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Mast cells and inflammation-associated colorectal carcinogenesis

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Abstract

Close association between chronic inflammation and cancer has been recently highlighted. Indeed, inflammatory bowel disease (IBD) has been strongly linked with an increased risk of development of colorectal cancer (CRC). Inflammatory cell-produced inflammatory mediators, such as proinflammatory cytokines and inducible enzymes, contribute to this association. In an inflammatory microenvironment, infiltrating macrophages and mast cells mediate production of these inflammatory mediators to promote growth of tumors in target tissues. In contrast to macrophages, contribution of mast cells to CRC development in inflamed colon is not well understood. This study aimed to determine the role of mast cells in inflammation-associated colorectal carcinogenesis. CRC was induced by administration of the colonic carcinogen, azoxymethane (AOM), and the tumor promoter dextran sodium sulfate (DSS) in male mast cell-deficient WBBF1-kit W/W-v (W/Wv) and mast cell-normal WBB6F1-+/+(WT) mice. At week 12, the W/Wv mice had markedly lower inflammation scores in the colon when compared with WT mice. The mRNA levels of colonic proinflammatory cytokines and inducible enzymes were also decreased in W/WV mice at weeks 12 and 20, when compared with WT counterparts. Colorectal tumors, including CRC, were identified by histopathological analysis performed 20 weeks thereafter. Importantly, there were less neoplastic and preneoplastic colonic lesions in the W/Wv mice compared with the WT mice. Thus, for the first time, our study shows that mice lacking mast cells are less susceptible to inflammation-associated colorectal carcinogenesis. Our findings also suggest that mast cells and their selected cytokines could play an important role in inflammation-mediated tumorigenesis through regulation of proinflammatory cytokines and inducible inflammatory enzymes.

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References

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

    Article  PubMed  CAS  Google Scholar 

  2. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899

    Article  PubMed  CAS  Google Scholar 

  3. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444

    Article  PubMed  CAS  Google Scholar 

  4. Sodir NM, Swigart LB, Karnezis AN, Hanahan D, Evan GI, Soucek L (2011) Endogenous Myc maintains the tumor microenvironment. Genes Dev 25:907–916

    Article  PubMed  CAS  Google Scholar 

  5. Tanaka T, Suzuki R (2007) Inflammation and cancer. In: Tanaka T (ed) Cancer: Disease progression and chemoprevention 2007. Research Signpost, Kerala, pp 27–44

    Google Scholar 

  6. Balkwill FR, Mantovani A (2012) Cancer-related inflammation: common themes and therapeutic opportunities. Semin Cancer Biol 22:33–40

    Article  PubMed  CAS  Google Scholar 

  7. Tanaka T, Kohno H, Murakami M, Shimada R, Kagami S (2000) Colitis-related rat colon carcinogenesis induced by 1-hydroxy-anthraquinone and methylazoxymethanol acetate (review). Oncol Rep 7:501–508

    PubMed  CAS  Google Scholar 

  8. Tanaka T (2009) Colorectal carcinogenesis: review of human and experimental animal studies. J Carcinog 8:5

    Article  PubMed  Google Scholar 

  9. Kaser A, Zeissig S, Blumberg RS (2010) Genes and environment: how will our concepts on the pathophysiology of IBD develop in the future? Dig Dis 28:395–405

    Article  PubMed  Google Scholar 

  10. Lakatos PL, Lakatos L (2008) Risk for colorectal cancer in ulcerative colitis: changes, causes and management strategies. World J Gastroenterol 14:3937–3947

    Article  PubMed  Google Scholar 

  11. Munkholm P (2003) Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease. Aliment Pharmacol Ther 18(Suppl 2):1–5

    Article  PubMed  Google Scholar 

  12. Eaden JA, Abrams KR, Mayberry JF (2001) The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 48:526–535

    Article  PubMed  CAS  Google Scholar 

  13. Sung JJ, Lau JY, Goh KL, Leung WK (2005) Increasing incidence of colorectal cancer in Asia: implications for screening. Lancet Oncol 6:871–876

    Article  PubMed  Google Scholar 

  14. Tanaka T, Kohno H, Suzuki R, Yamada Y, Sugie S, Mori H (2003) A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate. Cancer Sci 94:965–973

    Article  PubMed  CAS  Google Scholar 

  15. Tanaka T (2012) Development of an inflammation-associated colorectal cancer model and its application for research on carcinogenesis and chemoprevention. Int. J. Inflammation: in press

