero, A., Hannon, G.J. (1998) The INK4 family of CDK inhibitors. Curr Top Microbiol Immunol 227, 43–55

    CAS  PubMed  Google Scholar 

  164. Cairns, P., Thomas, J.P., Eby, Y., Tokino, K., Califano, J., Merlo, A., Mao, L., Her-ath, J., Jenkins, R., Westra, W., et al. (1995) Frequency of homozygous deletion at p16/ CDKN2 in primary human tumours. Nat Genet 11, 210–212

    CAS  PubMed  Google Scholar 

  165. Hsieh, C.J., Klump, B., Holzmann, K., Bor-chard, F., Gregor, M., Porschen, R. (1998) Hypermethylation of the p16INK4a promoter in colectomy specimens of patients with long-standing and extensive ulcerative colitis. Cancer Res 58, 3942–3945

    CAS  PubMed  Google Scholar 

  166. Meltzer, S.J., Mane, S.M., Wood, P.K., Resau, J.H., Newkirk, C., Terzakis, J.A., Korelitz, B.I., Weinstein, W.M., Needleman, S.W. (1990) Activation of c-Ki-ras in human gastrointestinal dysplasias determined by direct sequencing of polymerase chain reaction products. Cancer Res 50, 3627–3630

    CAS  PubMed  Google Scholar 

  167. Burmer, G.C., Levine, D.S., Kulander, B.G., Haggitt, R.C., Rubin, C.E., Rabinovitch, P.S. (1990) c-Ki-ras mutations in chronic ulcerative colitis and sporadic colon carcinoma. Gastroenterology 99, 416–420

    CAS  PubMed  Google Scholar 

  168. Bell, S.M., Kelly, S.A., Hoyle, J.A., Lewis, F.A., Taylor, G.R., Thompson, H., Dixon, M.F., Quirke, P. (1991) c-Ki-ras gene mutations in dysplasia and carcinomas complicating ulcerative colitis. Br J Cancer 64, 174–178

    CAS  PubMed  Google Scholar 

  169. Brentnall, T.A., Crispin, D.A., Bronner, M.P., Cherian, S.P., Hueffed, M., Rabino-vitch, P.S., Rubin, C.E., Haggitt, R.C., Boland, C.R. (1996) Microsatellite instability in nonneoplastic mucosa from patients with chronic ulcerative colitis. Cancer Res 56, 1237–1240

    CAS  PubMed  Google Scholar 

  170. Heinen, C.D., Noffsinger, A.E., Belli, J., Straughen, J., Fischer, J., Groden, J., Fenoglio-Preiser, C.M. (1997) Regenerative lesions in ulcerative colitis are characterized by microsatellite mutation. Genes Chromosomes Cancer 19, 170–175

    CAS  PubMed  Google Scholar 

  171. Suzuki, H., Harpaz, N., Tarmin, L., Yin, J., Jiang, H.Y., Bell, J.D., Hontanosas, M., Groisman, G.M., Abraham, J.M., Meltzer, S.J. (1994) Microsatellite instability in ulcer-ative colitis-associated colorectal dysplasias and cancers. Cancer Res 54, 4841–4844

    CAS  PubMed  Google Scholar 

  172. Cawkwell, L., Sutherland, F., Murgatroyd, H., Jarvis, P., Gray, S., Cross, D., Shepherd, N., Day, D., Quirke, P. (2000) Defective hMSH2/hMLH1 protein expression is seen infrequently in ulcerative colitis associated colorectal cancers. Gut 46, 367–369

    CAS  PubMed  Google Scholar 

  173. Noffsinger, A., Kretschmer, S., Belli, J., Fogt, F., Fenoglio-Preiser, C. (2000) Mic-rosatellite instability is uncommon in intestinal mucosa of patients with Crohn's disease. Dig Dis Sci 45, 378–384

    CAS  PubMed  Google Scholar 

  174. Pokorny, R.M., Hofmeister, A., Galandiuk, S., Dietz, A.B., Cohen, N.D., Neibergs, H.L. (1997) Crohn's disease and ulcerative colitis are associated with the DNA repair gene MLH1. Ann Surg 225, 718–723; discussion 723–715

    CAS  PubMed  Google Scholar 

  175. Fleisher, A.S., Esteller, M., Harpaz, N., Leytin, A., Rashid, A., Xu, Y., Liang, J., Stine, O.C., Yin, J., Zou, T.T., Abraham, J.M., Kong, D., Wilson, K.T., James, S.P., Herman, J.G., Meltzer, S.J. (2000) Micro-satellite instability in inflammatory bowel disease-associated neoplastic lesions is associated with hypermethylation and diminished expression of the DNA mismatch repair gene, hMLH1. Cancer Res 60, 4864–4868

    CAS  PubMed  Google Scholar 

  176. Souza, R.F., Yin, J., Smolinski, K.N., Zou, T.T., Wang, S., Shi, Y.Q., Rhyu, M.G., Cot-trell, J., Abraham, J.M., Biden, K., Simms, L., Leggett, B., Bova, G.S., Frank, T., Powell, S.M., Sugimura, H., Young, J., Harpaz, N., Shimizu, K., Matsubara, N., Meltzer, S.J. (1997) Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors. Cancer Res 57, 2350–2353

    CAS  PubMed  Google Scholar 

  177. Souza, R.F., Appel, R., Yin, J., Wang, S., Smolinski, K.N., Abraham, J.M., Zou, T.T., Shi, Y.Q., Lei, J., Cottrell, J., Cymes, K., Biden, K., Simms, L., Leggett, B., Lynch, P.M., Frazier, M., Powell, S.M., Harpaz, N., Sugimura, H., Young, J., Meltzer, S.J. (1996) Microsatellite instability in the insulin-like growth factor II receptor gene in gastrointestinal tumours. Nat Genet 14, 255–257

    CAS  PubMed  Google Scholar 

  178. Toyota, M., Ahuja, N., Ohe-Toyota, M., Herman, J.G., Baylin, S.B., Issa, J.P. (1999) CpG island methylator phenotype in color-ectal cancer. Proc Natl Acad Sci USA 96, 8681–8686

    CAS  PubMed  Google Scholar 

  179. Santini, V., Kantarjian, H.M. Issa, J.P. (2001) Changes in DNA methylation in neoplasia: pathophysiology and therapeutic implications. Ann Intern Med 134, 573–586

