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
Kirsner, J.B. (2001) Historical origins of current IBD concepts. World J Gastroenterol 7, 175–184
Crohn, B.B., Ginzburg, L., Oppenheimer, G.D. (2000) Regional ileitis: a pathologic and clinical entity. 1932. Mt Sinai J Med 67, 263–268
Balkwill, F., Mantovani, A. (2001) Inflammation and cancer: back to Virchow? Lancet 357, 539–545
Coussens, L.M., Werb, Z. (2002) Inflammation and cancer. Nature 420, 860–867
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
Kewenter, J., Ahlman, H., Hulten, L. (1978) Cancer risk in extensive ulcerative colitis. Ann Surg 188, 824–828
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
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
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
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
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
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
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
Greenson, J.K. (2002) Dysplasia in inflammatory bowel disease. Semin Diagn Pathol 19, 31–37
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
Fiocchi, C. (1998) Inflammatory bowel disease: etiology and pathogenesis. Gastroen-terology 115, 182–205
Bouma, G., Strober, W. (2003) The immu-nological and genetic basis of inflammatory bowel disease. Nat Rev Immunol 3, 521– 533
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Strober, W., Fuss, I.J., Blumberg, R.S. (2002) The immunology of mucosal models of inflammation. Annu Rev Immunol 20, 495–549
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
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
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
Brown, S.J., Mayer, L. (2007) The immune response in inflammatory bowel disease. Am J Gastroenterol, 102, 2058–2069
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
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
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
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
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
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
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
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
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
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
MacDonald, T.T., Pender, S.L. (1998) Lamina propria T cells. Chem Immunol 71, 103–117
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
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
Trinchieri, G. (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3, 133–146
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
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
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
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
Katz, S. (2005) Update in medical therapy of ulcerative colitis: newer concepts and therapies. J Clin Gastroenterol 39, 557–569
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
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
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
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
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
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
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
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
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
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
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
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
Babbs, C.F. (1992) Oxygen radicals in ulcerative colitis. Free Radic Biol Med 13, 169–181
Grisham, M.B. (1994) Oxidants and free radicals in inflammatory bowel disease. Lancet 344, 859–861
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Keshavarzian, A., Morgan, G., Sedghi, S., Gordon, J.H., Doria, M. (1990) Role of reactive oxygen metabolites in experimental colitis. Gut 31, 786–790
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
Rachmilewitz, D., Karmeli, F., Okon, E., Bursztyn, M. (1995) Experimental colitis is ameliorated by inhibition of nitric oxide synthase activity. Gut 37, 247–255
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
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
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
Buffinton, G.D., Doe, W.F. (1995) Depleted mucosal antioxidant defences in inflammatory bowel disease. Free Radic Biol Med 19, 911–918
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
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
Russel, M.G., Stockbrugger, R.W. (1996) Epidemiology of inflammatory bowel disease: an update. Scand J Gastroenterol 31, 417–427
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
Wild, G.E. (2004) The role of antibiotics in the management of Crohn's disease. Inflamm Bowel Dis 10, 321–323
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
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
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
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
Burke, D.A., Axon, A.T. (1987) Ulcerative colitis and Escherichia coli with adhesive properties. J Clin Pathol 40, 782–786
Roediger, W.E., Moore, J., Babidge, W. (1997) Colonic sulfide in pathogenesis and treatment of ulcerative colitis. Dig Dis Sci 42, 1571–1579
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
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
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
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
van der Wiel-Korstanje, J.A. Winkler, K.C. (1975) The faecal flora in ulcerative colitis. J Med Microbiol 8, 491–501
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
Sartor, R.B. (2004) Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics. Gastroenterology 126, 1620– 1633
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
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
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
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
Papadakis, K.A., Targan, S.R. (2000) Role of cytokines in the pathogenesis of inflammatory bowel disease. Annu Rev Med 51, 289–298
Podolsky, D.K. (2002) Inflammatory bowel disease. N Engl J Med 347, 417–429
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
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
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
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
Podolsky, D.K., Isselbacher, K.J. (1984) Glycoprotein composition of colonic mucosa. Specific alterations in ulcerative colitis. Gastroenterology 87, 991–998
Rhodes, J.M. (1989) Colonic mucus and mucosal glycoproteins: the key to colitis and cancer? Gut 30, 1660–1666
Kim, Y.I. (1998) Short-chain fatty acids in ulcerative colitis. Nutr Rev 56, 17–24
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
Sandborn, W.J. (2003) Strategies for targeting tumour necrosis factor in IBD. Best Pract Res Clin Gastroenterol 17, 105–117
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
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
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
Itzkowitz, S.H. (2002) Cancer prevention in patients with inflammatory bowel disease. Gastroenterol Clin North Am 31, 1133– 1144
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
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
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
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
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
Jass, J.R., Whitehall, V.L., Young, J., Leg-gett, B.A. (2002) Emerging concepts in colorectal neoplasia. Gastroenterology 123, 862–876
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
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
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
Hammarberg, C., Slezak, P., Tribukait, B. (1984) Early detection of malignancy in ulcerative colitis. A flow-cytometric DNA study. Cancer 53, 291–295
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
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
Levine, A.J. (1997) p53, the cellular gatekeeper for growth and division. Cell 88, 323–331
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Benedict, W.F., Xu, H.J. Takahashi, R. (1990) The retinoblastoma gene: its role in human malignancies. Cancer Invest 8, 535– 540
