Mouse models of inflammatory bowel disease - Insights into the mechanisms of inflammation-associated colorectal cancer

In Vivo

Volumn 26, Issue 4, 2012, Pages 627-646

  Mladenova, Dessislava ^a   Kohonen Corish, Maija R J ^a,b,c  

^a GARVAN INSTITUTE OF MEDICAL RESEARCH   (Australia)

^b UNIVERSITY OF NEW SOUTH WALES   (Australia)

^c UNIVERSITY OF WESTERN SYDNEY   (Australia)

Author keywords

Colorectal cancer; Inflammatory bowel disease; Mouse models inflammation; Review

Indexed keywords

INTERLEUKIN 10; TRANSFORMING GROWTH FACTOR BETA; TRANSCRIPTION FACTOR;

ADAPTIVE IMMUNITY; ANIMAL MODEL; CANCER INCIDENCE; CARCINOGENESIS; CELL MIGRATION; CHROMOSOMAL INSTABILITY; CHROMOSOME 2Q; COLORECTAL CANCER; CPG ISLAND; CROHN DISEASE; DENDRITIC CELL; DISEASE COURSE; DISEASE EXACERBATION; ENTERITIS; HELICOBACTER HEPATICUS; HELICOBACTER INFECTION; HUMAN; IMMUNE SYSTEM; INCIDENCE; INTESTINE EPITHELIUM CELL; MICROSATELLITE INSTABILITY; MUTATION; NEUTROPHIL; NONHUMAN; PHENOTYPE; RESEARCH; REVIEW; SIGNAL TRANSDUCTION; ULCERATIVE COLITIS; ANIMAL; COLORECTAL TUMOR; DISEASE MODEL; METABOLISM; MOUSE; PATHOLOGY; PHYSIOLOGY;

ANIMALS; COLORECTAL NEOPLASMS; DISEASE MODELS, ANIMAL; INFLAMMATORY BOWEL DISEASES; INTERLEUKIN-10; MICE; SIGNAL TRANSDUCTION; TRANSCRIPTION FACTORS; TRANSFORMING GROWTH FACTOR BETA;

EID: 84865098489     PISSN: 0258851X     EISSN: 17917549     Source Type: Journal    
DOI: None     Document Type: Review

References (223)