    CAS  PubMed  Google Scholar 

  180. Issa, J.P., Ahuja, N., Toyota, M., Bronner, M.P., Brentnall, T.A. (2001) Accelerated age-related CpG island methylation in ulcer-ative colitis. Cancer Res 61, 3573–3577

    CAS  PubMed  Google Scholar 

  181. Sato, F., Harpaz, N., Shibata, D., Xu, Y., Yin, J., Mori, Y., Zou, T.T., Wang, S., Desai, K., Leytin, A., Selaru, F.M., Abraham, J.M., Meltzer, S.J. (2002) Hypermethylation of the p14(ARF) gene in ulcerative colitis-associated colorectal carcinogenesis. Cancer Res 62, 1148–1151

    CAS  PubMed  Google Scholar 

  182. Hussain, S.P., Hofseth, L.J., Harris, C.C. (2003) Radical causes of cancer. Nat Rev Cancer 3, 276–285

    CAS  PubMed  Google Scholar 

  183. Marnett, L.J. (2000) Oxyradicals and DNA damage. Carcinogenesis 21, 361–370

    CAS  PubMed  Google Scholar 

  184. Wang, D., Kreutzer, D.A., Essigmann, J.M. (1998) Mutagenicity and repair of oxidative DNA damage: insights from studies using defined lesions. Mutat Res 400, 99–115

    CAS  PubMed  Google Scholar 

  185. Morgan, W.F., Corcoran, J., Hartmann, A., Kaplan, M.I., Limoli, C.L., Ponnaiya, B. (1998) DNA double-strand breaks, chromosomal rearrangements, and genomic instability. Mutat Res 404, 125–128

    CAS  PubMed  Google Scholar 

  186. Kinouchi, Y., Hiwatashi, N., Chida, M., Nagashima, F., Takagi, S., Maekawa, H., Toyota, T. (1998) Telomere shortening in the colonic mucosa of patients with ulcera-tive colitis. J Gastroenterol 33, 343–348

    CAS  PubMed  Google Scholar 

  187. Artandi, S.E., DePinho, R.A. (2000) A critical role for telomeres in suppressing and facilitating carcinogenesis. Curr Opin Genet Dev 10, 39–46

    CAS  PubMed  Google Scholar 

  188. Cottliar, A., Fundia, A., Boerr, L., Sambuelli, A., Negreira, S., Gil, A., Gomez, J.C., Cho-pita, N., Bernedo, A., Slavutsky, I. (2000) High frequencies of telomeric associations, chromosome aberrations, and sister chro-matid exchanges in ulcerative colitis. Am J Gastroenterol 95, 2301–2307

    CAS  PubMed  Google Scholar 

  189. Nair, J., Barbin, A., Velic, I., Bartsch, H. (1999) Etheno DNA-base adducts from endogenous reactive species. Mutat Res 424, 59–69

    CAS  PubMed  Google Scholar 

  190. Hussain, S.P., Harris, C.C. (1998) Molecular epidemiology of human cancer: contribution of mutation spectra studies of tumor suppressor genes. Cancer Res 58, 4023–4037

    CAS  PubMed  Google Scholar 

  191. Wink, D.A., Vodovotz, Y., Laval, J., Laval, F., Dewhirst, M.W., Mitchell, J.B. (1998) The multifaceted roles of nitric oxide in cancer. Carcinogenesis 19, 711–721

    CAS  PubMed  Google Scholar 

  192. Cerda, S., Weitzman, S.A. (1997) Influence of oxygen radical injury on DNA methyla-tion. Mutat Res 386, 141–152

    CAS  PubMed  Google Scholar 

  193. Gasche, C., Chirtina, C.L., Rhees, J., Goel, A., Boland, C.R. (2001) Oxidative stress increases frameshift mutations in human colorectal cancer cells. Cancer Res 61, 7444–7448

    CAS  PubMed  Google Scholar 

  194. Chang, C.L., Marra, G., Chauhan, D.P., Ha, H.T., Chang, D.K., Ricciardiello, L., Randolph, A., Carethers, J.M., Boland, C.R. (2002) Oxidative stress inactivates the human DNA mismatch repair system. Am J Physiol Cell Physiol 283, C148–C154

    CAS  PubMed  Google Scholar 

  195. Agoff, S.N., Brentnall, T.A., Crispin, D.A., Taylor, S.L., Raaka, S., Haggitt, R.C., Reed, M.W., Afonina, I.A., Rabinovitch, P.S., Stevens, A.C., Feng, Z., Bronner, M.P. (2000) The role of cyclooxygenase 2 in ulcerative colitis-associated neoplasia. Am J Pathol 157, 737–745

    CAS  PubMed  Google Scholar 

  196. Steele, V.E., Hawk, E.T., Viner, J.L., Lubet, R.A. (2003) Mechanisms and applications of non-steroidal anti-inflammatory drugs in the chemoprevention of cancer. Mutat Res 523–524, 137–144

    PubMed  Google Scholar 

  197. Gupta, R.A., DuBois, R.N., Wallace, M.C. (2002) New avenues for the prevention of colorectal cancer: targeting cyclo-oxygen-ase-2 activity. Best Pract Res Clin Gastroen-terol 16, 945–956

    CAS  Google Scholar 

  198. Hegazi, R.A., Mady, H.H., Melhem, M.F., Sepulveda, A.R., Mohi, M., Kandil, H.M. (2003) Celecoxib and rofecoxib potentiate chronic colitis and premalignant changes in interleukin 10 knockout mice. Inflamm Bowel Dis 9, 230–236

    PubMed  Google Scholar 

  199. Bull, A.W. (2003) The role of peroxisome proliferator-activated receptor gamma in colon cancer and inflammatory bowel disease. Arch Pathol Lab Med 127, 1121– 1123

    CAS  PubMed  Google Scholar 

  200. Niho, N., Takahashi, M., Kitamura, T., Shoji, Y., Itoh, M., Noda, T., Sugimura, T., Wakabayashi, K. (2003) Concomitant suppression of hyperlipidemia and intestinal polyp formation in Apc-deficient mice by peroxisome proliferator-activated receptor ligands. Cancer Res 63, 6090–6095

    CAS  PubMed  Google Scholar 

  201. Landers, C.J., Cohavy, O., Misra, R., Yang, H., Lin, Y.C., Braun, J., Targan, S.R. (2002) Selected loss of tolerance evidenced by Crohn's disease-associated immune responses to auto- and microbial antigens. Gastroenterology 123, 689–699

