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Inflammation, Obesity, and Colon Cancer

  • Stephanie K. Doerner
  • Jason D. HeaneyEmail author
Chapter
  • 1.6k Downloads
Part of the Energy Balance and Cancer book series (EBAC, volume 7)

Abstract

The general focus of this chapter is to overview the contribution of obesity-­induced intestinal inflammation to colorectal cancer (CRC) incidence. Using inflammatory bowel disease as a model, the mechanisms by which gastrointestinal microbes and obesity-associated, adipose-derived mediators of inflammatory increase CRC risk will be discussed. Particular emphasis will be placed on the direct impact of these factors on intestinal epithelial cell proliferation, survival, and neoplastic transformation. Additionally, the influence of inflammatory factors on immune cell function and the indirect effect of altered immunity on intestinal epithelial cell proliferation and survival, and CRC risk will be explored.

Keywords

Ulcerative Colitis Adenomatous Polyposis Coli Dextran Sodium Sulfate Intestinal Inflammation Aberrant Crypt Focus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Altekruse SF, Korsay CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin KA (2012) SEER cancer statistics review, 1975–2009 (vintage 2009 populations). National Cancer Institute, Bethesda, MD.Google Scholar
  2. 2.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90PubMedGoogle Scholar
  3. 3.
    Schoen RE (2000) Families at risk for colorectal cancer: risk assessment and genetic testing. J Clin Gastroenterol 31:114–120PubMedGoogle Scholar
  4. 4.
    Heijstek MW, Kranenburg O, Borel Rinkes IH (2005) Mouse models of colorectal cancer and liver metastases. Dig Surg 22:16–25PubMedGoogle Scholar
  5. 5.
    Terzic J, Grivennikov S, Karin E, Karin M (2010) Inflammation and colon cancer. Gastroenterology 138:2101–2114PubMedGoogle Scholar
  6. 6.
    Cho KR, Vogelstein B (1992) Genetic alterations in the adenoma—carcinoma sequence. Cancer 70:1727–1731PubMedGoogle Scholar
  7. 7.
    Parkin DM, Bray F, Ferlay J, Pisani P (2001) Estimating the world cancer burden: Globocan 2000. Int J Cancer 94:153–156PubMedGoogle Scholar
  8. 8.
    American Cancer Society (2007) Cancer facts and figures 2007. American Cancer Society, Atlanta, GAGoogle Scholar
  9. 9.
    Vogelstein B, Kinzler KW (1993) The multistep nature of cancer. Trends Genet 9:138–141PubMedGoogle Scholar
  10. 10.
    Johns LE, Houlston RS (2001) A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol 96:2992–3003PubMedGoogle Scholar
  11. 11.
    Lerman C, Shields AE (2004) Genetic testing for cancer susceptibility: the promise and the pitfalls. Nat Rev Cancer 4:235–241PubMedGoogle Scholar
  12. 12.
    Bulow S (1987) Familial polyposis coli. Dan Med Bull 34:1–15PubMedGoogle Scholar
  13. 13.
    Kinzler KW, Nilbert MC, Su LK et al (1991) Identification of FAP locus genes from chromosome 5q21. Science 253:661–665PubMedGoogle Scholar
  14. 14.
    Nishisho I, Nakamura Y, Miyoshi Y et al (1991) Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253:665–669PubMedGoogle Scholar
  15. 15.
    Heyer J, Yang K, Lipkin M, Edelmann W, Kucherlapati R (1999) Mouse models for colorectal cancer. Oncogene 18:5325–5333PubMedGoogle Scholar
  16. 16.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674PubMedGoogle Scholar
  17. 17.
    Fearon ER (2011) Molecular genetics of colorectal cancer. Annu Rev Pathol 6:479–507PubMedGoogle Scholar
  18. 18.
    Thibodeau SN, French AJ, Roche PC et al (1996) Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. Cancer Res 56:4836–4840PubMedGoogle Scholar
  19. 19.
    Fodde R, Smits R, Clevers H (2001) APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer 1:55–67PubMedGoogle Scholar
  20. 20.
    Suzuki H, Watkins DN, Jair KW et al (2004) Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet 36:417–422PubMedGoogle Scholar
  21. 21.
    Nusse R (2005) Wnt signaling in disease and in development. Cell Res 15:28–32PubMedGoogle Scholar
  22. 22.
    Clevers H, Nusse R (2012) Wnt/beta-catenin signaling and disease. Cell 149:1192–1205PubMedGoogle Scholar
  23. 23.
    Tetsu O, McCormick F (1999) Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398:422–426PubMedGoogle Scholar
  24. 24.
    Brabletz T, Jung A, Dag S, Hlubek F, Kirchner T (1999) Beta-catenin regulates the expression of the matrix metalloproteinase-7 in human colorectal cancer. Am J Pathol 155:1033–1038PubMedGoogle Scholar
  25. 25.
    Miwa N, Furuse M, Tsukita S, Niikawa N, Nakamura Y, Furukawa Y (2001) Involvement of claudin-1 in the beta-catenin/Tcf signaling pathway and its frequent upregulation in human colorectal cancers. Oncol Res 12:469–476PubMedGoogle Scholar
  26. 26.
    McCart AE, Vickaryous NK, Silver A (2008) Apc mice: models, modifiers and mutants. Pathol Res Pract 204:479–490PubMedGoogle Scholar
  27. 27.
    Fantini MC, Pallone F (2008) Cytokines: from gut inflammation to colorectal cancer. Curr Drug Targets 9:375–380PubMedGoogle Scholar
  28. 28.
    Xavier RJ, Podolsky DK (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature 448:427–434PubMedGoogle Scholar
  29. 29.
    Kappelman MD, Rifas-Shiman SL, Kleinman K et al (2007) The prevalence and geographic distribution of Crohn’s disease and ulcerative colitis in the United States. Clin Gastroenterol Hepatol 5:1424–1429PubMedGoogle Scholar
  30. 30.
    Loftus EV Jr (2007) The burden of inflammatory bowel disease in the United States: a moving target? Clin Gastroenterol Hepatol 5:1383–1384PubMedGoogle Scholar
  31. 31.
    Rubin DC, Shaker A, Levin MS (2012) Chronic intestinal inflammation: inflammatory bowel disease and colitis-associated colon cancer. Front Immunol 3:107PubMedGoogle Scholar
  32. 32.
    Pohl C, Hombach A, Kruis W (2000) Chronic inflammatory bowel disease and cancer. Hepatogastroenterology 47:57–70PubMedGoogle Scholar
  33. 33.