1. Kaser A, Zeissig S and Blumberg RS: Inflammatory bowel disease. Annu Rev Immunol 28: 573-621, 2010.
2. Maloy KJ and Powrie F: Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474(7351): 298-306, 2011.
3. Cosnes J, Gower-Rousseau C, Seksik P and Cortot A: Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology 140(6): 1785-1794, 2011.
4. Munkholm P: Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease. Aliment Pharmacol Ther 18(Suppl 2) : 1-5, 2003.
5. Khor B, Gardet A and Xavier RJ: Genetics and pathogenesis of inflammatory bowel disease. Nature 474(7351): 307-317, 2011.
6. Baumgart DC and Sandborn WJ: Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet 369(9573): 1641-1657, 2007.
7. Louis E, Collard A, Oger AF, Degroote E, Aboul Nasr El Yafi FA and Belaiche J: Behaviour of Crohn's disease according to the Vienna classification: changing pattern over the course of the disease. Gut 49(6): 777-782, 2001.
8. Ullman TA and Itzkowitz SH: Intestinal inflammation and cancer. Gastroenterology 140 (6) : 1807-1816, 2011.
9. Ekbom A, Helmick C, Zack M and Adami HO: Increased risk of large-bowel cancer in Crohn's disease with colonic involvement. Lancet 336(8711) : 357-359, 1990.
10. Nuako KW, Ahlquist DA, Mahoney DW, Schaid DJ, Siems DM and Lindor NM: Familial predisposition for colorectal cancer in chronic ulcerative colitis: a case-control study. Gastroenterology 115(5): 1079-1083, 1998.
11. Askling J, Dickman PW, Karlen P, Brostrom O, Lapidus A, Lofberg R and Ekbom A: Colorectal cancer rates among firstdegree relatives of patients with inflammatory bowel disease: a population-based cohort study. Lancet 357 (9252) : 262-266, 2001.
12. Kornfeld D, Ekbom A and Ihre T: Is there an excess risk for colorectal cancer in patients with ulcerative colitis and concomitant primary sclerosing cholangitis? A population based study. Gut 41(4) : 522-525, 1997.
13. Hussain SP, Amstad P, Raja K, Ambs S, Nagashima M, Bennett WP, Shields PG, Ham AJ, Swenberg JA, Marrogi AJ and Harris CC: Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. Cancer Res 60(13): 3333-3337, 2000.
14. Lyda MH, Noffsinger A, Belli J and Fenoglio-Preiser CM: Microsatellite instability and K-ras mutations in patients with ulcerative colitis. Hum Pathol 31(6): 665-671, 2000.
15. Terzic J, Grivennikov S, Karin E and Karin M: Inflammation and colon cancer. Gastroenterology 138(6) : 2101-2114 e2105, 2010.
16. Boland CR and Goel A: Microsatellite instability in colorectal cancer. Gastroenterology 138(6): 2073-2087 e2073, 2010.
17. Cawkwell L, Sutherland F, Murgatroyd H, Jarvis P, Gray S, Cross D, Shepherd N, Day D and Quirke P: Defective hMSH2/hMLH1 protein expression is seen infrequently in ulcerative colitis-associated colorectal cancers. Gut 46 (3) : 367- 369, 2000.
18. Schulmann K, Mori Y, Croog V, Yin J, Olaru A, Sterian A, Sato F, Wang S, Xu Y, Deacu E, Berki AT, Hamilton JP, Kan T, Abraham JM, Schmiegel W, Harpaz N and Meltzer SJ: Molecular phenotype of inflammatory bowel disease-associated neoplasms with microsatellite instability. Gastroenterology 129(1) : 74-85, 2005.
19. Frigola J, Song J, Stirzaker C, Hinshelwood RA, Peinado MA and Clark SJ: Epigenetic remodeling in colorectal cancer results in coordinate gene suppression across an entire chromosome band. Nat Genet 38(5) : 540-549, 2006.
20. Lao VV and Grady WM: Epigenetics and colorectal cancer. Nat Rev Gastroenterol Hepatol 8(12): 686-700, 2011.
21. Irizarry RA, Ladd-Acosta C, Wen B, Wu Z, Montano C, Onyango P, Cui H, Gabo K, Rongione M, Webster M, Ji H, Potash JB, Sabunciyan S and Feinberg AP: The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 41(2) : 178-186, 2009.
22. Issa JP, Ahuja N, Toyota M, Bronner MP and Brentnall TA: Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res 61(9): 3573-3577, 2001.
23. Fleisher AS, Esteller M, Harpaz N, Leytin A, Rashid A, Xu Y, Liang J, Stine OC, Yin J, Zou TT, Abraham JM, Kong D, Wilson KT, James SP, Herman JG and Meltzer SJ: Microsatellite instability in inflammatory bowel diseaseassociated neoplastic lesions is associated with hypermethylation and diminished expression of the DNA mismatch repair gene, hMLH1 . Cancer Res 60(17) : 4864-4868, 2000.
24. Hsieh CJ, Klump B, Holzmann K, Borchard F, Gregor M and Porschen R: Hypermethylation of the p16INK4a promoter in colectomy specimens of patients with long-standing and extensive ulcerative colitis. Cancer Res 58 (17) : 3942-3945, 1998.
25. Moriyama T, Matsumoto T, Nakamura S, Jo Y, Mibu R, Yao T and Iida M: Hypermethylation of p14 (ARF) may be predictive of colitic cancer in patients with ulcerative colitis. Dis Colon Rectum 50(9) : 1384-1392, 2007.
26. Konishi K, Shen L, Wang S, Meltzer SJ, Harpaz N and Issa JP: Rare CpG island methylator phenotype in ulcerative colitisassociated neoplasias. Gastroenterology 132 (4) : 1254-1260, 2007.
27. Pocard M, Salmon RJ, Muleris M, Remvikos Y, Bara J, Dutrillaux B and Poupon MF: Two colons-two cancers? Proximal or distal adenocarcinoma: arguments for a different carcinogenesis. Bull Cancer 82(1) : 10-21, 1995 (in French).
28. Distler P and Holt PR: Are right- and left-sided colon neoplasms distinct tumors? Dig Dis 15(4- 5): 302-311, 1997.
29. Delattre O, Olschwang S, Law DJ, Melot T, Remvikos Y, Salmon RJ, Sastre X, Validire P, Feinberg AP and Thomas G: Multiple genetic alterations in distal and proximal colorectal cancer. Lancet 2(8659): 353-356, 1989.
30. Jernvall P, Makinen M, Karttunen T, Makela J and Vihko P: Conserved region mutations of the p53 gene are concentrated in distal colorectal cancers. Int J Cancer 74(1): 97-101, 1997.
31. Gervaz P, Bucher P and Morel P: Two colons-two cancers: paradigm shift and clinical implications. J Surg Oncol 88(4): 261-266, 2004.
32. Issa JP: CpG island methylator phenotype in cancer. Nat Rev Cancer 4 (12) : 988-993, 2004.
33. Toyota M, Ohe-Toyota M, Ahuja N and Issa JP: Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype. Proc Natl Acad Sci USA 97(2): 710-715, 2000.
34. Hawkins N, Norrie M, Cheong K, Mokany E, Ku SL, Meagher A, O'Connor T and Ward R: CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability. Gastroenterology 122(5): 1376-1387, 2002.
35. Choi PM and Zelig MP: Similarity of colorectal cancer in Crohn's disease and ulcerative colitis: implications for carcinogenesis and prevention. Gut 35(7): 950-954, 1994.
36. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S and Medzhitov R: Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118 (2): 229-241, 2004.
37. Iwasaki A and Kelsall BL: Freshly isolated Peyer's patch, but not spleen, dendritic cells produce interleukin 10 and induce the differentiation of T-helper type 2 cells. J Exp Med 190(2): 229- 239, 1999.
38. Kelsall BL and Leon F: Involvement of intestinal dendritic cells in oral tolerance, immunity to pathogens, and inflammatory bowel disease. Immunol Rev 206: 132-148, 2005.
39. Turner JR: Intestinal mucosal barrier function in health and disease. Nat Rev Immunol 9 (11): 799-809, 2009.
40. Ganz T: Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol 3(9): 710-720, 2003.
41. Artis D: Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nat Rev Immunol 8(6) : 411-420, 2008.
42. Blikslager AT, Moeser AJ, Gookin JL, Jones SL and Odle J: Restoration of barrier function in injured intestinal mucosa. Physiol Rev 87(2) : 545-564, 2007.
43. Jung HC, Eckmann L, Yang SK, Panja A, Fierer J, Morzycka- Wroblewska E and Kagnoff MF: A distinct array of proinflammatory cytokines is expressed in human colon epithelial cells in response to bacterial invasion. J Clin Invest 95(1) : 55-65, 1995.
44. Serhan CN and Savill J: Resolution of inflammation: the beginning programs the end. Nat Immunol 6 (12): 1191-1197, 2005.
45. Gewirtz AT, McCormick B, Neish AS, Petasis NA, Gronert K, Serhan CN and Madara JL: Pathogen-induced chemokine secretion from model intestinal epithelium is inhibited by lipoxin A4 analogs. J Clin Invest 101 (9): 1860-1869, 1998.
46. An G, Wei B, Xia B, McDaniel JM, Ju T, Cummings RD, Braun J and Xia L: Increased susceptibility to colitis and colorectal tumors in mice lacking core 3-derived O-glycans. J Exp Med 204(6): 1417-1429, 2007.
47. Byrd JC and Bresalier RS: Mucins and mucin binding proteins in colorectal cancer. Cancer Metastasis Rev 23(1- 2) : 77-99, 2004.
48. Jass JR and Walsh MD: Altered mucin expression in the gastrointestinal tract: a review. J Cell Mol Med 5(3): 327-351, 2001.
49. Van der Sluis M, De Koning BA, De Bruijn AC, Velcich A, Meijerink JP, Van Goudoever JB, Buller HA, Dekker J, Van Seuningen I, Renes IB and Einerhand AW: Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131(1): 117-129, 2006.
50. Velcich A, Yang W, Heyer J, Fragale A, Nicholas C, Viani S, Kucherlapati R, Lipkin M, Yang K and Augenlicht L: Colorectal cancer in mice genetically deficient in the mucin Muc2. Science 295(5560): 1726-1729, 2002.
51. Hermiston ML and Gordon JI: Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin. Science 270(5239): 1203-1207, 1995.
52. Baribault H, Penner J, Iozzo RV and Wilson-Heiner M: Colorectal hyperplasia and inflammation in keratin 8-deficient FVB/N mice. Genes Dev 8(24) : 2964-2973, 1994.
53. Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y and Nakaya R: A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 98(3): 694-702, 1990.
54. Tanaka T, Kohno H, Suzuki R, Yamada Y, Sugie S and Mori H: A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate. Cancer Sci 94(11): 965-973, 2003.
55. Izcue A and Powrie F: Special regulatory T-cell review: Regulatory T-cells and the intestinal tract-patrolling the frontier. Immunology 123(1): 6-10, 2008.
56. Powrie F, Leach MW, Mauze S, Caddle LB and Coffman RL: Phenotypically distinct subsets of CD4+ T-cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int Immunol 5 (11): 1461-1471, 1993.
57. Uhlig HH, Coombes J, Mottet C, Izcue A, Thompson C, Fanger A, Tannapfel A, Fontenot JD, Ramsdell F and Powrie F: Characterization of Foxp3+ CD4+ CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis. J Immunol 177 (9): 5852-5860, 2006.
58. Powrie F, Read S, Mottet C, Uhlig H and Maloy K: Control of immune pathology by regulatory T cells. Novartis Found Symp 252 : 92-98; discussion 98-105, 106-114, 2003.
59. Murai M, Turovskaya O, Kim G, Madan R, Karp CL, Cheroutre H and Kronenberg M: Interleukin 10 acts on regulatory T-cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat Immunol 10(11): 1178-1184, 2009.
60. Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schaffer AA, Noyan F, Perro M, Diestelhorst J, Allroth A, Murugan D, Hatscher N, Pfeifer D, Sykora KW, Sauer M, Kreipe H, Lacher M, Nustede R, Woellner C, Baumann U, Salzer U, Koletzko S, Shah N, Segal AW, Sauerbrey A, Buderus S, Snapper SB, Grimbacher B and Klein C: Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med 361(21): 2033-2045, 2009.
61. Kuhn R, Lohler J, Rennick D, Rajewsky K and Muller W: Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75(2): 263-274, 1993.
62. Berg DJ, Davidson N, Kuhn R, Muller W, Menon S, Holland G, Thompson-Snipes L, Leach MW and Rennick D: Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. J Clin Invest 98(4): 1010-1020, 1996.
63. Davidson NJ, Leach MW, Fort MM, Thompson-Snipes L, Kuhn R, Muller W, Berg DJ and Rennick DM: T-Helper cell 1-type CD4+ T-cells, but not B-cells, mediate colitis in interleukin 10- deficient mice. J Exp Med 184(1): 241-251, 1996.
64. Kullberg MC, Rothfuchs AG, Jankovic D, Caspar P, Wynn TA, Gorelick PL, Cheever AW and Sher A: Helicobacter hepaticusinduced colitis in interleukin-10-deficient mice: cytokine requirements for the induction and maintenance of intestinal inflammation. Infect Immun 69(7): 4232-4241, 2001.
65. Watanabe N, Ikuta K, Okazaki K, Nakase H, Tabata Y, Matsuura M, Tamaki H, Kawanami C, Honjo T and Chiba T: Elimination of local macrophages in intestine prevents chronic colitis in interleukin-10-deficient mice. Dig Dis Sci 48(2): 408- 414, 2003.
66. Xu W, Roos A, Schlagwein N, Woltman AM, Daha MR and van Kooten C: IL-10-producing macrophages preferentially clear early apoptotic cells. Blood 107(12) : 4930-4937, 2006.
67. Glauben R, Batra A, Stroh T, Erben U, Fedke I, Lehr HA, Leoni F, Mascagni P, Dinarello CA, Zeitz M and Siegmund B: Histone deacetylases: novel targets for prevention of colitisassociated cancer in mice. Gut 57(5) : 613-622, 2008.
68. O'Mahony L, Feeney M, O'Halloran S, Murphy L, Kiely B, Fitzgibbon J, Lee G, O'Sullivan G, Shanahan F and Collins JK: Probiotic impact on microbial flora, inflammation and tumour development in IL-10 knockout mice. Aliment Pharmacol Ther 15(8): 1219-1225, 2001.