Carnero, A., Hannon, G.J. (1998) The INK4 family of CDK inhibitors. Curr Top Microbiol Immunol 227, 43–55
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Hussain, S.P., Hofseth, L.J., Harris, C.C. (2003) Radical causes of cancer. Nat Rev Cancer 3, 276–285
Marnett, L.J. (2000) Oxyradicals and DNA damage. Carcinogenesis 21, 361–370
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
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
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
Artandi, S.E., DePinho, R.A. (2000) A critical role for telomeres in suppressing and facilitating carcinogenesis. Curr Opin Genet Dev 10, 39–46
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
Nair, J., Barbin, A., Velic, I., Bartsch, H. (1999) Etheno DNA-base adducts from endogenous reactive species. Mutat Res 424, 59–69
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
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
Cerda, S., Weitzman, S.A. (1997) Influence of oxygen radical injury on DNA methyla-tion. Mutat Res 386, 141–152
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
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
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
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
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
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
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
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
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
Stadnicki, A., Colman, R.W. (2003) Experimental models of inflammatory bowel disease. Arch Immunol Ther Exp (Warsz) 51, 149–155
Kuhn, R., Löhler, J., Rennick, D., Rajew-sky, K., Muller, W. (1993) Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274
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
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
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
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
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
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
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
Warren, B.F., Watkins, P.E. (1994) Animal models of inflammatory bowel disease. J Pathol 172, 313–316
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
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
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
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
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
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
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
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
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
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
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
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.
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
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
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
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
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
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
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
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
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
Hibi, T., Ogata, H., Sakuraba, A. (2002) Animal models of inflammatory bowel disease. J Gastroenterol 37, 409–417
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
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
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
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
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
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
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
Balish, E., Warner, T. (2002) Enterococcus faecalis induces inflammatory bowel disease in interleukin-10 knockout mice. Am J Pathol 160, 2253–2257
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
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
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
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
Itzkowitz, S.H., Harpaz, N. (2004) Diagnosis and management of dysplasia in patients with inflammatory bowel diseases. Gastroen-terology 126, 1634–1648
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
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
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
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
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
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
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
Rakoff-Nahoum, S., Hao, L., Medzhitov, R. (2006) Role of toll-like receptors in spontaneous commensal-dependent colitis. Immunity 25, 319–329
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Kollias, G. (2005) TNF pathophysiology in murine models of chronic inflammation and autoimmunity. Semin Arthritis Rheum 34, 3–6
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
Strober, W., Fuss I., Mannon, P. (2007) The fundamental basis of inflammatory bowel disease. J Clin Invest 117, 514–521
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
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
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
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
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
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
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
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
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
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
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
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
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
Croog, V.J., Ulman, T.A., Itzkowitz, S.H. (2003) Chemoprevention of colorectal cancer in ulcerative colitis. Int J Colorectal Dis 18, 392–400
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
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
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
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
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
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
Graf, E., Eaton, J.W. (1985) Dietary suppression of colonic cancer. Fiber or phytate? Cancer 56, 717–718
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
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
Ullah, A., Shamsuddin, A.M. (1990) Dose-dependent inhibition of large intestinal cancer by inositol hexaphosphate in F344 rats. Carcinogenesis 11, 2219–2222
Reddy, B.S. (1999) Prevention of colon car-cinogenesis by components of dietary fiber. Anticancer Res 19, 3681–3683
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
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
Reddy, B.S. (1999) Role of dietary fiber in colon cancer: an overview. Am J Med 106, 16S–19S; discussion 50S–51S
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
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
Vucenik, I., Yang, G.Y., Shamsuddin, A.M. (1995) Inositol hexaphosphate and inositol inhibit DMBA-induced rat mammary cancer. Carcinogenesis 16, 1055–1058
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
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
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
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
Wattenberg, L.W. (1999) Chemopreven-tion of pulmonary carcinogenesis by myo-inositol. Anticancer Res 19, 3659–3661
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
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
Singh, R.P., Agarwal, R. (2005) Prostate cancer and inositol hexaphosphate: efficacy and mechanisms. Anticancer Res 25, 2891– 2903
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
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
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
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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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
Publisher Name: Humana Press
Print ISBN: 978-1-934115-14-5
Online ISBN: 978-1-59745-447-6
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