    Eaden JA, Abrams KR, Mayberry JF (2001) The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 48:526–535PubMedGoogle Scholar
  34. 34.
    World Health Organization (2003) World cancer report. IARC Nonserial Publication, Geneva, SwitzerlandGoogle Scholar
  35. 35.
    World Health Organization (2006) Global database on body mass index, vol 9, No. 5. Public Health Nutrition, Geneva, Switzerland, pp 658–660Google Scholar
  36. 36.
    National Center for Health Statistics (2011) Health, United States, 2010: with special features on death and dying. Department of Health and Human Services, Hyattsville, MDGoogle Scholar
  37. 37.
    Ogden CL, Carroll MD, Curtin LR, Lamb MM, Flegal KM (2010) Prevalence of high body mass index in US children and adolescents, 2007–2008. JAMA 303:242–249PubMedGoogle Scholar
  38. 38.
    Farooqi IS, O’Rahilly S (2005) Monogenic obesity in humans. Annu Rev Med 56:443–458PubMedGoogle Scholar
  39. 39.
    Nkondjock A, Shatenstein B, Maisonneuve P, Ghadirian P (2003) Specific fatty acids and human colorectal cancer: an overview. Cancer Detect Prev 27:55–66PubMedGoogle Scholar
  40. 40.
    Wynder EL (1976) Nutrition and cancer. Fed Proc 35:1309–1315PubMedGoogle Scholar
  41. 41.
    Stein CJ, Colditz GA (2004) The epidemic of obesity. J Clin Endocrinol Metab 89:2522–2525PubMedGoogle Scholar
  42. 42.
    Yehuda-Shnaidman E, Schwartz B (2012) Mechanisms linking obesity, inflammation and altered metabolism to colon carcinogenesis. Obes Rev 13(12):1083–1095PubMedGoogle Scholar
  43. 43.
    Pais R, Silaghi H, Silaghi AC, Rusu ML, Dumitrascu DL (2009) Metabolic syndrome and risk of subsequent colorectal cancer. World J Gastroenterol 15:5141–5148PubMedGoogle Scholar
  44. 44.
    Sung MK, Yeon JY, Park SY, Park JH, Choi MS (2011) Obesity-induced metabolic stresses in breast and colon cancer. Ann N Y Acad Sci 1229:61–68PubMedGoogle Scholar
  45. 45.
    Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI (2006) An obesity-­associated gut microbiome with increased capacity for energy harvest. Nature 444:1027–1031PubMedGoogle Scholar
  46. 46.
    Backhed F, Manchester JK, Semenkovich CF, Gordon JI (2007) Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci U S A 104:979–984PubMedGoogle Scholar
  47. 47.
    Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI (2005) Host-bacterial mutualism in the human intestine. Science 307:1915–1920PubMedGoogle Scholar
  48. 48.
    Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI (2007) The human microbiome project. Nature 449:804–810PubMedGoogle Scholar
  49. 49.
    Pull SL, Doherty JM, Mills JC, Gordon JI, Stappenbeck TS (2005) Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc Natl Acad Sci U S A 102:99–104PubMedGoogle Scholar
  50. 50.
    Zoetendal EG, Rajilic-Stojanovic M, de Vos WM (2008) High-throughput diversity and functionality analysis of the gastrointestinal tract microbiota. Gut 57:1605–1615PubMedGoogle Scholar
  51. 51.
    Ivanov II, Frutos RL, Manel N et al (2008) Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4:337–349PubMedGoogle Scholar
  52. 52.
    Mazmanian SK, Round JL, Kasper DL (2008) A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453:620–625PubMedGoogle Scholar
  53. 53.
    Marks DJ, Segal AW (2008) Innate immunity in inflammatory bowel disease: a disease hypothesis. J Pathol 214:260–266PubMedGoogle Scholar
  54. 54.
    Sollid LM, Johansen FE (2008) Animal models of inflammatory bowel disease at the dawn of the new genetics era. PLoS Med 5:e198PubMedGoogle Scholar
  55. 55.
    Strober W, Fuss IJ, Blumberg RS (2002) The immunology of mucosal models of inflammation. Annu Rev Immunol 20:495–549PubMedGoogle Scholar
  56. 56.
    Sartor RB (2004) Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics. Gastroenterology 126:1620–1633PubMedGoogle Scholar
  57. 57.
    Winslet MC, Allan A, Poxon V, Youngs D, Keighley MR (1994) Faecal diversion for Crohn’s colitis: a model to study the role of the faecal stream in the inflammatory process. Gut 35:236–242PubMedGoogle Scholar
  58. 58.
    Rutgeerts P, Goboes K, Peeters M et al (1991) Effect of faecal stream diversion on recurrence of Crohn’s disease in the neoterminal ileum. Lancet 338:771–774PubMedGoogle Scholar
  59. 59.
    Gophna U, Sommerfeld K, Gophna S, Doolittle WF, Veldhuyzen van Zanten SJ (2006) Differences between tissue-associated intestinal microfloras of patients with Crohn’s disease and ulcerative colitis. J Clin Microbiol 44:4136–4141PubMedGoogle Scholar
  60. 60.
    Manichanh C, Rigottier-Gois L, Bonnaud E et al (2006) Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach. Gut 55:205–211PubMedGoogle Scholar
  61. 61.
    Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ, Brummer RJ (2008) Review article: the role of butyrate on colonic function. Aliment Pharmacol Ther 27:104–119PubMedGoogle Scholar
  62. 62.
    Vinolo MA, Rodrigues HG, Nachbar RT, Curi R (2011) Regulation of inflammation by short chain fatty acids. Nutrients 3:858–876PubMedGoogle Scholar
  63. 63.
    Sokol H, Pigneur B, Watterlot L et al (2008) Faecalibacterium prausnitzii is an anti-­inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A 105:16731–16736PubMedGoogle Scholar
  64. 64.
    Thibault R, Blachier F, Darcy-Vrillon B, de Coppet P, Bourreille A, Segain JP (2010) Butyrate utilization by the colonic mucosa in inflammatory bowel diseases: a transport deficiency. Inflamm Bowel Dis 16:684–695PubMedGoogle Scholar
  65. 65.
    Rabizadeh S, Rhee KJ, Wu S et al (2007) Enterotoxigenic bacteroides fragilis: a potential instigator of colitis. Inflamm Bowel Dis 13:1475–1483PubMedGoogle Scholar
  66. 66.
    Barnich N, Darfeuille-Michaud A (2007) Adherent-invasive Escherichia coli and Crohn’s disease. Curr Opin Gastroenterol 23:16–20PubMedGoogle Scholar
  67. 67.