    CAS  PubMed  Google Scholar 

  202. Stadnicki, A., Colman, R.W. (2003) Experimental models of inflammatory bowel disease. Arch Immunol Ther Exp (Warsz) 51, 149–155

    Google Scholar 

  203. Kuhn, R., Löhler, J., Rennick, D., Rajew-sky, K., Muller, W. (1993) Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274

    CAS  PubMed  Google Scholar 

  204. Mombaerts, P., Mombaerts, E., Grusby, M.J., Glimcher, L.H., Bhan, A.K., Ton-egawa, S. (1993) Spontaneous development of inflammatory bowel disease in T cell receptor mutant mice. Cell 75, 274–282

    CAS  PubMed  Google Scholar 

  205. Sadlack, B., Merz, H., Schorle, H., Schimpl, A., Feller, A.C., Horak, I. (1993) Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253–261

    CAS  PubMed  Google Scholar 

  206. Elson, C.O., Cong, Y., McCracken, V.J., Dimmitt, R.A., Lorenz, R.G., Weaver, C.T. (2005) Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota. Immunol Rev 206, 260–276

    PubMed  Google Scholar 

  207. Strober, W., Fuss, I.J., Ehrhardt, R.O., Neurath, M., Boirivant, M., Ludviksson, B.R. (1998) Mucosal immunoregula-tion and inflammatory bowel disease: new insights from murine models of inflammation. Scand J Immunol 48, 453–458

    CAS  PubMed  Google Scholar 

  208. Brown, S.J., Miller, A.M., Cowan, P.J., Slavin, J., Connell, W.R., Moore, G.T., Bell, S., Elliott, P.R., Desmond, P.V., d'Apice, A.J. (2004) Altered immune system gly-cosylation causes colitis in alpha1,2-fucosyl-transferase transgenic mice. Inflamm Bowel Dis 10, 546–556

    PubMed  Google Scholar 

  209. Hollander, G.A., Simpson, S.J., Mizoguchi, E., Nichogiannopoulou, A., She, J., Gutierrez-Ramos, J.C., Bhan, A.K., Burakoff, S.J., Wang, B., Terhorst, C. (1995) Severe colitis in mice with aberrant thymic selection. Immunity 3, 27–38

    CAS  PubMed  Google Scholar 

  210. Dieleman, L.A., Ridwan, B.U., Tennyson, G.S., Beagley, K.W., Bucy, R.P., Elson, C.O. (1994) Dextran sulfate sodium-induced colitis occurs in severe combined immunodeficient mice. Gastroenterology 107, 1643–1652

    CAS  PubMed  Google Scholar 

  211. Warren, B.F., Watkins, P.E. (1994) Animal models of inflammatory bowel disease. J Pathol 172, 313–316

    CAS  PubMed  Google Scholar 

  212. Okayasu, I., Hatakeyama, S., Yamada, M., Ohkusa, T., Inagaki, Y., Nakaya, R. (1990) A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 98, 694– 702

    CAS  PubMed  Google Scholar 

  213. Cooper, H.S., Murthy, S.N., Shah, R.S., Sedergran, D.J. (1993) Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest 69, 238–249

    CAS  PubMed  Google Scholar 

  214. Ohkusa, T., Okayasu, I., Tokoi, S., Araki, A., Ozaki, Y. (1995) Changes in bacterial phagocytosis of macrophages in experimental ulcerative colitis. Digestion 56, 159–164

    CAS  PubMed  Google Scholar 

  215. Seril, D.N., Liao, J., Yang, G.Y., Yang, C.S. (2003) Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models. Carcinogenesis 24, 353–362

    CAS  PubMed  Google Scholar 

  216. Seril, D.N., Liao, J., Ho, K.L., Warsi, A., Yang, C.S., Yang, G.Y. (2002) Dietary iron supplementation enhances DSS-induced colitis and associated colorectal carcinoma development in mice. Dig Dis Sci 47, 1266– 1278

    CAS  PubMed  Google Scholar 

  217. Seril, D.N., Liao, J., Yang, G.-Y., Yang, C.S. (2003) Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models. Carcinogenesis 24, 353–362

    CAS  PubMed  Google Scholar 

  218. Tanaka, T., Kohno, H., Suzuki, R., Hata, K., Sugie, S., Niho, N., Sakano, K., Taka-hashi, M., Wakabayashi, K. (2006) Dextran sodium sulfate strongly promotes colorectal carcinogenesis in Apc(Min/+) mice: inflammatory stimuli by dextran sodium sulfate results in development of multiple colonic neoplasms. Int J Cancer 118, 25–34

    CAS  PubMed  Google Scholar 

  219. Cooper, H.S., Everley, L., Chang, W.C., Pfeiffer, G., Lee, B., Murthy, S., Clapper, M.L. (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

    CAS  PubMed  Google Scholar 

  220. Chang, W.C.C., Renata, A., Clapper, M.L., Zhang, X., Williams, K.L., Spittle, C.S., Li, T., Cooper, H.S. (2007) Loss of p53 enhances the induction of colitis-associated neoplasia by dextran sulfate sodium. Car-cinogenesis 28, 2375–2381

    CAS  Google Scholar 

  221. Fujii, S., Fujimori, T., Kawamata, H., Takeda, J., Kitajima, K., Omotehara, F., Kaihara, T., Kusaka, T., Ichikawa, K., Ohkura, Y., Ono, Y., Imura, J., Yamaoka, S., Sakamoto, C., Ueda, Y., Chiba, T. (2004) Development of colonic neoplasia in p53 deficient mice with experimental colitis induced by dextran sulphate sodium. Gut 53, 710–716

    CAS  PubMed  Google Scholar 

  222. Kohonen-Corish, M.R., Daniel, J.J., te Riele, H., Buffinton, G.D., Dahlstrom, J.E. (2002) Susceptibility of Msh2-deficient mice to inflammation-associated colorectal tumors. Cancer Res 62, 2092–2097

    CAS  PubMed  Google Scholar 

  223. Liao, J., Seril, D.N., Lu. G.G., Zhang, M., Toyokuni, S., Yang, A.L., Yang, G.Y. (2008) Increased susceptibility of chronic ulcerative colitis-induced carcinoma development in DNA repair enzyme Ogg1 deficient mice. Mol Carcinog. 47(8):638–646.