69. Chichlowski M, Sharp JM, Vanderford DA, Myles MH and Hale LP: Helicobacter typhlonius and Helicobacter rodentium differentially affect the severity of colon inflammation and inflammation-associated neoplasia in Il10-deficient mice. Comp Med 58(6) : 534-541, 2008.
70. Hegazi RA, Mady HH, Melhem MF, Sepulveda AR, Mohi M and Kandil HM: Celecoxib and rofecoxib potentiate chronic colitis and premalignant changes in interleukin 10 knockout mice. Inflamm Bowel Dis 9(4): 230-236, 2003.
71. Li A, Goto M, Horinouchi M, Tanaka S, Imai K, Kim YS, Sato E and Yonezawa S: Expression of MUC1 and MUC2 mucins and relationship with cell proliferative activity in human colorectal neoplasia. Pathol Int 51(11) : 853-860, 2001.
72. Beatty PL, Plevy SE, Sepulveda AR and Finn OJ: Cutting edge: transgenic expression of human MUC1 in Il- 10-/- mice accelerates inflammatory bowel disease and progression to colon cancer. J Immunol 179(2): 735-739, 2007.
73. Sturlan S, Oberhuber G, Beinhauer BG, Tichy B, Kappel S, Wang J and Rogy MA: Interleukin-10-deficient mice and inflammatory bowel disease associated cancer development. Carcinogenesis 22(4) : 665-671, 2001.
74. Li MO and Flavell RA: Contextual regulation of inflammation: a duet by transforming growth factor-beta and interleukin-10. Immunity 28(4) : 468-476, 2008.
75. Fantini MC, Rizzo A, Fina D, Caruso R, Sarra M, Stolfi C, Becker C, Macdonald TT, Pallone F, Neurath MF and Monteleone G: Smad7 controls resistance of colitogenic T-cells to regulatory T-cell-mediated suppression. Gastroenterology 136(4) : 1308-1316, e1301-1303, 2009.
76. Souza RF, Lei J, Yin J, Appel R, Zou TT, Zhou X, Wang S, Rhyu MG, Cymes K, Chan O, Park WS, Krasna MJ, Greenwald BD, Cottrell J, Abraham JM, Simms L, Leggett B, Young J, Harpaz N and Meltzer SJ: A transforming growth factor beta 1 receptor type II mutation in ulcerative colitis-associated neoplasms. Gastroenterology 112(1): 40-45, 1997.
77. Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D and et al.: Targeted disruption of the mouse transforming growth factorbeta 1 gene results in multifocal inflammatory disease. Nature 359(6397): 693-699, 1992.
78. Engle SJ, Hoying JB, Boivin GP, Ormsby I, Gartside PS and Doetschman T: Transforming growth factor beta1 suppresses nonmetastatic colon cancer at an early stage of tumorigenesis. Cancer Res 59(14) : 3379-3386, 1999.
79. Engle SJ, Ormsby I, Pawlowski S, Boivin GP, Croft J, Balish E and Doetschman T: Elimination of colon cancer in germ-free transforming growth factor beta 1-deficient mice. Cancer Res 62(22) : 6362-6366, 2002.
80. Graff JM, Bansal A and Melton DA: Xenopus Mad proteins transduce distinct subsets of signals for the TGF beta superfamily. Cell 85 (4): 479-487, 1996.
81. Zhu Y, Richardson JA, Parada LF and Graff JM: Smad3-mutant mice develop metastatic colorectal cancer. Cell 94 (6) : 703-714, 1998.
82. Yang X, Letterio JJ, Lechleider RJ, Chen L, Hayman R, Gu H, Roberts AB and Deng C: Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T-cell responsiveness to TGF-beta. EMBO J 18 (5) : 1280-1291, 1999.
83. Maggio-Price L, Treuting P, Zeng W, Tsang M, Bielefeldt- Ohmann H and Iritani BM: Helicobacter infection is required for inflammation and colon cancer in SMAD3-deficient mice. Cancer Res 66(2): 828-838, 2006.
84. Erdman SE, Poutahidis T, Tomczak M, Rogers AB, Cormier K, Plank B, Horwitz BH and Fox JG: CD4+ CD25+ regulatory T-lymphocytes inhibit microbially induced colon cancer in Rag2- deficient mice. Am J Pathol 162(2) : 691-702, 2003.
85. Erdman SE, Rao VP, Poutahidis T, Ihrig MM, Ge Z, Feng Y, Tomczak M, Rogers AB, Horwitz BH and Fox JG: CD4(+) CD25(+) regulatory lymphocytes require interleukin 10 to interrupt colon carcinogenesis in mice. Cancer Res 63(18): 6042-6050, 2003.
86. Poutahidis T, Haigis KM, Rao VP, Nambiar PR, Taylor CL, Ge Z, Watanabe K, Davidson A, Horwitz BH, Fox JG and Erdman SE: Rapid reversal of interleukin-6-dependent epithelial invasion in a mouse model of microbially induced colon carcinoma. Carcinogenesis 28(12): 2614-2623, 2007.
87. Kado S, Uchida K, Funabashi H, Iwata S, Nagata Y, Ando M, Onoue M, Matsuoka Y, Ohwaki M and Morotomi M: Intestinal microflora are necessary for development of spontaneous adenocarcinoma of the large intestine in T-cell receptor beta chain and p53 double-knockout mice. Cancer Res 61(6): 2395- 2398, 2001.
88. Cote-Sierra J, Foucras G, Guo L, Chiodetti L, Young HA, Hu- Li J, Zhu J and Paul WE: Interleukin 2 plays a central role in Th2 differentiation. Proc Natl Acad Sci USA 101(11): 3880- 3885, 2004.
89. Fontenot JD, Rasmussen JP, Gavin MA and Rudensky AY: A function for interleukin 2 in Foxp3-expressing regulatory Tcells. Nat Immunol 6 (11): 1142-1151, 2005.
90. Kundig TM, Schorle H, Bachmann MF, Hengartner H, Zinkernagel RM and Horak I: Immune responses in interleukin- 2-deficient mice. Science 262(5136) : 1059-1061, 1993.
91. Schorle H, Holtschke T, Hunig T, Schimpl A and Horak I: Development and function of T-cells in mice rendered interleukin-2 deficient by gene targeting. Nature 352(6336): 621-624, 1991.
92. Sadlack B, Merz H, Schorle H, Schimpl A, Feller AC and Horak I: Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75(2): 253-261, 1993.
93. Kramer S, Schimpl A and Hunig T: Immunopathology of interleukin (IL) 2-deficient mice: thymus dependence and suppression by thymus-dependent cells with an intact IL-2 gene. J Exp Med 182(6): 1769-1776, 1995.
94. Contractor NV, Bassiri H, Reya T, Park AY, Baumgart DC, Wasik MA, Emerson SG and Carding SR: Lymphoid hyperplasia, autoimmunity, and compromised intestinal intraepithelial lymphocyte development in colitis-free gnotobiotic IL-2-deficient mice. J Immunol 160(1): 385-394, 1998.
95. McVay LD, Li B, Biancaniello R, Creighton MA, Bachwich D, Lichtenstein G, Rombeau JL and Carding SR: Changes in human mucosal gamma delta T-cell repertoire and function associated with the disease process in inflammatory bowel disease. Mol Med 3(3) : 183-203, 1997.
96. Simpson SJ, Mizoguchi E, Allen D, Bhan AK and Terhorst C: Evidence that CD4+, but not CD8+ T-cells are responsible for murine interleukin-2-deficient colitis. Eur J Immunol 25 (9): 2618-2625, 1995.