    Powell DW, Pinchuk IV, Saada JI, Chen X, Mifflin RC (2011) Mesenchymal cells of the intestinal lamina propria. Annu Rev Physiol 73:213–237PubMedGoogle Scholar
  68. 68.
    Hanson PJ, Moran AP, Butler K (2011) Paracellular permeability is increased by basal lipopolysaccharide in a primary culture of colonic epithelial cells; an effect prevented by an activator of toll-like receptor-2. Innate Immun 17:269–282PubMedGoogle Scholar
  69. 69.
    Testro AG, Visvanathan K (2009) Toll-like receptors and their role in gastrointestinal disease. J Gastroenterol Hepatol 24:943–954PubMedGoogle Scholar
  70. 70.
    Wyatt J, Vogelsang H, Hubl W, Waldhoer T, Lochs H (1993) Intestinal permeability and the prediction of relapse in Crohn’s disease. Lancet 341:1437–1439PubMedGoogle Scholar
  71. 71.
    D’Inca R, Di Leo L, Corrao G et al (1999) Intestinal permeability test as a predictor of clinical course in Crohn’s disease. Am J Gastroenterol 94:2956–2960PubMedGoogle Scholar
  72. 72.
    Peeters M, Geypens B, Claus D et al (1997) Clustering of increased small intestinal permeability in families with Crohn’s disease. Gastroenterology 113:802–807PubMedGoogle Scholar
  73. 73.
    Teahon K, Smethurst P, Levi AJ, Menzies IS, Bjarnason I (1992) Intestinal permeability in patients with Crohn’s disease and their first degree relatives. Gut 33:320–323PubMedGoogle Scholar
  74. 74.
    Clayburgh DR, Shen L, Turner JR (2004) A porous defense: the leaky epithelial barrier in intestinal disease. Lab Invest 84:282–291PubMedGoogle Scholar
  75. 75.
    Bruewer M, Luegering A, Kucharzik T et al (2003) Proinflammatory cytokines disrupt epithelial barrier function by apoptosis-independent mechanisms. J Immunol 171:6164–6172PubMedGoogle Scholar
  76. 76.
    Yang R, Han X, Uchiyama T et al (2003) IL-6 is essential for development of gut barrier dysfunction after hemorrhagic shock and resuscitation in mice. Am J Physiol Gastrointest Liver Physiol 285:G621–G629PubMedGoogle Scholar
  77. 77.
    McGuckin MA, Eri R, Simms LA, Florin TH, Radford-Smith G (2009) Intestinal barrier dysfunction in inflammatory bowel diseases. Inflamm Bowel Dis 15:100–113PubMedGoogle Scholar
  78. 78.
    Cario E, Podolsky DK (2000) Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun 68:7010–7017PubMedGoogle Scholar
  79. 79.
    Yu LC, Wang JT, Wei SC, Ni YH (2012) Host-microbial interactions and regulation of intestinal epithelial barrier function: from physiology to pathology. World J Gastrointest Pathophysiol 3:27–43PubMedGoogle Scholar
  80. 80.
    Rakoff-Nahoum S, Medzhitov R (2007) Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science 317:124–127PubMedGoogle Scholar
  81. 81.
    Greten FR, Eckmann L, Greten TF et al (2004) IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118:285–296PubMedGoogle Scholar
  82. 82.
    Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315:1650–1659PubMedGoogle Scholar
  83. 83.
    Grivennikov SI, Wang K, Mucida D et al (2012) Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491:254–258PubMedGoogle Scholar
  84. 84.
    Sussman DA, Santaolalla R, Strobel S, Dheer R, Abreu MT (2012) Cancer in inflammatory bowel disease: lessons from animal models. Curr Opin Gastroenterol 28:327–333PubMedGoogle Scholar
  85. 85.
    Rakoff-Nahoum S, Medzhitov R (2008) Role of toll-like receptors in tissue repair and tumorigenesis. Biochemistry (Mosc) 73:555–561Google Scholar
  86. 86.
    Vannucci L, Stepankova R, Kozakova H, Fiserova A, Rossmann P, Tlaskalova-Hogenova H (2008) Colorectal carcinogenesis in germ-free and conventionally reared rats: different intestinal environments affect the systemic immunity. Int J Oncol 32:609–617PubMedGoogle Scholar
  87. 87.
    Reddy BS, Narisawa T, Wright P, Vukusich D, Weisburger JH, Wynder EL (1975) Colon carcinogenesis with azoxymethane and dimethylhydrazine in germ-free rats. Cancer Res 35:287–290PubMedGoogle Scholar
  88. 88.
    Backhed F, Ding H, Wang T et al (2004) The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A 101:15718–15723PubMedGoogle Scholar
  89. 89.
    Turnbaugh PJ, Hamady M, Yatsunenko T et al (2009) A core gut microbiome in obese and lean twins. Nature 457:480–484PubMedGoogle Scholar
  90. 90.
    Turnbaugh PJ, Gordon JI (2009) The core gut microbiome, energy balance and obesity. J Physiol 587:4153–4158PubMedGoogle Scholar
  91. 91.
    Ley RE, Turnbaugh PJ, Klein S, Gordon JI (2006) Microbial ecology: human gut microbes associated with obesity. Nature 444:1022–1023PubMedGoogle Scholar
  92. 92.
    de La Serre CB, Ellis CL, Lee J, Hartman AL, Rutledge JC, Raybould HE (2010) Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation. Am J Physiol Gastrointest Liver Physiol 299:G440–G448Google Scholar
  93. 93.
    Erridge C, Attina T, Spickett CM, Webb DJ (2007) A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Am J Clin Nutr 86:1286–1292PubMedGoogle Scholar
  94. 94.
    Cani PD, Amar J, Iglesias MA et al (2007) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56:1761–1772PubMedGoogle Scholar
  95. 95.
    Suzuki T, Hara H (2010) Dietary fat and bile juice, but not obesity, are responsible for the increase in small intestinal permeability induced through the suppression of tight junction protein expression in LETO and OLETF rats. Nutr Metab (Lond) 7:19Google Scholar
  96. 96.
    Fessler MB, Rudel LL, Brown JM (2009) Toll-like receptor signaling links dietary fatty acids to the metabolic syndrome. Curr Opin Lipidol 20:379–385PubMedGoogle Scholar
  97. 97.
    Fuss IJ, Becker C, Yang Z et al (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 12:9–15PubMedGoogle Scholar
  98. 98.
    Neurath MF, Fuss I, Kelsall BL, Stuber E, Strober W (1995) Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med 182:1281–1290PubMedGoogle Scholar
  99. 99.