    CAS  PubMed  Google Scholar 

  224. Torres, M.I., Gracìa-Martin, M., Fernandez, M.I., Nieto, N., Gil, A., Rios, A. (1999) Experimental colitis induced by trinitroben-zenesulfonic acid: an ultrastructural and histochemical study. Dig Dis Sci 44, 2523– 2529

    CAS  PubMed  Google Scholar 

  225. Neurath, M.F., Fuss, I., Pasparakis, M., Alexopoulou, L., Haralambous, S., Meyer zum Buschenfelde, K.H., Strober, W., Kol-lias, G. (1997) Predominant pathogenic role of tumor necrosis factor in experimental colitis in mice. Eur J Immunol 27, 1743–1750

    CAS  PubMed  Google Scholar 

  226. Neurath, M.F., Fuss, I., Kelsall, B.L., Stuber, E., Strober, W. (1995) Antibodies to inter-leukin 12 abrogate established experimental colitis in mice. J Exp Med 182, 1281–1290

    CAS  PubMed  Google Scholar 

  227. Camoglio, L., Juffermans, N.P., Peppelen-bosch, M., te Velde, A.A., ten Kate, F.J., van Deventer, S.J., Kopf, M. (2002) Contrasting roles of IL-12p40 and IL-12p35 in the development of hapten-induced colitis. Eur J Immunol 32, 261–269

    CAS  PubMed  Google Scholar 

  228. Gao, D., Wagner, A.H., Fankhaenel, S., Stojanovic, T., Schweyer, S., Panzner, S., Hecker, M. (2005) CD40 antisense oligo-nucleotide inhibition of trinitrobenzene sulphonic acid induced rat colitis. Gut 54, 70–77

    CAS  PubMed  Google Scholar 

  229. Ten Hove, T.Corbaz, A., Amitai, H., Aloni, S., Belzer, I., Graber, P., Drillenburg, P., van Deventer, S.J., Chvatchko, Y., Te Velde, A.A. (2001) Blockade of endogenous IL-18 ameliorates TNBS-induced colitis by decreasing local TNF-alpha production in mice. Gastroenterology 121, 1372–1379

    PubMed  Google Scholar 

  230. Hans, W., Schölmerich, J., Gross, V., Falk, W. (2000) Interleukin-12 induced inter-feron-gamma increases inflammation in acute dextran sulfate sodium induced colitis in mice. Eur Cytokine Netw 11, 67–74

    CAS  PubMed  Google Scholar 

  231. Stallmach, A., Marth, T., Weiss, B., Wittig, B.M., Hombach, A., Schmidt, C., Neurath, M., Zeitz, M., Zeuzem, S., Abken, H. (2004) An interleukin 12 p40-IgG2b fusion protein abrogates T cell mediated inflammation: anti-inflammatory activity in Crohn's disease and experimental colitis in vivo. Gut 53, 339–345

    CAS  PubMed  Google Scholar 

  232. D'Argenio, G., Cosenza, V., Delle Cave, M., Iovino, P., Delle Valle, N., Lombardi, G., Mazzacca, G. (1996) Butyrate enemas in experimental colitis and protection against large bowel cancer in a rat model. Gastroen-terology 110, 1727–1734

    Google Scholar 

  233. Hibi, T., Ogata, H., Sakuraba, A. (2002) Animal models of inflammatory bowel disease. J Gastroenterol 37, 409–417

    CAS  PubMed  Google Scholar 

  234. Barmeyer, C., Harren, M., Schmitz, H., Heinzel-Pleines, U., Mankertz, J., Seidler, U., Horak, I., Wiedenmann, B., Fromm, M., Schulzke, J.D. (2004) Mechanisms of diarrhea in the interleukin-2-deficient mouse model of colonic inflammation. Am J Physiol Gastrointest Liver Physiol 286, G244–252

    CAS  PubMed  Google Scholar 

  235. Sohn, K.J., Shah, S.A., Reid, S., Choi, M., Carrier, J., Comiskey, M., Terhorst, C., Kim, Y.I. (2001) Molecular genetics of ulcerative colitis-associated colon cancer in the inter-leukin 2- and beta(2)-microglobulin-defi-cient mouse. Cancer Res 61, 6912–6917

    CAS  PubMed  Google Scholar 

  236. Ludviksson, B.R., Gray, B., Strober, W., Ehrhardt, R.O. (1997) Dysregulated intrathymic development in the IL-2-defi-cient mouse leads to colitis-inducing thy-mocytes. J Immunol 158, 104–111

    CAS  PubMed  Google Scholar 

  237. Dresner-Pollak, R., Gelb, N., Rachmilewitz, D., Karmeli, F., Weinreb, M. (2004) Inter-leukin 10-deficient mice develop osteopenia, decreased bone formation, and mechanical fragility of long bones. Gastroenterology 127, 792–801

    CAS  PubMed  Google Scholar 

  238. Berg, D.J., Davidson, N., Kuhn, R., Muller, W., Menon, S., Holland, G., Thompson-Snipes, L., Leach, M.W., Rennick, D. (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

    CAS  PubMed  Google Scholar 

  239. Sydora, B.C., Tavernini, M.M., Wessler, A., Jewell, L.D., Fedorak, R.N. (2003) Lack of interleukin-10 leads to intestinal inflammation, independent of the time at which lumi-nal microbial colonization occurs. Inflamm Bowel Dis 9, 87–97

    PubMed  Google Scholar 

  240. Mahler, M., Leiter, E.H. (2002) Genetic and environmental context determines the course of colitis developing in IL-10-defi-cient mice. Inflamm Bowel Dis 8, 347–355

    PubMed  Google Scholar 

  241. Balish, E., Warner, T. (2002) Enterococcus faecalis induces inflammatory bowel disease in interleukin-10 knockout mice. Am J Pathol 160, 2253–2257

    CAS  PubMed  Google Scholar 

  242. Scheinin, T., Butler, D.M., Salway, F., Scal-lon, B., Feldmann, M. (2003) Validation of the interleukin-10 knockout mouse model of colitis: antitumour necrosis factor-antibodies suppress the progression of colitis. Clin Exp Immunol 133, 38–43

    CAS  PubMed  Google Scholar 

  243. Steidler, L., Hans, W., Schotte, L., Neir-ynck, S., Obermeier, F., Falk, W., Fiers, W., Remaut, E. (2000) Treatment of murine colitis by Lactococcus lactis secreting inter-leukin-10. Science 289, 1352–1355