  16. Rosenberg DW, Giardina C, Tanaka T (2009) Mouse models for the study of colon carcinogenesis. Carcinogenesis 30:183–196

    Article  PubMed  CAS  Google Scholar 

  17. Tanaka T, Yasui Y, Ishigamori-Suzuki R, Oyama T (2008) Citrus compounds inhibit inflammation- and obesity-related colon carcinogenesis in mice. Nutr Cancer 60(Suppl 1):70–80

    Article  PubMed  CAS  Google Scholar 

  18. Westphal E (1891) Uber Mastzellen. In: Ehrlich E (ed) Farbenanalytische Untersuchungen. Hirschwald, Berlin, pp 17–41

    Google Scholar 

  19. Crivellato E, Beltrami C, Mallardi F, Ribatti D (2003) Paul Ehrlich's doctoral thesis: a milestone in the study of mast cells. Br J Haematol 123:19–21

    Article  PubMed  Google Scholar 

  20. Wasiuk A, de Vries VC, Hartmann K, Roers A, Noelle RJ (2009) Mast cells as regulators of adaptive immunity to tumours. Clin Exp Immunol 155:140–146

    Article  PubMed  CAS  Google Scholar 

  21. Lachter J, Stein M, Lichtig C, Eidelman S, Munichor M (1995) Mast cells in colorectal neoplasias and premalignant disorders. Dis Colon Rectum 38:290–293

    Article  PubMed  CAS  Google Scholar 

  22. Gounaris E, Erdman SE, Restaino C, Gurish MF, Friend DS, Gounari F, Lee DM, Zhang G, Glickman JN, Shin K, Rao VP, Poutahidis T, Weissleder R, McNagny KM, Khazaie K (2007) Mast cells are an essential hematopoietic component for polyp development. Proc Natl Acad Sci USA 104:19977–19982

    Article  PubMed  CAS  Google Scholar 

  23. Colombo MP, Piconese S (2009) Polyps wrap mast cells and Treg within tumorigenic tentacles. Cancer Res 69:5619–5622

    Article  PubMed  CAS  Google Scholar 

  24. Gounaris E, Blatner NR, Dennis K, Magnusson F, Gurish MF, Strom TB, Beckhove P, Gounari F, Khazaie K (2009) T-regulatory cells shift from a protective anti-inflammatory to a cancer-promoting proinflammatory phenotype in polyposis. Cancer Res 69:5490–5497

    Article  PubMed  CAS  Google Scholar 

  25. He SH (2004) Key role of mast cells and their major secretory products in inflammatory bowel disease. World J Gastroenterol 10:309–318

    PubMed  CAS  Google Scholar 

  26. De Winter BY, van den Wijngaard RM, de Jonge WJ (2012) Intestinal mast cells in gut inflammation and motility disturbances. Biochim Biophys Acta 1822:66–73

    Article  PubMed  Google Scholar 

  27. Stein J, Ries J, Barrett KE (1998) Disruption of intestinal barrier function associated with experimental colitis: possible role of mast cells. Am J Physiol 274:G203–G209

    PubMed  CAS  Google Scholar 

  28. Sanchez-Munoz F, Dominguez-Lopez A, Yamamoto-Furusho JK (2008) Role of cytokines in inflammatory bowel disease. World J Gastroenterol 14:4280–4288

    Article  PubMed  CAS  Google Scholar 

  29. Wershil BK (2000) IX. Mast cell-deficient mice and intestinal biology. Am J Physiol Gastrointest Liver Physiol 278:G343–G348

    PubMed  CAS  Google Scholar 

  30. Oyama T, Yasui Y, Sugie S, Koketsu M, Watanabe K, Tanaka T (2009) Dietary tricin suppresses inflammation-related colon carcinogenesis in male Crj: CD-1 mice. Cancer Prev Res (Phila) 2:1031–1038

    Article  CAS  Google Scholar 

  31. Suzuki R, Kohno H, Sugie S, Tanaka T (2005) Dose-dependent promoting effect of dextran sodium sulfate on mouse colon carcinogenesis initiated with azoxymethane. Histol Histopathol 20:483–492

    PubMed  CAS  Google Scholar 

  32. Suzuki R, Kohno H, Sugie S, Tanaka T (2004) Sequential observations on the occurrence of preneoplastic and neoplastic lesions in mouse colon treated with azoxymethane and dextran sodium sulfate. Cancer Sci 95:721–727