    Liu Z, Geboes K, Heremans H et al (2001) Role of interleukin-12 in the induction of mucosal inflammation and abrogation of regulatory T cell function in chronic experimental colitis. Eur J Immunol 31:1550–1560PubMedGoogle Scholar
  100. 100.
    Kikly K, Liu L, Na S, Sedgwick JD (2006) The IL-23/Th(17) axis: therapeutic targets for autoimmune inflammation. Curr Opin Immunol 18:670–675PubMedGoogle Scholar
  101. 101.
    Strober W, Fuss IJ (2011) Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology 140:1756–1767PubMedGoogle Scholar
  102. 102.
    Vignali DA, Collison LW, Workman CJ (2008) How regulatory T cells work. Nat Rev Immunol 8:523–532PubMedGoogle Scholar
  103. 103.
    Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 cells. Annu Rev Immunol 27:485–517PubMedGoogle Scholar
  104. 104.
    Aggarwal S, Gurney AL (2002) IL-17: prototype member of an emerging cytokine family. J Leukoc Biol 71:1–8PubMedGoogle Scholar
  105. 105.
    Tosolini M, Kirilovsky A, Mlecnik B et al (2011) Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res 71:1263–1271PubMedGoogle Scholar
  106. 106.
    Boirivant M, Fuss IJ, Chu A, Strober W (1998) Oxazolone colitis: a murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4. J Exp Med 188:1929–1939PubMedGoogle Scholar
  107. 107.
    Heller F, Fuss IJ, Nieuwenhuis EE, Blumberg RS, Strober W (2002) Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 17:629–638PubMedGoogle Scholar
  108. 108.
    Fuss IJ, Heller F, Boirivant M et al (2004) Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest 113:1490–1497PubMedGoogle Scholar
  109. 109.
    Strober W, Fuss I, Mannon P (2007) The fundamental basis of inflammatory bowel disease. J Clin Invest 117:514–521PubMedGoogle Scholar
  110. 110.
    Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179–189PubMedGoogle Scholar
  111. 111.
    Meng G, Zhang F, Fuss I, Kitani A, Strober W (2009) A mutation in the Nlrp3 gene causing inflammasome hyperactivation potentiates Th17 cell-dominant immune responses. Immunity 30:860–874PubMedGoogle Scholar
  112. 112.
    Kim S, Keku TO, Martin C et al (2008) Circulating levels of inflammatory cytokines and risk of colorectal adenomas. Cancer Res 68:323–328PubMedGoogle Scholar
  113. 113.
    Becker C, Fantini MC, Schramm C et al (2004) TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity 21:491–501PubMedGoogle Scholar
  114. 114.
    Grivennikov S, Karin E, Terzic J et al (2009) IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15:103–113PubMedGoogle Scholar
  115. 115.
    Karin M (2009) NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harb Perspect Biol 1:a000141PubMedGoogle Scholar
  116. 116.
    Kaler P, Augenlicht L, Klampfer L (2009) Macrophage-derived IL-1beta stimulates Wnt signaling and growth of colon cancer cells: a crosstalk interrupted by vitamin D3. Oncogene 28:3892–3902PubMedGoogle Scholar
  117. 117.
    Liu W, Reinmuth N, Stoeltzing O et al (2003) Cyclooxygenase-2 is up-regulated by interleukin-­1 beta in human colorectal cancer cells via multiple signaling pathways. Cancer Res 63:3632–3636PubMedGoogle Scholar
  118. 118.
    Corredor J, Yan F, Shen CC et al (2003) Tumor necrosis factor regulates intestinal epithelial cell migration by receptor-dependent mechanisms. Am J Physiol Cell Physiol 284:C953–C961PubMedGoogle Scholar
  119. 119.
    Pickert G, Neufert C, Leppkes M et al (2009) STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med 206:1465–1472PubMedGoogle Scholar
  120. 120.
    Mandal D, Levine AD (2010) Elevated IL-13Ralpha2 in intestinal epithelial cells from ulcerative colitis or colorectal cancer initiates MAPK pathway. Inflamm Bowel Dis 16:753–764PubMedGoogle Scholar
  121. 121.
    Francipane MG, Alea MP, Lombardo Y, Todaro M, Medema JP, Stassi G (2008) Crucial role of interleukin-4 in the survival of colon cancer stem cells. Cancer Res 68:4022–4025PubMedGoogle Scholar
  122. 122.
    Kanai T, Watanabe M, Hayashi A et al (2000) Regulatory effect of interleukin-4 and interleukin-­13 on colon cancer cell adhesion. Br J Cancer 82:1717–1723PubMedGoogle Scholar
  123. 123.
    Barderas R, Bartolome RA, Fernandez-Acenero MJ, Torres S, Casal JI (2012) High expression of IL-13 receptor alpha2 in colorectal cancer is associated with invasion, liver metastasis, and poor prognosis. Cancer Res 72:2780–2790PubMedGoogle Scholar
  124. 124.
    Huber S, Gagliani N, Zenewicz LA et al (2012) IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491:259–263PubMedGoogle Scholar
  125. 125.
    Chae WJ, Bothwell AL (2011) IL-17F deficiency inhibits small intestinal tumorigenesis in ApcMin/+ mice. Biochem Biophys Res Commun 414:31–36PubMedGoogle Scholar
  126. 126.
    Chae WJ, Gibson TF, Zelterman D, Hao L, Henegariu O, Bothwell AL (2010) Ablation of IL-17A abrogates progression of spontaneous intestinal tumorigenesis. Proc Natl Acad Sci U S A 107:5540–5544PubMedGoogle Scholar
  127. 127.
    Koller FL, Hwang DG, Dozier EA, Fingleton B (2010) Epithelial interleukin-4 receptor expression promotes colon tumor growth. Carcinogenesis 31:1010–1017PubMedGoogle Scholar
  128. 128.
    Old LJ (1985) Tumor necrosis factor (TNF). Science 230:630–632PubMedGoogle Scholar
  129. 129.
    Baltgalvis KA, Berger FG, Pena MM, Davis JM, Muga SJ, Carson JA (2008) Interleukin-6 and cachexia in ApcMin/+ mice. Am J Physiol Regul Integr Comp Physiol 294:R393–R401PubMedGoogle Scholar
  130. 130.
    Mudter J, Neurath MF (2007) Il-6 signaling in inflammatory bowel disease: pathophysiological role and clinical relevance. Inflamm Bowel Dis 13:1016–1023PubMedGoogle Scholar
  131. 131.
    Fukata M, Chen A, Vamadevan AS et al (2007) Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology 133:1869–1881PubMedGoogle Scholar
  132. 132.