97. Shah SA, Simpson SJ, Brown LF, Comiskey M, de Jong YP, Allen D and Terhorst C: Development of colonic adenocarcinomas in a mouse model of ulcerative colitis. Inflamm Bowel Dis 4(3) : 196-202, 1998.
98. Sohn KJ, Shah SA, Reid S, Choi M, Carrier J, Comiskey M, Terhorst C and Kim YI: Molecular genetics of ulcerative colitisassociated colon cancer in the interleukin 2- and beta(2)- microglobulin-deficient mouse. Cancer Res 61(18): 6912-6917, 2001.
99. Bicknell DC, Rowan A and Bodmer WF: Beta 2-microglobulin gene mutations: a study of established colorectal cell lines and fresh tumors. Proc Natl Acad Sci USA 91 (11) : 4751-4755, 1994.
100. Fridman WH, Pages F, Sautes-Fridman C and Galon J: The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12(4) : 298-306, 2012.
101. Neves SR, Ram PT and Iyengar R: G protein pathways. Science 296 (5573): 1636-1639, 2002.
102. Rudolph U, Finegold MJ, Rich SS, Harriman GR, Srinivasan Y, Brabet P, Boulay G, Bradley A and Birnbaumer L: Ulcerative colitis and adenocarcinoma of the colon in G alpha i2-deficient mice. Nat Genet 10(2): 143-150, 1995.
103. Edwards RA, Witherspoon M, Wang K, Afrasiabi K, Pham T, Birnbaumer L and Lipkin SM: Epigenetic repression of DNA mismatch repair by inflammation and hypoxia in inflammatory bowel disease-associated colorectal cancer. Cancer Res 69(16): 6423-6429, 2009.
104. Hanada T, Kobayashi T, Chinen T, Saeki K, Takaki H, Koga K, Minoda Y, Sanada T, Yoshioka T, Mimata H, Kato S and Yoshimura A: IFNgamma-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice. J Exp Med 203(6): 1391-1397, 2006.
105. Deng L, Zhou JF, Sellers RS, Li JF, Nguyen AV, Wang Y, Orlofsky A, Liu Q, Hume DA, Pollard JW, Augenlicht L and Lin EY: A novel mouse model of inflammatory bowel disease links mammalian target of rapamycin-dependent hyperproliferation of colonic epithelium to inflammation-associated tumorigenesis. Am J Pathol 176(2): 952-967, 2010.
106. Coombes JL and Powrie F: Dendritic cells in intestinal immune regulation. Nat Rev Immunol 8(6): 435-446, 2008.
107. Niess JH, Brand S, Gu X, Landsman L, Jung S, McCormick BA, Vyas JM, Boes M, Ploegh HL, Fox JG, Littman DR and Reinecker HC: CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307(5707): 254-258, 2005.
108. Rescigno M, Rotta G, Valzasina B and Ricciardi-Castagnoli P: Dendritic cells shuttle microbes across gut epithelial monolayers. Immunobiology 204(5): 572-581, 2001.
109. Rescigno M, Urbano M, Valzasina B, Francolini M, Rotta G, Bonasio R, Granucci F, Kraehenbuhl JP and Ricciardi- Castagnoli P: Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol 2(4): 361-367, 2001.
110. Saenz SA, Taylor BC and Artis D: Welcome to the neighborhood: epithelial cell-derived cytokines license innate and adaptive immune responses at mucosal sites. Immunol Rev 226 : 172-190, 2008.
111. Taylor BC, Zaph C, Troy AE, Du Y, Guild KJ, Comeau MR and Artis D: TSLP regulates intestinal immunity and inflammation in mouse models of helminth infection and colitis. J Exp Med 206(3): 655-667, 2009.
112. Glimcher LH: Trawling for treasure: tales of T-bet. Nat Immunol 8(5): 448-450, 2007.
113. Lugo-Villarino G, Ito S, Klinman DM and Glimcher LH: The adjuvant activity of CpG DNA requires T-bet expression in dendritic cells. Proc Natl Acad Sci USA 102(37): 13248-13253, 2005.
114. Garrett WS, Punit S, Gallini CA, Michaud M, Zhang D, Sigrist KS, Lord GM, Glickman JN and Glimcher LH: Colitisassociated colorectal cancer driven by T-bet deficiency in dendritic cells. Cancer Cell 16(3): 208-219, 2009.
115. Garrett WS and Glimcher LH: T- bet-/- RAG2-/- ulcerative colitis: the role of T-bet as a peacekeeper of host-commensal relationships. Cytokine 48(1- 2): 144-147, 2009.
116. Ermann J, Garrett WS, Kuchroo J, Rourida K, Glickman JN, Bleich A and Glimcher LH: Severity of innate immunemediated colitis is controlled by the cytokine deficiencyinduced colitis susceptibility-1 (Cdcs1) locus. Proc Natl Acad Sci USA 108(17) : 7137-7141, 2011.
117. Okayasu I, Ohkusa T, Kajiura K, Kanno J and Sakamoto S: Promotion of colorectal neoplasia in experimental murine ulcerative colitis. Gut 39(1): 87-92, 1996.
118. Blackburn AC, Doe WF and Buffinton GD: Salicylate hydroxylation as an indicator of hydroxyl radical generation in dextran sulfate-induced colitis. Free Radic Biol Med 25(3): 305-313, 1998.
119. Blackburn AC, Doe WF and Buffinton GD: Protein carbonyl formation on mucosal proteins in vitro and in dextran sulfateinduced colitis. Free Radic Biol Med 27(3-4): 262-270, 1999.
120. Buffinton GD and Doe WF: Depleted mucosal antioxidant defences in inflammatory bowel disease. Free Radic Biol Med 19(6): 911-918, 1995.
121. Buffinton GD and Doe WF: Altered ascorbic acid status in the mucosa from inflammatory bowel disease patients. Free Radic Res 22(2): 131-143, 1995.
122. Kohonen-Corish MR, Daniel JJ, te Riele H, Buffinton GD and Dahlstrom JE: Susceptibility of Msh2-deficient mice to inflammation-associated colorectal tumors. Cancer Res 62(7): 2092-2097, 2002.
123. Cooper HS, Murthy S, Kido K, Yoshitake H and Flanigan A: Dysplasia and cancer in the dextran sulfate sodium mouse colitis model. Relevance to colitis-associated neoplasia in the human: a study of histopathology, β-catenin and p53 expression and the role of inflammation. Carcinogenesis 21(4): 757-768, 2000.
124. Chang WC, Coudry RA, Clapper ML, Zhang X, Williams KL, Spittle CS, Li T and Cooper HS: Loss of p53 enhances the induction of colitis-associated neoplasia by dextran sulfate sodium. Carcinogenesis 28(11): 2375-2381, 2007.
125. Tanaka T: Development of an inflammation-associated colorectal cancer model and its application for research on carcinogenesis and chemoprevention. Int J Inflam 2012: 658786, 2012.
126. Hardwick JC, van den Brink GR, Offerhaus GJ, van Deventer SJ and Peppelenbosch MP: NF-kappaB, p38 MAPK and JNK are highly expressed and active in the stroma of human colonic adenomatous polyps. Oncogene 20(7) : 819-827, 2001.
127. Lind DS, Hochwald SN, Malaty J, Rekkas S, Hebig P, Mishra G, Moldawer LL, Copeland EM, 3rd and Mackay S: Nuclear factor-kappa B is up-regulated in colorectal cancer. Surgery 130(2): 363-369, 2001.
128. Rogler G, Brand K, Vogl D, Page S, Hofmeister R, Andus T, Knuechel R, Baeuerle PA, Scholmerich J and Gross V: Nuclear factor kappaB is activated in macrophages and epithelial cells of inflamed intestinal mucosa. Gastroenterology 115(2) : 357- 369, 1998.