    CAS  PubMed  Google Scholar 

  244. Moore, K.W., de Waal Malefyt, R., Coffman, R.L., O'Garra, A. (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19, 683–765

    CAS  PubMed  Google Scholar 

  245. Sturlan, S., Oberhuber, G., Beinhauer, B.G., Tichy, B., Kappel, S., Wang, J., Rogy, M.A. (2001) Interleukin-10-deficient mice and inflammatory bowel disease associated cancer development. Carcinogenesis 22, 665–671

    CAS  PubMed  Google Scholar 

  246. Itzkowitz, S.H., Harpaz, N. (2004) Diagnosis and management of dysplasia in patients with inflammatory bowel diseases. Gastroen-terology 126, 1634–1648

    Google Scholar 

  247. Schreiber, S., Fedorak, R.N., Nielsen, O.H., Wild, G., Williams, C.N., Nikolaus, S., Jacyna, M., Lashner, B.A., Gangl, A., Rut-geerts, P., Isaacs, K., van Deventer, S.J., Koningsberger, J.C., Cohard, M., LeBeaut, A., Hanauer, S.B. (2000) Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn's disease. Crohn's Disease IL-10 Cooperative Study Group. Gastroenterology 119, 1461–1472

    CAS  PubMed  Google Scholar 

  248. Fedorak, R.N., Gangl, A., Elson, C.O., Rut-geerts, P., Schreiber, S., Wild, G., Hanauer, S.B., Kilian, A., Cohard, M., LeBeaut, A., Feagan, B. (2000) Recombinant human interleukin 10 in the treatment of patients with mild to moderately active Crohn's disease. The Interleukin 10 Inflammatory Bowel Disease Cooperative Study Group. Gastroenterology 119, 1473–1482

    CAS  PubMed  Google Scholar 

  249. De Winter, H., Elewaut, D., Turovskaya, O., Huflejt, M., Shimeld, C., Hagenbaugh, A., Binder, S., Takahashi, I., Kronenberg, M., Cheroutre, H. (2002) Regulation of mucosal immune responses by recombinant interleukin 10 produced by intestinal epithelial cells in mice. Gastroenterology 122, 1829–1841

    PubMed  Google Scholar 

  250. Nakase, H., Okazaki, K., Tabata, Y., Ozeki, M., Watanabe, N., Ohana, M., Uose, S., Uchida, K., Nishi, T., Mastuura, M., Tamaki, H., Itoh, T., Kawanami, C., Chiba, T. (2002) New cytokine delivery system using gelatin microspheres containing interleukin-10 for experimental inflammatory bowel disease. J Pharmacol Exp Ther 301, 59–65

    CAS  PubMed  Google Scholar 

  251. Lindsay, J.O., Ciesielski, C.J., Scheinin, T., Brennan, F.M., Hodgson, H.J. (2003) Local delivery of adenoviral vectors encoding murine interleukin 10 induces colonic interleukin 10 production and is therapeutic for murine colitis. Gut 52, 981–987

    CAS  PubMed  Google Scholar 

  252. Spencer, S.D., Di Marco, F., Hooley, J., Pitts-Meek, S., Bauer, M., Ryan, A.M., Sordat, B., Gibbs, V.C., Aguet, M. (1998) The orphan receptor CRF2–4 is an essential subunit of the interleukin 10 receptor. J Exp Med 187, 571–578

    CAS  PubMed  Google Scholar 

  253. Kobayashi, M., Kweon, M.N., Kuwata, H., Schreiber, R.D., Kiyono, H., Takeda, K., Akira, S. (2003) Toll-like receptor-dependent production of IL-12p40 causes chronic enterocolitis in myeloid cell-specific Stat3-deficient mice. J Clin Invest 111, 1297– 1308

    CAS  PubMed  Google Scholar 

  254. Rakoff-Nahoum, S., Hao, L., Medzhitov, R. (2006) Role of toll-like receptors in spontaneous commensal-dependent colitis. Immunity 25, 319–329

    CAS  PubMed  Google Scholar 

  255. O'Mahony, L., Feeney, M., O'Halloran, S., Murphy, L., Kiely, B., Fitzgibbon, J., Lee, G., O'Sullivan, G., Shanahan, F., Collins, J.K. (2001) Probiotic impact on microbial flora, inflammation and tumour development in IL-10 knockout mice. Aliment Pharmacol Ther 15, 1219–1225

    PubMed  Google Scholar 

  256. Hahm, K.B., Im, Y.H., Parks, T.W., Park, S.H., Markowitz, S., Jung, H.Y., Green, J., Kim, S.J. (2001) Loss of transforming growth factor beta signalling in the intestine contributes to tissue injury in inflammatory bowel disease. Gut 49, 190–198

    CAS  PubMed  Google Scholar 

  257. Mandelbrot, D.A., McAdam, A.J., Sharpe, A.H. (1999) B7–1 or B7–2 is required to produce the lymphoproliferative phenotype in mice lacking cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). J Exp Med 189, 435–440

    CAS  PubMed  Google Scholar 

  258. Nakamura, K., Kitani, A., Fuss, I., Pedersen, A., Harada, N., Nawata, H., Strober, W. (2004) TGF-beta 1 plays an important role in the mechanism of CD4 + CD25 + regulatory T cell activity in both humans and mice. J Immunol 172, 834–842

    CAS  PubMed  Google Scholar 

  259. Erdman, S.E., Poutahidis, T., Tomczak, M., Rogers, A.B., Cormier, K., Plank, B., Hor-witz, B.H., Fox, J.G. (2003) CD4 + CD25 + regulatory T lymphocytes inhibit microbi-ally induced colon cancer in Rag2-deficient mice. Am J Pathol 162, 691–702

    CAS  PubMed  Google Scholar 

  260. Engle, S.J., Hoying, J.B., Boivin, G.P., Ormsby, I., Gartside, P.S., Doetschman, T. (1999) Transforming growth factor beta1 suppresses nonmetastatic colon cancer at an early stage of tumorigenesis. Cancer Res 59, 3379–3386

    CAS  PubMed  Google Scholar 

  261. Engle, S.J., Ormsby, I., Pawlowski, S., Boivin, G.P., Croft, J., Balish, E., Doet-schman, T. (2002) Elimination of colon cancer in germ-free transforming growth factor beta 1-deficient mice. Cancer Res 62, 6362–6366