    Sheehan KM, Sheahan K, O’Donoghue DP et al (1999) The relationship between cyclooxygenase-­2 expression and colorectal cancer. JAMA 282:1254–1257PubMedGoogle Scholar
  133. 133.
    Arber N, Eagle CJ, Spicak J et al (2006) Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 355:885–895PubMedGoogle Scholar
  134. 134.
    Taketo MM (1998) COX-2 and colon cancer. Inflamm Res 47(Suppl 2):S112–S116PubMedGoogle Scholar
  135. 135.
    Pugh S, Thomas GA (1994) Patients with adenomatous polyps and carcinomas have increased colonic mucosal prostaglandin E2. Gut 35:675–678PubMedGoogle Scholar
  136. 136.
    Kawamori T, Uchiya N, Sugimura T, Wakabayashi K (2003) Enhancement of colon carcinogenesis by prostaglandin E2 administration. Carcinogenesis 24:985–990PubMedGoogle Scholar
  137. 137.
    Yang VW, Shields JM, Hamilton SR et al (1998) Size-dependent increase in prostanoid levels in adenomas of patients with familial adenomatous polyposis. Cancer Res 58:1750–1753PubMedGoogle Scholar
  138. 138.
    Chizzolini C, Brembilla NC (2009) Prostaglandin E2: igniting the fire. Immunol Cell Biol 87:510–511PubMedGoogle Scholar
  139. 139.
    Awane M, Andres PG, Li DJ, Reinecker HC (1999) NF-kappa B-inducing kinase is a common mediator of IL-17-, TNF-alpha-, and IL-1 beta-induced chemokine promoter activation in intestinal epithelial cells. J Immunol 162:5337–5344PubMedGoogle Scholar
  140. 140.
    Lee JW, Wang P, Kattah MG et al (2008) Differential regulation of chemokines by IL-17 in colonic epithelial cells. J Immunol 181:6536–6545PubMedGoogle Scholar
  141. 141.
    Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867PubMedGoogle Scholar
  142. 142.
    Maeda H, Akaike T (1998) Nitric oxide and oxygen radicals in infection, inflammation, and cancer. Biochemistry (Mosc) 63:854–865Google Scholar
  143. 143.
    Hussain SP, Amstad P, Raja K et al (2000) Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. Cancer Res 60:3333–3337PubMedGoogle Scholar
  144. 144.
    Xie J, Itzkowitz SH (2008) Cancer in inflammatory bowel disease. World J Gastroenterol 14:378–389PubMedGoogle Scholar
  145. 145.
    Liao J, Seril DN, Lu GG et al (2008) Increased susceptibility of chronic ulcerative colitis-­induced carcinoma development in DNA repair enzyme Ogg1 deficient mice. Mol Carcinog 47:638–646PubMedGoogle Scholar
  146. 146.
    Meira LB, Bugni JM, Green SL et al (2008) DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice. J Clin Invest 118:2516–2525PubMedGoogle Scholar
  147. 147.
    Andoh A, Bamba S, Brittan M, Fujiyama Y, Wright NA (2007) Role of intestinal ­subepithelial myofibroblasts in inflammation and regenerative response in the gut. Pharmacol Ther 114:94–106PubMedGoogle Scholar
  148. 148.
    Andoh A, Bamba S, Fujiyama Y, Brittan M, Wright NA (2005) Colonic subepithelial myofibroblasts in mucosal inflammation and repair: contribution of bone marrow-derived stem cells to the gut regenerative response. J Gastroenterol 40:1089–1099PubMedGoogle Scholar
  149. 149.
    Andoh A, Fujino S, Okuno T, Fujiyama Y, Bamba T (2002) Intestinal subepithelial myofibroblasts in inflammatory bowel diseases. J Gastroenterol 37(Suppl 14):33–37PubMedGoogle Scholar
  150. 150.
    Andoh A, Zhang Z, Inatomi O et al (2005) Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology 129:969–984PubMedGoogle Scholar
  151. 151.
    Sugarman BJ, Aggarwal BB, Hass PE, Figari IS, Palladino MA Jr, Shepard HM (1985) Recombinant human tumor necrosis factor-alpha: effects on proliferation of normal and transformed cells in vitro. Science 230:943–945PubMedGoogle Scholar
  152. 152.
    Odegaard JI, Chawla A (2011) Alternative macrophage activation and metabolism. Annu Rev Pathol 6:275–297PubMedGoogle Scholar
  153. 153.
    Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445PubMedGoogle Scholar
  154. 154.
    Cinti S, Mitchell G, Barbatelli G et al (2005) Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 46:2347–2355PubMedGoogle Scholar
  155. 155.
    Murano I, Barbatelli G, Parisani V et al (2008) Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice. J Lipid Res 49:1562–1568PubMedGoogle Scholar
  156. 156.
    Fernandez-Riejos P, Najib S, Santos-Alvarez J et al (2010) Role of leptin in the activation of immune cells. Mediators Inflamm 2010:568343PubMedGoogle Scholar
  157. 157.
    Nishimura S, Manabe I, Nagasaki M et al (2009) CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15:914–920PubMedGoogle Scholar
  158. 158.
    Winer S, Chan Y, Paltser G et al (2009) Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 15:921–929PubMedGoogle Scholar
  159. 159.
    Feuerer M, Herrero L, Cipolletta D et al (2009) Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15:930–939PubMedGoogle Scholar
  160. 160.
    Liu Z, Brooks RS, Ciappio ED et al (2012) Diet-induced obesity elevates colonic TNF-alpha in mice and is accompanied by an activation of Wnt signaling: a mechanism for obesity-­associated colorectal cancer. J Nutr Biochem 23(10):1207–1213PubMedGoogle Scholar
  161. 161.
    Park SY, Kim JS, Seo YR, Sung MK (2012) Effects of diet-induced obesity on colitis-­associated colon tumor formation in A/J mice. Int J Obes (Lond) 36:273–280Google Scholar
  162. 162.
    Tataranni PA, Ortega E (2005) A burning question: does an adipokine-induced activation of the immune system mediate the effect of overnutrition on type 2 diabetes? Diabetes 54:917–927PubMedGoogle Scholar
  163. 163.
    MacDougald OA, Burant CF (2007) The rapidly expanding family of adipokines. Cell Metab 6:159–161PubMedGoogle Scholar
  164. 164.
    Trayhurn P, Bing C (2006) Appetite and energy balance signals from adipocytes. Philos Trans R Soc Lond B Biol Sci 361:1237–1249PubMedGoogle Scholar
  165. 165.