129. Neurath MF, Pettersson S, Meyer zum Buschenfelde KH and Strober W: Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-kappa B abrogates established experimental colitis in mice. Nat Med 2(9) : 998- 1004, 1996.
130. Karin M and Greten FR: NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5 (10): 749-759, 2005.
131. Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, Kagnoff MF and Karin M: IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118(3): 285-296, 2004.
132. Eckmann L, Nebelsiek T, Fingerle AA, Dann SM, Mages J, Lang R, Robine S, Kagnoff MF, Schmid RM, Karin M, Arkan MC and Greten FR: Opposing functions of IKKbeta during acute and chronic intestinal inflammation. Proc Natl Acad Sci USA 105(39): 15058-15063, 2008.
133. Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, Scheller J, Rose-John S, Cheroutre H, Eckmann L and Karin M: IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15(2) : 103-113, 2009.
134. Li Y, de Haar C, Chen M, Deuring J, Gerrits MM, Smits R, Xia B, Kuipers EJ and van der Woude CJ: Disease-related expression of the IL6/STAT3/SOCS3 signalling pathway in ulcerative colitis and ulcerative colitis-related carcinogenesis. Gut 59(2): 227-235, 2010.
135. Rigby RJ, Simmons JG, Greenhalgh CJ, Alexander WS and Lund PK: Suppressor of cytokine signaling 3 (SOCS3) limits damage-induced crypt hyper-proliferation and inflammation-associated tumorigenesis in the colon. Oncogene 26(33) : 4833- 4841, 2007.
136. Tebbutt NC, Giraud AS, Inglese M, Jenkins B, Waring P, Clay FJ, Malki S, Alderman BM, Grail D, Hollande F, Heath JK and Ernst M: Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nat Med 8(10): 1089-1097, 2002.
137. Dann SM, Spehlmann ME, Hammond DC, Iimura M, Hase K, Choi LJ, Hanson E and Eckmann L: IL-6-dependent mucosal protection prevents establishment of a microbial niche for attaching/effacing lesion-forming enteric bacterial pathogens. J Immunol 180(10) : 6816-6826, 2008.
138. Kishimoto T: Interleukin-6: from basic science to medicine-40 years in immunology. Annu Rev Immunol 23(1-21, 2005.
139. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL and Kuchroo VK: Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T-cells. Nature 441 (7090): 235-238, 2006.
140. Waldner MJ, Wirtz S, Jefremow A, Warntjen M, Neufert C, Atreya R, Becker C, Weigmann B, Vieth M, Rose-John S and Neurath MF: VEGF receptor signaling links inflammation and tumorigenesis in colitis-associated cancer. J Exp Med 207(13): 2855-2868, 2010.
141. Fina D, Sarra M, Fantini MC, Rizzo A, Caruso R, Caprioli F, Stolfi C, Cardolini I, Dottori M, Boirivant M, Pallone F, Macdonald TT and Monteleone G: Regulation of gut inflammation and th17 cell response by interleukin-21. Gastroenterology 134(4): 1038-1048, 2008.
142. Stolfi C, Rizzo A, Franze E, Rotondi A, Fantini MC, Sarra M, Caruso R, Monteleone I, Sileri P, Franceschilli L, Caprioli F, Ferrero S, MacDonald TT, Pallone F and Monteleone G: Involvement of interleukin-21 in the regulation of colitis-associated colon cancer. J Exp Med 208(11): 2279-2290, 2011.
143. Balkwill F: Tumor necrosis factor or tumor promoting factor? Cytokine Growth Factor Rev 13(2) : 135-141, 2002.
144. Jaiswal M, LaRusso NF, Burgart LJ and Gores GJ: Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism. Cancer Res 60(1) : 184-190, 2000.
145. Leber TM and Balkwill FR: Regulation of monocyte MMP-9 production by TNF-alpha and a tumour-derived soluble factor (MMPSF). Br J Cancer 78(6): 724-732, 1998.
146. Gordon HM, Kucera G, Salvo R and Boss JM: Tumor necrosis factor induces genes involved in inflammation, cellular and tissue repair, and metabolism in murine fibroblasts. J Immunol 148(12) : 4021-4027, 1992.
147. Yoshida S, Ono M, Shono T, Izumi H, Ishibashi T, Suzuki H and Kuwano M: Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis. Mol Cell Biol 17(7) : 4015-4023, 1997.
148. Grivennikov SI, Kuprash DV, Liu ZG and Nedospasov SA: Intracellular signals and events activated by cytokines of the tumor necrosis factor superfamily: From simple paradigms to complex mechanisms. Int Rev Cytol 252: 129-161, 2006.
149. Popivanova BK, Kitamura K, Wu Y, Kondo T, Kagaya T, Kaneko S, Oshima M, Fujii C and Mukaida N: Blocking TNFalpha in mice reduces colorectal carcinogenesis associated with chronic colitis. J Clin Invest 118(2): 560-570, 2008.
150. Medzhitov R: Toll-like receptors and innate immunity. Nat Rev Immunol 1(2) : 135-145, 2001.
151. Karin M, Lawrence T and Nizet V: Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 124(4): 823-835, 2006.
152. Salcedo R, Worschech A, Cardone M, Jones Y, Gyulai Z, Dai RM, Wang E, Ma W, Haines D, O'HUigin C, Marincola FM and Trinchieri G: MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18. J Exp Med 207(8): 1625-1636, 2010.
153. Xiao H, Gulen MF, Qin J, Yao J, Bulek K, Kish D, Altuntas CZ, Wald D, Ma C, Zhou H, Tuohy VK, Fairchild RL, de la Motte C, Cua D, Vallance BA and Li X: The Toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis. Immunity 26(4): 461-475, 2007.
154. Fukata M, Chen A, Vamadevan AS, Cohen J, Breglio K, Krishnareddy S, Hsu D, Xu R, Harpaz N, Dannenberg AJ, Subbaramaiah K, Cooper HS, Itzkowitz SH and Abreu MT: Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology 133(6) : 1869- 1881, 2007.
155. Nakanishi M, Menoret A, Tanaka T, Miyamoto S, Montrose DC, Vella AT and Rosenberg DW: Selective PGE(2) suppression inhibits colon carcinogenesis and modifies local mucosal immunity. Cancer Prev Res 4(8) : 1198-1208, 2011.
156. Kanneganti TD, Lamkanfi M and Nunez G: Intracellular NODlike receptors in host defense and disease. Immunity 27 (4): 549-559, 2007.
157. Ghayur T, Banerjee S, Hugunin M, Butler D, Herzog L, Carter A, Quintal L, Sekut L, Talanian R, Paskind M, Wong W, Kamen R, Tracey D and Allen H: Caspase-1 processes IFN-gammainducing factor and regulates LPS-induced IFN-gamma production. Nature 386 (6625): 619-623, 1997.
158. Kuida K, Lippke JA, Ku G, Harding MW, Livingston DJ, Su MS and Flavell RA: Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. Science 267 (5206): 2000-2003, 1995.
159. Zitvogel L, Kepp O, Galluzzi L and Kroemer G: Inflammasomes in carcinogenesis and anticancer immune responses. Nat Immunol 13(4): 343-351, 2012.