    CAS  PubMed  Google Scholar 

  262. Erdman, S.E., Rao, V.P., Poutahidis, T., Ihrig, M.M., Ge, Z., Feng, Y., Tomczak, M., Rogers, A.B., Horwitz, B.H., Fox, J.G. (2003) CD4(+)CD25(+) regulatory lymphocytes require interleukin 10 to interrupt colon carcinogenesis in mice. Cancer Res 63, 6042–6050

    CAS  PubMed  Google Scholar 

  263. Mizoguchi, A., Mizoguchi, E., Bhan, A.K. (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, 320–326

    CAS  PubMed  Google Scholar 

  264. Mizoguchi, A., Mizoguchi, E., Smith, R.N., Preffer, F.I., Bhan, A.K. (1997) Suppres-sive role of B cells in chronic colitis of T cell receptor alpha mutant mice. J Exp Med 186, 1749–1756

    CAS  PubMed  Google Scholar 

  265. Kado, S., Uchida, K., Funabashi, H., Iwata, S., Nagata, Y., Ando, M., Onoue, M., Matsuoka, Y., Ohwaki, M., Morotomi, M. (2001) Intestinal microflora are necessary for development of spontaneous adenocarci-noma of the large intestine in T-cell receptor beta chain and p53 double-knockout mice. Cancer Res 61, 2395–2398

    CAS  PubMed  Google Scholar 

  266. Funabashi, H., Uchida, K., Kado, S., Mat-suoka, Y., Ohwaki, M. (2001) Establishment of a Tcrb and Trp53 genes deficient mouse strain as an animal model for spontaneous colorectal cancer. Exp Anim 50, 41–47

    CAS  PubMed  Google Scholar 

  267. Bjursten, M., Hultgren, O.H., Hultgren Hornquist, E. (2004) Enhanced pro-inflammatory cytokine production in Galphai2-deficient mice on colitis prone and colitis resistant 129Sv genetic backgrounds. Cell Immunol 228, 77–80

    CAS  PubMed  Google Scholar 

  268. Rudolph, U., Finegold, M.J., Rich, S.S., Harriman, G.R., Srinivasan, Y., Brabet, P., Boulay, G., Bradley, A., Birnbaumer, L. (1995) Ulcerative colitis and adenocarci-noma of the colon in G alpha i2-deficient mice. Nat Genet 10, 143–150

    CAS  PubMed  Google Scholar 

  269. Kader, H.A., Tchernev, V.T., Satyaraj, E., Lejnine, S., Kotler, G., Kingsmore, S.F., Patel, D.D. (2005) Protein microarray analysis of disease activity in pediatric inflammatory bowel disease demonstrates elevated serum PLGF, IL-7, TGF-beta1, and IL-12p40 levels in Crohn's disease and ulcera-tive colitis patients in remission versus active disease. Am J Gastroenterol 100, 414–423

    CAS  PubMed  Google Scholar 

  270. Okada, E., Yamazaki, M., Tanabe, M., Takeuchi, T., Nanno, M., Oshima, S., Okamoto, R., Tsuchiya, K., Nakamura, T., Kanai, T., Hibi, T., Watanabe, M. (2005) IL-7 exacerbates chronic colitis with expansion of memory IL-7Rhigh CD4 + mucosal T cells in mice. Am J Physiol Gastrointest Liver Physiol 288, G745–G754

    CAS  PubMed  Google Scholar 

  271. Kontoyiannis, D., Pasparakis, M., Pizarro, T.T., Cominelli, F., Kollias, G. (1999) Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 10, 387–398

    CAS  PubMed  Google Scholar 

  272. Targan, S.R., Hanauer, S.B., van Deventer, S.J., Mayer, L., Present, D.H., Braakman, T., DeWoody, K.L., Schaible, T.F., Rutgeerts, P.J. (1997) A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N Engl J Med 337, 1029–1035

    CAS  PubMed  Google Scholar 

  273. Present, D.H., Rutgeerts, P., Targan, S., Hanauer, S.B., Mayer, L., van Hogezand, R.A., Podolsky, D.K., Sands, B.E., Braak-man, T., DeWoody, K.L., Schaible, T.F., van Deventer, S.J. (1999) Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 340, 1398–1405

    CAS  PubMed  Google Scholar 

  274. Hanauer, S.B., Feagan, B.G., Lichtenstein, G.R., Mayer, L.F., Schreiber, S., Colombel, J.F., Rachmilewitz, D., Wolf, D.C., Olson, A., Bao, W., Rutgeerts, P. (2002) Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 359, 1541–1549

    CAS  PubMed  Google Scholar 

  275. Kollias, G. (2005) TNF pathophysiology in murine models of chronic inflammation and autoimmunity. Semin Arthritis Rheum 34, 3–6

    CAS  PubMed  Google Scholar 

  276. Hammer, R.E., Richardson, J.A., Simmons, W.A., White, A.L., Breban, M., Taurog, J.D. (1995) High prevalence of colorectal cancer in HLA-B27 transgenic F344 rats with chronic inflammatory bowel disease. J Investig Med 43, 262–268

    CAS  PubMed  Google Scholar 

  277. Strober, W., Fuss I., Mannon, P. (2007) The fundamental basis of inflammatory bowel disease. J Clin Invest 117, 514–521

    CAS  PubMed  Google Scholar 

  278. Brandwein, S.L., McCabe, R.P., Cong, Y., Waites, K.B., Ridwan, B.U., Dean, P.A., Ohkusa, T., Birkenmeier, E.H., Sundberg, J.P., Elson, C.O. (1997) Spontaneously col-itic C3H/HeJBir mice demonstrate selective antibody reactivity to antigens of the enteric bacterial flora. J Immunol 159, 44–52

    CAS  PubMed  Google Scholar 

  279. Cong, Y., Brandwein, S.L., McCabe, R.P., Lazenby, A., Birkenmeier, E.H., Sundberg, J.P., Elson, C.O. (1998) CD4 + T cells reactive to enteric bacterial antigens in spontaneously colitic C3H/HeJBir mice: increased T helper cell type 1 response and ability to transfer disease. J Exp Med 187, 855–864

    CAS  PubMed  Google Scholar 

  280. Cong, Y., Weaver, C.T., Lazenby, A., Elson, C.O. (2002) Bacterial-reactive T regulatory cells inhibit pathogenic immune responses to the enteric flora. J Immunol 169, 6112– 6119