    Faggioni R, Feingold KR, Grunfeld C (2001) Leptin regulation of the immune response and the immunodeficiency of malnutrition. FASEB J 15:2565–2571PubMedGoogle Scholar
  166. 166.
    Drew JE, Farquharson AJ, Padidar S et al (2007) Insulin, leptin, and adiponectin receptors in colon: regulation relative to differing body adiposity independent of diet and in response to dimethylhydrazine. Am J Physiol Gastrointest Liver Physiol 293:G682–G691PubMedGoogle Scholar
  167. 167.
    Hardwick JC, van den Brink GR, Offerhaus GJ, Van Deventer SJ, Peppelenbosch MP (2001) Leptin is a growth factor for colonic epithelial cells. Gastroenterology 121:79–90PubMedGoogle Scholar
  168. 168.
    Considine RV, Sinha MK, Heiman ML et al (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334:292–295PubMedGoogle Scholar
  169. 169.
    Stattin P, Palmqvist R, Soderberg S et al (2003) Plasma leptin and colorectal cancer risk: a prospective study in Northern Sweden. Oncol Rep 10:2015–2021PubMedGoogle Scholar
  170. 170.
    Stattin P, Lukanova A, Biessy C et al (2004) Obesity and colon cancer: does leptin provide a link? Int J Cancer 109:149–152PubMedGoogle Scholar
  171. 171.
    Chia VM, Newcomb PA, Lampe JW et al (2007) Leptin concentrations, leptin receptor polymorphisms, and colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev 16:2697–2703PubMedGoogle Scholar
  172. 172.
    Calle EE, Kaaks R (2004) Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 4:579–591PubMedGoogle Scholar
  173. 173.
    Harriss DJ, Atkinson G, George K et al (2009) Lifestyle factors and colorectal cancer risk (1): systematic review and meta-analysis of associations with body mass index. Colorectal Dis 11:547–563PubMedGoogle Scholar
  174. 174.
    Frezza EE, Wachtel MS, Chiriva-Internati M (2006) Influence of obesity on the risk of developing colon cancer. Gut 55:285–291PubMedGoogle Scholar
  175. 175.
    Rutter M, Saunders B, Wilkinson K et al (2004) Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 126:451–459PubMedGoogle Scholar
  176. 176.
    Drew JE (2012) Molecular mechanisms linking adipokines to obesity-related colon cancer: focus on leptin. Proc Nutr Soc 71:175–180PubMedGoogle Scholar
  177. 177.
    Hoda MR, Keely SJ, Bertelsen LS, Junger WG, Dharmasena D, Barrett KE (2007) Leptin acts as a mitogenic and antiapoptotic factor for colonic cancer cells. Br J Surg 94:346–354PubMedGoogle Scholar
  178. 178.
    Ogunwobi OO, Beales IL (2007) The anti-apoptotic and growth stimulatory actions of leptin in human colon cancer cells involves activation of JNK mitogen activated protein kinase, JAK2 and PI3 kinase/Akt. Int J Colorectal Dis 22:401–409PubMedGoogle Scholar
  179. 179.
    Ogunwobi OO, Beales IL (2007) Cyclo-oxygenase-independent inhibition of apoptosis and stimulation of proliferation by leptin in human colon cancer cells. Dig Dis Sci 52:1934–1945PubMedGoogle Scholar
  180. 180.
    Abolhassani M, Aloulou N, Chaumette MT et al (2008) Leptin receptor-related immune response in colorectal tumors: the role of colonocytes and interleukin-8. Cancer Res 68:9423–9432PubMedGoogle Scholar
  181. 181.
    Aparicio T, Kotelevets L, Tsocas A et al (2005) Leptin stimulates the proliferation of human colon cancer cells in vitro but does not promote the growth of colon cancer xenografts in nude mice or intestinal tumorigenesis in Apc(Min/+) mice. Gut 54:1136–1145PubMedGoogle Scholar
  182. 182.
    Ealey KN, Lu S, Archer MC (2008) Development of aberrant crypt foci in the colons of ob/ob and db/db mice: evidence that leptin is not a promoter. Mol Carcinog 47:667–677PubMedGoogle Scholar
  183. 183.
    Endo H, Hosono K, Uchiyama T et al (2011) Leptin acts as a growth factor for colorectal tumours at stages subsequent to tumour initiation in murine colon carcinogenesis. Gut 60:1363–1371PubMedGoogle Scholar
  184. 184.
    Fenton JI, Hursting SD, Perkins SN, Hord NG (2006) Interleukin-6 production induced by leptin treatment promotes cell proliferation in an Apc (Min/+) colon epithelial cell line. Carcinogenesis 27:1507–1515PubMedGoogle Scholar
  185. 185.
    Padidar S, Farquharson AJ, Williams LM et al (2011) Leptin up-regulates pro-inflammatory cytokines in discrete cells within mouse colon. J Cell Physiol 226:2123–2130PubMedGoogle Scholar
  186. 186.
    Yang SK, Eckmann L, Panja A, Kagnoff MF (1997) Differential and regulated expression of C-X-C, C-C, and C-chemokines by human colon epithelial cells. Gastroenterology 113:1214–1223PubMedGoogle Scholar
  187. 187.
    Waugh DJ, Wilson C (2008) The interleukin-8 pathway in cancer. Clin Cancer Res 14:6735–6741PubMedGoogle Scholar
  188. 188.
    Palacio A, Lopez M, Perez-Bravo F, Monkeberg F, Schlesinger L (2002) Leptin levels are associated with immune response in malnourished infants. J Clin Endocrinol Metab 87:3040–3046PubMedGoogle Scholar
  189. 189.
    Busso N, So A, Chobaz-Peclat V et al (2002) Leptin signaling deficiency impairs humoral and cellular immune responses and attenuates experimental arthritis. J Immunol 168:875–882PubMedGoogle Scholar
  190. 190.
    Matarese G, Di GA, Sanna V et al (2001) Requirement for leptin in the induction and ­progression of autoimmune encephalomyelitis. J Immunol 166:5909–5916PubMedGoogle Scholar
  191. 191.
    Stofkova A (2009) Leptin and adiponectin: from energy and metabolic dysbalance to inflammation and autoimmunity. Endocr Regul 43:157–168PubMedGoogle Scholar
  192. 192.
    John BJ, Irukulla S, Abulafi AM, Kumar D, Mendall MA (2006) Systematic review: adipose tissue, obesity and gastrointestinal diseases. Aliment Pharmacol Ther 23:1511–1523PubMedGoogle Scholar
  193. 193.
    Tartaglia LA, Dembski M, Weng X et al (1995) Identification and expression cloning of a leptin receptor, OB-R. Cell 83:1263–1271PubMedGoogle Scholar
  194. 194.