160. Villani AC, Lemire M, Fortin G, Louis E, Silverberg MS, Collette C, Baba N, Libioulle C, Belaiche J, Bitton A, Gaudet D, Cohen A, Langelier D, Fortin PR, Wither JE, Sarfati M, Rutgeerts P, Rioux JD, Vermeire S, Hudson TJ and Franchimont D: Common variants in the NLRP3 region contribute to Crohn's disease susceptibility. Nat Genet 41(1) : 71-76, 2009.
161. Zhernakova A, Festen EM, Franke L, Trynka G, van Diemen CC, Monsuur AJ, Bevova M, Nijmeijer RM, van 't Slot R, Heijmans R, Boezen HM, van Heel DA, van Bodegraven AA, Stokkers PC, Wijmenga C, Crusius JB and Weersma RK: Genetic analysis of innate immunity in Crohn's disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP. Am J Hum Genet 82 (5) : 1202-1210, 2008.
162. Siegmund B: Interleukin-18 in intestinal inflammation: friend and foe? Immunity 32(3): 300-302, 2010.
163. Hu B, Elinav E, Huber S, Booth CJ, Strowig T, Jin C, Eisenbarth SC and Flavell RA: Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4. Proc Natl Acad Sci USA 107(50) : 21635-21640, 2010.
164. Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA, Booth CJ, Peaper DR, Bertin J, Eisenbarth SC, Gordon JI and Flavell RA: NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145(5): 745-757, 2011.
165. Zaki MH, Vogel P, Body-Malapel M, Lamkanfi M and Kanneganti TD: IL-18 production downstream of the Nlrp3 inflammasome confers protection against colorectal tumor formation. J Immunol 185(8) : 4912-4920, 2010.
166. Dunn GP, Koebel CM and Schreiber RD: Interferons, immunity and cancer immunoediting. Nat Rev Immunol 6(11) : 836-848, 2006.
167. Okamura H, Tsutsi H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, Torigoe K, Okura T, Nukada Y, Hattori K et al: Cloning of a new cytokine that induces IFN-gamma production by T-cells. Nature 378(6552): 88-91, 1995.
168. Takeda K, Tsutsui H, Yoshimoto T, Adachi O, Yoshida N, Kishimoto T, Okamura H, Nakanishi K and Akira S: Defective NK cell activity and Th1 response in Il-18-deficient mice. Immunity 8(3): 383-390, 1998.
169. Allen IC, TeKippe EM, Woodford RM, Uronis JM, Holl EK, Rogers AB, Herfarth HH, Jobin C and Ting JP: The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J Exp Med 207(5): 1045-1056, 2010.
170. Chen GY, Shaw MH, Redondo G and Nunez G: The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis. Cancer Res 68 (24): 10060-10067, 2008.
171. Colgan SP and Taylor CT: Hypoxia: an alarm signal during intestinal inflammation. Nat Rev Gastroenterol Hepatol 7(5): 281-287, 2010.
172. Semenza GL: Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3(10): 721-732, 2003.
173. Wang T, Marquardt C and Foker J: Aerobic glycolysis during lymphocyte proliferation. Nature 261(5562) : 702-705, 1976.
174. Borregaard N and Herlin T: Energy metabolism of human neutrophils during phagocytosis. J Clin Invest 70(3) : 550-557, 1982.
175. MacDonald HR and Koch CJ: Energy metabolism and T-cellmediated cytolysis. I. Synergism between inhibitors of respiration and glycolysis. J Exp Med 146(3): 698-709, 1977.
176. Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N and Johnson RS: HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 112(5): 645-657, 2003.
177. Makino Y, Nakamura H, Ikeda E, Ohnuma K, Yamauchi K, Yabe Y, Poellinger L, Okada Y, Morimoto C and Tanaka H: Hypoxia-inducible factor regulates survival of antigen receptordriven T-cells. J Immunol 171(12) : 6534-6540, 2003.
178. Biju MP, Neumann AK, Bensinger SJ, Johnson RS, Turka LA and Haase VH: Vhlh gene deletion induces Hif-1-mediated cell death in thymocytes. Mol Cell Biol 24 (20): 9038-9047, 2004.
179. Kojima H, Gu H, Nomura S, Caldwell CC, Kobata T, Carmeliet P, Semenza GL and Sitkovsky MV: Abnormal B lymphocyte development and autoimmunity in hypoxia-inducible factor 1alpha -deficient chimeric mice. Proc Natl Acad Sci USA 99(4): 2170-2174, 2002.
180. Hellwig-Burgel T, Stiehl DP, Wagner AE, Metzen E and Jelkmann W: Review: hypoxia-inducible factor-1 (HIF-1): a novel transcription factor in immune reactions. J Interferon Cytokine Res 25(6): 297-310, 2005.
181. Bracken CP, Whitelaw ML and Peet DJ: The hypoxia-inducible factors: key transcriptional regulators of hypoxic responses. Cell Mol Life Sci 60(7): 1376-1393, 2003.
182. Peyssonnaux C, Cejudo-Martin P, Doedens A, Zinkernagel AS, Johnson RS and Nizet V: Cutting edge: Essential role of hypoxia inducible factor-1alpha in development of lipopolysaccharide-induced sepsis. J Immunol 178(12) : 7516- 7519, 2007.
183. Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG and Karin M: NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature 453 (7196): 807-811, 2008.
184. Taylor CT: Interdependent roles for hypoxia inducible factor and nuclear factor-kappaB in hypoxic inflammation. J Physiol 586(Pt 17): 4055-4059, 2008.
185. Shah YM, Ito S, Morimura K, Chen C, Yim SH, Haase VH and Gonzalez FJ: Hypoxia-inducible factor augments experimental colitis through an MIF-dependent inflammatory signaling cascade. Gastroenterology 134 (7) : 2036-2048, 2048 e2031- 2033, 2008.
186. Hirota SA, Beck PL and MacDonald JA: Targeting hypoxiainducible factor-1 (HIF-1) signaling in therapeutics: implications for the treatment of inflammatory bowel disease. Recent Pat Inflamm Allergy Drug Discov 3 (1) : 1-16, 2009.
187. Cummins EP, Seeballuck F, Keely SJ, Mangan NE, Callanan JJ, Fallon PG and Taylor CT: The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis. Gastroenterology 134(1): 156-165, 2008.
188. Tambuwala MM, Cummins EP, Lenihan CR, Kiss J, Stauch M, Scholz CC, Fraisl P, Lasitschka F, Mollenhauer M, Saunders SP, Maxwell PH, Carmeliet P, Fallon PG, Schneider M and Taylor CT: Loss of Prolyl Hydroxylase-1 Protects Against Colitis Through Reduced Epithelial Cell Apoptosis and Increased Barrier Function. Gastroenterology 139(6): 2093- 2101, 2010.
189. Robinson A, Keely S, Karhausen J, Gerich ME, Furuta GT and Colgan SP: Mucosal protection by hypoxia-inducible factor prolyl hydroxylase inhibition. Gastroenterology 134(1) : 145- 155, 2008.
190. Eltzschig HK, Thompson LF, Karhausen J, Cotta RJ, Ibla JC, Robson SC and Colgan SP: Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism. Blood 104(13) : 3986- 3992, 2004.