    CAS  PubMed  Google Scholar 

  281. Cong, Y., Weaver, C.T., Lazenby, A., Elson, C.O. (2000) Colitis induced by enteric bacterial antigen-specific CD4 + T cells requires CD40–CD40 ligand interactions for a sustained increase in mucosal IL-12. J Immunol 165, 2173–2182

    CAS  PubMed  Google Scholar 

  282. Targan, S.R., Landers, C.J., Yang, H., Lodes, M.J., Cong, Y., Papadakis, K.A., Vasiliauskas, E., Elson, C.O., Hershberg, R.M. (2005) Antibodies to CBir1 flagellin define a unique response that is associated independently with complicated Crohn's disease. Gastroenterology 128, 2020–2028

    CAS  PubMed  Google Scholar 

  283. Robinson, W.H., Fontoura, P., Lee, B.J., de Vegvar, H.E., Tom, J., Pedotti, R., DiGen-naro, C.D., Mitchell, D.J., Fong, D., Ho, P.P., Ruiz, P.J., Maverakis, E., Stevens, D.B., Bernard, C.C., Martin, R., Kuchroo, V.K., van Noort, J.M., Genain, C.P., Amor, S., Olsson, T., Utz, P.J., Garren, H., Steinman, L. (2003) Protein microarrays guide toler-izing DNA vaccine treatment of autoimmune encephalomyelitis. Nat Biotechnol 21, 1033–1039

    CAS  PubMed  Google Scholar 

  284. Beckwith, J., Cong, Y., Sundberg, J.P., Elson, C.O., Leiter, E.H. (2005) Cdcs1, a major colitogenic locus in mice, regulates innate and adaptive immune response to enteric bacterial antigens. Gastroenterology 129, 1473–1484

    CAS  PubMed  Google Scholar 

  285. Matsumoto, S., Okabe, Y., Setoyama, H., Takayama, K., Ohtsuka, J., Funahashi, H., Imaoka, A., Okada, Y., Umesaki, Y. (1998) Inflammatory bowel disease-like enteritis and caecitis in a senescence accelerated mouse P1/Yit strain. Gut 43 71–78

    CAS  PubMed  Google Scholar 

  286. Kosiewicz, M.M., Nast, C.C., Krishnan, A., Rivera-Nieves, J., Moskaluk, C.A., Mat-sumoto, S., Kozaiwa, K., Cominelli, F. (2001) Th1-type responses mediate spontaneous ileitis in a novel murine model of Crohn's disease. J Clin Invest 107, 695–702

    CAS  PubMed  Google Scholar 

  287. Rivera-Nieves, J., Bamias, G., Vidrich, A., Marini, M., Pizarro, T.T., McDuffie, M.J., Moskaluk, C.A., Cohn, S.M., Cominelli, F. (2003) Emergence of perianal fistulizing disease in the SAMP1/YitFc mouse, a spontaneous model of chronic ileitis. Gastroen-terology 124, 972–982

    Google Scholar 

  288. Bamias, G., Martin, C., Mishina, M., Ross, W.G., Rivera-Nieves, J., Marini, M., Com-inelli, F. (2005) Proinflammatory effects of TH2 cytokines in a murine model of chronic small intestinal inflammation. Gastroenterol-ogy 128, 654–666

    CAS  Google Scholar 

  289. Marini, M., Bamias, G., Rivera-Nieves, J., Moskaluk, C.A., Hoang, S.B., Ross, W.G., Pizarro, T.T., Cominelli, F. (2003) TNF-alpha neutralization ameliorates the severity of murine Crohn's-like ileitis by abrogation of intestinal epithelial cell apoptosis. Proc Natl Acad Sci USA 100, 8366–8371

    CAS  PubMed  Google Scholar 

  290. Matsumoto, S., Watanabe, N., Imaoka, A., Okabe, Y. (2001) Preventive effects of Bifi-dobacterium- and Lactobacillus-fermented milk on the development of inflammatory bowel disease in senescence-accelerated mouse P1/Yit strain mice. Digestion 64, 92–99

    CAS  PubMed  Google Scholar 

  291. Croog, V.J., Ulman, T.A., Itzkowitz, S.H. (2003) Chemoprevention of colorectal cancer in ulcerative colitis. Int J Colorectal Dis 18, 392–400

    PubMed  Google Scholar 

  292. Velayos, F.S., Terdiman, J.P., Walsh, J.M. (2005) Effect of 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and metaanalysis of observational studies. Am J Gastroenterol 100, 1345–1353

    CAS  PubMed  Google Scholar 

  293. McKenzie, S.M., Doe, W.F., Buffinton, G.D. (1999) 5-aminosalicylic acid prevents oxidant mediated damage of glyceralde-hyde-3-phosphate dehydrogenase in colon epithelial cells. Gut 44, 180–185

    CAS  PubMed  Google Scholar 

  294. Bus, P.J., Nagtegaal, I.D., Verspaget, H.W., Lamers, C.B., Geldof, H., Van Krieken, J.H., Griffioen, G. (1999) Mesalazine-induced apoptosis of colorectal cancer: on the verge of a new chemopreventive era? Aliment Pharmacol Ther 13, 1397–1402

    CAS  PubMed  Google Scholar 

  295. Nosal'ova, V., Cerna, S., Bauer, V. (2000) Effect of N-acetylcysteine on colitis induced by acetic acid in rats. Gen Pharmacol 35, 77–81

    PubMed  Google Scholar 

  296. Ardite, E., Sans, M., Panes, J., Romero, F.J., Pique, J.M., Fernandez-Checa, J.C. (2000) Replenishment of glutathione levels improves mucosal function in experimental acute colitis. Lab Invest 80, 735–744

    CAS  PubMed  Google Scholar 

  297. Seril, D.N., Liao, J., Ho, K.L., Yang, C.S., Yang, G.Y. (2002) Inhibition of chronic ulcerative colitis-associated colorectal aden-ocarcinoma development in a murine model by N-acetylcysteine. Carcinogenesis 23, 993–1001

    CAS  PubMed  Google Scholar 

  298. Graf, E., Eaton, J.W. (1985) Dietary suppression of colonic cancer. Fiber or phytate? Cancer 56, 717–718

    CAS  PubMed  Google Scholar 

  299. Liao, J., Seril, D.N., Yang, A.L., Lu, G.G., Yang, G.Y. (2007) Inhibition of chronic ulcerative colitis associated adenocarcinoma development in mice by inositol compounds. Carcinogenesis 28, 446–454