    Sanchez-Margalet V, Martin-Romero C, Santos-Alvarez J, Goberna R, Najib S, Gonzalez-­Yanes C (2003) Role of leptin as an immunomodulator of blood mononuclear cells: mechanisms of action. Clin Exp Immunol 133:11–19PubMedGoogle Scholar
  195. 195.
    McLean MH, Murray GI, Stewart KN et al (2011) The inflammatory microenvironment in colorectal neoplasia. PLoS One 6:e15366PubMedGoogle Scholar
  196. 196.
    Loffreda S, Yang SQ, Lin HZ et al (1998) Leptin regulates proinflammatory immune responses. FASEB J 12:57–65PubMedGoogle Scholar
  197. 197.
    Kiguchi N, Maeda T, Kobayashi Y, Fukazawa Y, Kishioka S (2009) Leptin enhances CC-chemokine ligand expression in cultured murine macrophage. Biochem Biophys Res Commun 384:311–315PubMedGoogle Scholar
  198. 198.
    Mattioli B, Giordani L, Quaranta MG, Viora M (2009) Leptin exerts an anti-apoptotic effect on human dendritic cells via the PI3K-Akt signaling pathway. FEBS Lett 583:1102–1106PubMedGoogle Scholar
  199. 199.
    Mattioli B, Straface E, Quaranta MG, Giordani L, Viora M (2005) Leptin promotes differentiation and survival of human dendritic cells and licenses them for Th1 priming. J Immunol 174:6820–6828PubMedGoogle Scholar
  200. 200.
    Mattioli B, Straface E, Matarrese P et al (2008) Leptin as an immunological adjuvant: enhanced migratory and CD8+ T cell stimulatory capacity of human dendritic cells exposed to leptin. FASEB J 22:2012–2022PubMedGoogle Scholar
  201. 201.
    Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI (1998) Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394:897–901PubMedGoogle Scholar
  202. 202.
    Sanchez-Margalet V, Martin-Romero C (2001) Human leptin signaling in human peripheral blood mononuclear cells: activation of the JAK-STAT pathway. Cell Immunol 211:30–36PubMedGoogle Scholar
  203. 203.
    Martin-Romero C, Sanchez-Margalet V (2001) Human leptin activates PI3K and MAPK pathways in human peripheral blood mononuclear cells: possible role of Sam68. Cell Immunol 212:83–91PubMedGoogle Scholar
  204. 204.
    Martin-Romero C, Santos-Alvarez J, Goberna R, Sanchez-Margalet V (2000) Human leptin enhances activation and proliferation of human circulating T lymphocytes. Cell Immunol 199:15–24PubMedGoogle Scholar
  205. 205.
    La CA, Matarese G (2004) The weight of leptin in immunity. Nat Rev Immunol 4:371–379Google Scholar
  206. 206.
    Batra A, Okur B, Glauben R et al (2010) Leptin: a critical regulator of CD4+ T-cell polarization in vitro and in vivo. Endocrinology 151:56–62PubMedGoogle Scholar
  207. 207.
    Lostao MP, Urdaneta E, Martinez-Anso E, Barber A, Martinez JA (1998) Presence of leptin receptors in rat small intestine and leptin effect on sugar absorption. FEBS Lett 423:302–306PubMedGoogle Scholar
  208. 208.
    Tilg H, Moschen AR (2006) Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 6:772–783PubMedGoogle Scholar
  209. 209.
    Dalamaga M, Diakopoulos KN, Mantzoros CS (2012) The role of adiponectin in cancer: a review of current evidence. Endocr Rev 33:547–594PubMedGoogle Scholar
  210. 210.
    Simpson F, Whitehead JP (2010) Adiponectin—it’s all about the modifications. Int J Biochem Cell Biol 42:785–788PubMedGoogle Scholar
  211. 211.
    Wang Y, Lam KS, Chan L et al (2006) Post-translational modifications of the four conserved lysine residues within the collagenous domain of adiponectin are required for the formation of its high molecular weight oligomeric complex. J Biol Chem 281:16391–16400PubMedGoogle Scholar
  212. 212.
    Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M (2008) Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371:569–578PubMedGoogle Scholar
  213. 213.
    Ziemke F, Mantzoros CS (2010) Adiponectin in insulin resistance: lessons from translational research. Am J Clin Nutr 91:258S–261SPubMedGoogle Scholar
  214. 214.
    Berg AH, Combs TP, Scherer PE (2002) ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab 13:84–89PubMedGoogle Scholar
  215. 215.
    Cnop M, Havel PJ, Utzschneider KM et al (2003) Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia 46:459–469PubMedGoogle Scholar
  216. 216.
    Wei EK, Giovannucci E, Fuchs CS, Willett WC, Mantzoros CS (2005) Low plasma adiponectin levels and risk of colorectal cancer in men: a prospective study. J Natl Cancer Inst 97:1688–1694PubMedGoogle Scholar
  217. 217.
    Nishihara T, Matsuda M, Araki H et al (2006) Effect of adiponectin on murine colitis induced by dextran sulfate sodium. Gastroenterology 131:853–861PubMedGoogle Scholar
  218. 218.
    Yoneda K, Tomimoto A, Endo H et al (2008) Expression of adiponectin receptors, AdipoR1 and AdipoR2, in normal colon epithelium and colon cancer tissue. Oncol Rep 20:479–483PubMedGoogle Scholar
  219. 219.
    Otani K, Kitayama J, Yasuda K et al (2010) Adiponectin suppresses tumorigenesis in Apc(Min)(/+) mice. Cancer Lett 288:177–182PubMedGoogle Scholar
  220. 220.
    Kim AY, Lee YS, Kim KH et al (2010) Adiponectin represses colon cancer cell proliferation via AdipoR1- and -R2-mediated AMPK activation. Mol Endocrinol 24:1441–1452PubMedGoogle Scholar
  221. 221.
    Byeon JS, Jeong JY, Kim MJ et al (2010) Adiponectin and adiponectin receptor in relation to colorectal cancer progression. Int J Cancer 127:2758–2767PubMedGoogle Scholar
  222. 222.
    Ogunwobi OO, Beales IL (2006) Adiponectin stimulates proliferation and cytokine secretion in colonic epithelial cells. Regul Pept 134:105–113PubMedGoogle Scholar
  223. 223.
    Lang K, Ratke J (2009) Leptin and adiponectin: new players in the field of tumor cell and leukocyte migration. Cell Commun Signal 7:27PubMedGoogle Scholar
  224. 224.