191. Furuta GT, Turner JR, Taylor CT, Hershberg RM, Comerford K, Narravula S, Podolsky DK and Colgan SP: Hypoxiainducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. J Exp Med 193(9) : 1027-1034, 2001.
192. Karhausen J, Furuta GT, Tomaszewski JE, Johnson RS, Colgan SP and Haase VH: Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. J Clin Invest 114(8): 1098-1106, 2004.
193. Cummins EP, Berra E, Comerford KM, Ginouves A, Fitzgerald KT, Seeballuck F, Godson C, Nielsen JE, Moynagh P, Pouyssegur J and Taylor CT: Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci USA 103(48): 18154-18159, 2006.
194. Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL and Simons JW: Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 59(22) : 5830-5835, 1999.
195. Olaru AV, Selaru FM, Mori Y, Vazquez C, David S, Paun B, Cheng Y, Jin Z, Yang J, Agarwal R, Abraham JM, Dassopoulos T, Harris M, Bayless TM, Kwon J, Harpaz N, Livak F and Meltzer SJ: Dynamic changes in the expression of MicroRNA- 31 during inflammatory bowel disease-associated neoplastic transformation. Inflamm Bowel Dis 17(1): 221-231, 2011.
196. Abraham C and Cho J: Interleukin-23/Th17 pathways and inflammatory bowel disease. Inflamm Bowel Dis 15 (7): 1090- 1100, 2009.
197. Uhlig HH and Powrie F: Mouse models of intestinal inflammation as tools to understand the pathogenesis of inflammatory bowel disease. Eur J Immunol 39(8): 2021-2026, 2009.
198. Wu S, Rhee KJ, Albesiano E, Rabizadeh S, Wu X, Yen HR, Huso DL, Brancati FL, Wick E, McAllister F, Housseau F, Pardoll DM and Sears CL: A human colonic commensal promotes colon tumorigenesis via activation of T-helper type 17 T-cell responses. Nat Med 15 (9) : 1016-1022, 2009.
199. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, Bordman Z, Fu J, Kim Y, Yen HR, Luo W, Zeller K, Shimoda L, Topalian SL, Semenza GL, Dang CV, Pardoll DM and Pan F: Control of T(H)17/T(reg) balance by hypoxia-inducible factor1. Cell 146(5) : 772-784, 2011.
200. Mladenova D, Daniel JJ, Dahlstrom JE, Bean E, Gupta R, Pickford R, Currey N, Musgrove EA and Kohonen-Corish MR: The NSAID sulindac is chemopreventive in the mouse distal colon but carcinogenic in the proximal colon. Gut 60(3): 350-360, 2011.
201. Sparmann A and Bar-Sagi D: Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6(5) : 447-458, 2004.
202. Waugh DJ and Wilson C: The interleukin-8 pathway in cancer. Clin Cancer Res 14(21) : 6735-6741, 2008.
203. Laiho P, Kokko A, Vanharanta S, Salovaara R, Sammalkorpi H, Jarvinen H, Mecklin JP, Karttunen TJ, Tuppurainen K, Davalos V, Schwartz S Jr., Arango D, Makinen MJ and Aaltonen LA: Serrated carcinomas form a subclass of colorectal cancer with distinct molecular basis. Oncogene 26(2): 312-320, 2007.
204. Sekirov I, Russell SL, Antunes LC and Finlay BB: Gut microbiota in health and disease. Physiol Rev 90(3): 859-904, 2010.
205. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ and Hazen SL: Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472(7341) : 57-63, 2011.
206. Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN, Kubo C and Koga Y: Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 558(Pt 1) : 263-275, 2004.
207. Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R and Gordon JI: The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med 1(6): 6ra14, 2009.
208. Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, Srinivasan S, Sitaraman SV, Knight R, Ley RE and Gewirtz AT: Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328 (5975): 228-231, 2010.
209. Garrett WS, Lord GM, Punit S, Lugo-Villarino G, Mazmanian SK, Ito S, Glickman JN and Glimcher LH: Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131 (1): 33-45, 2007.
210. Lepage P, Hasler R, Spehlmann ME, Rehman A, Zvirbliene A, Begun A, Ott S, Kupcinskas L, Dore J, Raedler A and Schreiber S: Twin study indicates loss of interaction between microbiota and mucosa of patients with ulcerative colitis. Gastroenterology 141 (1) : 227-236, 2011.
211. Uronis JM, Muhlbauer M, Herfarth HH, Rubinas TC, Jones GS and Jobin C: Modulation of the intestinal microbiota alters colitis-associated colorectal cancer susceptibility. PLoS One 4(6) : e6026, 2009.
212. Chu FF, Esworthy RS, Chu PG, Longmate JA, Huycke MM, Wilczynski S and Doroshow JH: Bacteria-induced intestinal cancer in mice with disrupted Gpx1 and Gpx2 genes. Cancer Res 64(3) : 962-968, 2004.
213. Roth KA, Kapadia SB, Martin SM and Lorenz RG: Cellular immune responses are essential for the development of Helicobacter felis -associated gastric pathology. J Immunol 163(3) : 1490-1497, 1999.
214. Mannick EE, Bravo LE, Zarama G, Realpe JL, Zhang XJ, Ruiz B, Fontham ET, Mera R, Miller MJ and Correa P: Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: effect of antibiotics and antioxidants. Cancer Res 56(14): 3238-3243, 1996.
215. Correa P and Houghton J: Carcinogenesis of Helicobacter pylori . Gastroenterology 133(2): 659-672, 2007.
216. Swidsinski A, Loening-Baucke V, Lochs H and Hale LP: Spatial organization of bacterial flora in normal and inflamed intestine: a fluorescence in situ hybridization study in mice. World J Gastroenterol 11(8): 1131-1140, 2005.
217. Maeda H and Akaike T: Nitric oxide and oxygen radicals in infection, inflammation, and cancer. Biochemistry (Mosc) 63(7) : 854-865, 1998.
218. Fulton AM, Loveless SE and Heppner GH: Mutagenic activity of tumor-associated macrophages in Salmonella typhimurium strains TA98 and TA 100. Cancer Res 44(10): 4308-4311, 1984.
219. Maeda S, Kamata H, Luo JL, Leffert H and Karin M: IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121(7): 977-990, 2005.
220. Fausto N: Liver regeneration. J Hepatol 32(1 Suppl) : 19-31, 2000.
221. Kanneganti M, Mino-Kenudson M and Mizoguchi E: Animal models of colitis-associated carcinogenesis. J Biomed Biotechnol 2011: 342637, 2011.
222. 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 and Chiba T: Development of colonic neoplasia in p53-deficient mice with experimental colitis induced by dextran sulphate sodium. Gut 53(5): 710-716, 2004.
223. Tanaka T, Kohno H, Suzuki R, Hata K, Sugie S, Niho N, Sakano K, Takahashi M and Wakabayashi K: Dextran sodium sulfate strongly promotes colorectal carcinogenesis in ApcMin/+ mice: inflammatory stimuli by dextran sodium sulfate results in development of multiple colonic neoplasms. Int J Cancer 118(1): 25-34, 2006.