    CAS  PubMed  Google Scholar 

  300. Shamsuddin, A.M., Elsayed, A.M., and Ullah, A. (1988) Suppression of large intestinal cancer in F344 rats by inositol hexa-phosphate. Carcinogenesis 9, 577–580

    CAS  PubMed  Google Scholar 

  301. Ullah, A., Shamsuddin, A.M. (1990) Dose-dependent inhibition of large intestinal cancer by inositol hexaphosphate in F344 rats. Carcinogenesis 11, 2219–2222

    CAS  PubMed  Google Scholar 

  302. Reddy, B.S. (1999) Prevention of colon car-cinogenesis by components of dietary fiber. Anticancer Res 19, 3681–3683

    CAS  PubMed  Google Scholar 

  303. Shamsuddin, A.M., Ullah, A. (1989) Inosi-tol hexaphosphate inhibits large intestinal cancer in F344 rats 5 months after induction by azoxymethane. Carcinogenesis 10, 625–626

    CAS  PubMed  Google Scholar 

  304. Thompson, L.U., Zhang, L. (1991) Phytic acid and minerals: effect on early markers of risk for mammary and colon carcinogenesis. Carcinogenesis 12, 2041–2045

    CAS  PubMed  Google Scholar 

  305. Reddy, B.S. (1999) Role of dietary fiber in colon cancer: an overview. Am J Med 106, 16S–19S; discussion 50S–51S

    CAS  PubMed  Google Scholar 

  306. Shamsuddin, A.M., Ullah, A., and Chakra-varthy, A.K. (1989) Inositol and inositol hexaphosphate suppress cell proliferation and tumor formation in CD-1 mice. Car-cinogenesis 10, 1461–1463

    CAS  Google Scholar 

  307. Vucenik, I., Yang, G.Y., Shamsuddin, A.M. (1997) Comparison of pure inositol hexa-phosphate and high-bran diet in the prevention of DMBA-induced rat mammary carcinogenesis. Nutr Cancer 28, 7–13

    CAS  PubMed  Google Scholar 

  308. Vucenik, I., Yang, G.Y., Shamsuddin, A.M. (1995) Inositol hexaphosphate and inositol inhibit DMBA-induced rat mammary cancer. Carcinogenesis 16, 1055–1058

    CAS  PubMed  Google Scholar 

  309. Vucenik, I., Sakamoto, K., Bansal, M., Shamsuddin, A.M. (1993) Inhibition of rat mammary carcinogenesis by inositol hexa-phosphate (phytic acid). A pilot study. Cancer Lett 75, 95–102

    CAS  PubMed  Google Scholar 

  310. Lee, H.J., Lee, S.A., Choi, H. (2005) Dietary administration of inositol and/or inositol-6-phosphate prevents chemically-induced rat hepatocarcinogenesis. Asian Pac J Cancer Prev 6, 41–47

    PubMed  Google Scholar 

  311. Vucenik, I., Zhang, Z.S., Shamsuddin, A.M. (1998) IP6 in treatment of liver cancer. II. Intra-tumoral injection of IP6 regresses pre-existing human liver cancer xenotrans-planted in nude mice. Anticancer Res 18, 4091–4096

    CAS  PubMed  Google Scholar 

  312. Vucenik, I., Tantivejkul, K., Zhang, Z.S., Cole, K.E., Saied, I., Shamsuddin, A.M. (1998) IP6 in treatment of liver cancer. I. IP6 inhibits growth and reverses transformed phenotype in HepG2 human liver cancer cell line. Anticancer Res 18, 4083–4090

    CAS  PubMed  Google Scholar 

  313. Wattenberg, L.W. (1999) Chemopreven-tion of pulmonary carcinogenesis by myo-inositol. Anticancer Res 19, 3659–3661

    CAS  PubMed  Google Scholar 

  314. Gupta, K.P., Singh, J., Bharathi, R. (2003) Suppression of DMBA-induced mouse skin tumor development by inositol hexaphosphate and its mode of action. Nutr Cancer 46, 66–72

    CAS  PubMed  Google Scholar 

  315. Ishikawa, T., Nakatsuru, Y., Zarkovic, M., Shamsuddin, A.M. (1999) Inhibition of skin cancer by IP6 in vivo: initiation-promotion model. Anticancer Res 19, 3749–3752

    CAS  PubMed  Google Scholar 

  316. Singh, R.P., Agarwal, R. (2005) Prostate cancer and inositol hexaphosphate: efficacy and mechanisms. Anticancer Res 25, 2891– 2903

    CAS  PubMed  Google Scholar 

  317. Sharma, G., Singh, R.P., Agarwal, R. (2003) Growth inhibitory and apoptotic effects of inositol hexaphosphate in transgenic adeno-carcinoma of mouse prostate (TRAMP-C1) cells. Int J Oncol 23, 1413–1418

    CAS  PubMed  Google Scholar 

  318. Vucenik, I., Tomazic, V.J., Fabian, D., Shamsuddin, A.M. (1992) Antitumor activity of phytic acid (inositol hexaphosphate) in murine transplanted and metastatic fibrosar-coma, a pilot study. Cancer Lett 65, 9–13

    CAS  PubMed  Google Scholar 

  319. Vucenik, I., Kalebic, T., Tantivejkul, K., Shamsuddin, A.M. (1998) Novel antican-cer function of inositol hexaphosphate: inhibition of human rhabdomyosarcoma in vitro and in vivo. Anticancer Res 18, 1377–1384

    CAS  PubMed  Google Scholar 

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Acknowledgments

This study was partially supported by NIH 1R01CA104741 grant, Crohn's & Colitis Foundation of America Senior Award, and the Sam Zell Scholar Fund.

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Authors and Affiliations

  1. Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

    Guang-Yu Yang, Sofia Taboada & Jie Liao

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  1. Guang-Yu Yang
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  1. National Cancer Institute at Frederick, SAIC-Frederick, Inc., Frederick, MD, USA

    Serguei V. Kozlov

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Yang, GY., Taboada, S., Liao, J. (2009). Inflammatory Bowel Disease: A Model of Chronic Inflammation-Induced Cancer. In: Kozlov, S.V. (eds) Inflammation and Cancer. Methods in Molecular Biology™, vol 511. Humana Press. https://doi.org/10.1007/978-1-59745-447-6_9

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  • DOI: https://doi.org/10.1007/978-1-59745-447-6_9

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