    Sugiyama M, Takahashi H, Hosono K et al (2009) Adiponectin inhibits colorectal cancer cell growth through the AMPK/mTOR pathway. Int J Oncol 34:339–344PubMedGoogle Scholar
  225. 225.
    Zakikhani M, Dowling RJ, Sonenberg N, Pollak MN (2008) The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase. Cancer Prev Res (Phila) 1:369–375Google Scholar
  226. 226.
    Habeeb BS, Kitayama J, Nagawa H (2011) Adiponectin supports cell survival in glucose deprivation through enhancement of autophagic response in colorectal cancer cells. Cancer Sci 102:999–1006PubMedGoogle Scholar
  227. 227.
    Saxena A, Chumanevich A, Fletcher E et al (1822) Adiponectin deficiency: role in chronic inflammation induced colon cancer. Biochim Biophys Acta 2012:527–536Google Scholar
  228. 228.
    Fujisawa T, Endo H, Tomimoto A et al (2008) Adiponectin suppresses colorectal carcinogenesis under the high-fat diet condition. Gut 57:1531–1538PubMedGoogle Scholar
  229. 229.
    Nishihara T, Baba M, Matsuda M et al (2008) Adiponectin deficiency enhances colorectal carcinogenesis and liver tumor formation induced by azoxymethane in mice. World J Gastroenterol 14:6473–6480PubMedGoogle Scholar
  230. 230.
    Fenton JI, Birmingham JM, Hursting SD, Hord NG (2008) Adiponectin blocks multiple signaling cascades associated with leptin-induced cell proliferation in Apc Min/+ colon epithelial cells. Int J Cancer 122:2437–2445PubMedGoogle Scholar
  231. 231.
    Fayad R, Pini M, Sennello JA et al (2007) Adiponectin deficiency protects mice from chemically induced colonic inflammation. Gastroenterology 132:601–614PubMedGoogle Scholar
  232. 232.
    Uji Y, Yamamoto H, Tsuchihashi H et al (2009) Adiponectin deficiency is associated with severe polymicrobial sepsis, high inflammatory cytokine levels, and high mortality. Surgery 145:550–557PubMedGoogle Scholar
  233. 233.
    Kamada Y, Tamura S, Kiso S et al (2003) Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin. Gastroenterology 125:1796–1807PubMedGoogle Scholar
  234. 234.
    Pang TT, Narendran P (2008) The distribution of adiponectin receptors on human peripheral blood mononuclear cells. Ann N Y Acad Sci 1150:143–145PubMedGoogle Scholar
  235. 235.
    Okamoto Y, Christen T, Shimizu K et al (2009) Adiponectin inhibits allograft rejection in murine cardiac transplantation. Transplantation 88:879–883PubMedGoogle Scholar
  236. 236.
    Ohashi K, Parker JL, Ouchi N et al (2010) Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype. J Biol Chem 285:6153–6160PubMedGoogle Scholar
  237. 237.
    Furukawa K, Hori M, Ouchi N et al (2004) Adiponectin down-regulates acyl-coenzyme A: cholesterol acyltransferase-1 in cultured human monocyte-derived macrophages. Biochem Biophys Res Commun 317:831–836PubMedGoogle Scholar
  238. 238.
    Wulster-Radcliffe MC, Ajuwon KM, Wang J, Christian JA, Spurlock ME (2004) Adiponectin differentially regulates cytokines in porcine macrophages. Biochem Biophys Res Commun 316:924–929PubMedGoogle Scholar
  239. 239.
    Wolf AM, Wolf D, Rumpold H, Enrich B, Tilg H (2004) Adiponectin induces the anti-­inflammatory cytokines IL-10 and IL-1RA in human leukocytes. Biochem Biophys Res Commun 323:630–635PubMedGoogle Scholar
  240. 240.
    Folco EJ, Rocha VZ, Lopez-Ilasaca M, Libby P (2009) Adiponectin inhibits pro-­inflammatory signaling in human macrophages independent of interleukin-10. J Biol Chem 284:25569–25575PubMedGoogle Scholar
  241. 241.
    Saijo S, Nagata K, Nakano Y, Tobe T, Kobayashi Y (2005) Inhibition by adiponectin of IL-8 production by human macrophages upon coculturing with late apoptotic cells. Biochem Biophys Res Commun 334:1180–1183PubMedGoogle Scholar
  242. 242.
    Yokota T, Oritani K, Takahashi I et al (2000) Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 96:1723–1732PubMedGoogle Scholar
  243. 243.
    Okamoto Y, Folco EJ, Minami M et al (2008) Adiponectin inhibits the production of CXC receptor 3 chemokine ligands in macrophages and reduces T-lymphocyte recruitment in atherogenesis. Circ Res 102:218–225PubMedGoogle Scholar
  244. 244.
    Wilk S, Scheibenbogen C, Bauer S et al (2011) Adiponectin is a negative regulator of antigen-­activated T cells. Eur J Immunol 41:2323–2332PubMedGoogle Scholar
  245. 245.
    Keller JJ, Giardiello FM (2003) Chemoprevention strategies using NSAIDs and COX-2 inhibitors. Cancer Biol Ther 2:S140–S149PubMedGoogle Scholar
  246. 246.
    Yamamoto Y, Yin MJ, Lin KM, Gaynor RB (1999) Sulindac inhibits activation of the NF-kappaB pathway. J Biol Chem 274:27307–27314PubMedGoogle Scholar
  247. 247.
    Lanas A (2009) Nonsteroidal antiinflammatory drugs and cyclooxygenase inhibition in the gastrointestinal tract: a trip from peptic ulcer to colon cancer. Am J Med Sci 338:96–106PubMedGoogle Scholar
  248. 248.
    Waldner MJ, Neurath MF (2009) Colitis-associated cancer: the role of T cells in tumor development. Semin Immunopathol 31:249–256PubMedGoogle Scholar
  249. 249.
    Rutgeerts P, Vermeire S, Van AG (2009) Biological therapies for inflammatory bowel diseases. Gastroenterology 136:1182–1197PubMedGoogle Scholar
  250. 250.
    Kim YS, Milner JA (2007) Dietary modulation of colon cancer risk. J Nutr 137:2576S–2579SPubMedGoogle Scholar
  251. 251.
    Tuan D, Solomon W, Li Q, London IM (1985) The “beta-like-globin” gene domain in human erythroid cells. Proc Natl Acad Sci U S A 82:6384–6388PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of GeneticsCase Western Reserve University School of MedicineClevelandUSA
  2. 2.Department of Molecular and Human GeneticsBaylor College of MedicineHoustonUSA

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