    Article  PubMed  CAS  Google Scholar 

  33. Kunder S, Calzada-Wack J, Holzlwimmer G, Muller J, Kloss C, Howat W, Schmidt J, Hofler H, Warren M, Quintanilla-Martinez L (2007) A comprehensive antibody panel for immunohistochemical analysis of formalin-fixed, paraffin-embedded hematopoietic neoplasms of mice: analysis of mouse specific and human antibodies cross-reactive with murine tissue. Toxicol Pathol 35:366–375

    Article  PubMed  CAS  Google Scholar 

  34. Kitamura Y, Go S, Hatanaka K (1978) Decrease of mast cells in W/Wv mice and their increase by bone marrow transplantation. Blood 52:447–452

    PubMed  CAS  Google Scholar 

  35. Shea-Donohue T, Stiltz J, Zhao A, Notari L (2010) Mast cells. Curr Gastroenterol Rep 12:349–357

    Article  PubMed  Google Scholar 

  36. Heib V, Becker M, Taube C, Stassen M (2008) Advances in the understanding of mast cell function. Br J Haematol 142:683–694

    Article  PubMed  CAS  Google Scholar 

  37. Stone KD, Prussin C, Metcalfe DD (2010) IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 125:S73–S80

    Article  PubMed  Google Scholar 

  38. Peterson CG, Sangfelt P, Wagner M, Hansson T, Lettesjo H, Carlson M (2007) Fecal levels of leukocyte markers reflect disease activity in patients with ulcerative colitis. Scand J Clin Lab Invest 67:810–820

    Article  PubMed  CAS  Google Scholar 

  39. Ardizzone S, Bianchi Porro G (2005) Biologic therapy for inflammatory bowel disease. Drugs 65:2253–2286

    Article  PubMed  CAS  Google Scholar 

  40. Bosani M, Ardizzone S, Porro GB (2009) Biologic targeting in the treatment of inflammatory bowel diseases. Biologics 3:77–97

    PubMed  CAS  Google Scholar 

  41. Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK, Lee SS (2001) Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res 480–481:243–268

    PubMed  Google Scholar 

  42. Dinarello CA (2011) A clinical perspective of IL-1beta as the gatekeeper of inflammation. Eur J Immunol 41:1203–1217

    Article  PubMed  CAS  Google Scholar 

  43. Fox CC, Lazenby AJ, Moore WC, Yardley JH, Bayless TM, Lichtenstein LM (1990) Enhancement of human intestinal mast cell mediator release in active ulcerative colitis. Gastroenterology 99:119–124

    PubMed  CAS  Google Scholar 

  44. Hamilton MJ, Sinnamon MJ, Lyng GD, Glickman JN, Wang X, Xing W, Krilis SA, Blumberg RS, Adachi R, Lee DM, Stevens RL (2011) Essential role for mast cell tryptase in acute experimental colitis. Proc Natl Acad Sci USA 108:290–295

    Article  PubMed  CAS  Google Scholar 

  45. Isozaki Y, Yoshida N, Kuroda M, Handa O, Takagi T, Kokura S, Ichikawa H, Naito Y, Okanoue T, Yoshikawa T (2006) Anti-tryptase treatment using nafamostat mesilate has a therapeutic effect on experimental colitis. Scand J Gastroenterol 41:944–953

    Article  PubMed  CAS  Google Scholar 

  46. He SH, Xie H, Fu YL (2005) Inhibition of tryptase release from human colon mast cells by histamine receptor antagonists. Asian Pac J Allergy Immunol 23:35–39

    PubMed  CAS  Google Scholar 

  47. Stoyanova II, Gulubova MV (2002) Mast cells and inflammatory mediators in chronic ulcerative colitis. Acta Histochem 104:185–192

    Article  PubMed  CAS  Google Scholar 

  48. Kolios G, Valatas V, Ward SG (2004) Nitric oxide in inflammatory bowel disease: a universal messenger in an unsolved puzzle. Immunology 113:427–437

    Article  PubMed  CAS  Google Scholar 

  49. Tanaka T, Suzuki R, Kohno H, Sugie S, Takahashi M, Wakabayashi K (2005) Colonic adenocarcinomas rapidly induced by the combined treatment with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and dextran sodium sulfate in male ICR mice possess beta-catenin gene mutations and increases immunoreactivity for beta-catenin, cyclooxygenase-2 and inducible nitric oxide synthase. Carcinogenesis 26:229–238

    Article  PubMed  CAS  Google Scholar 

  50. Kraus S, Arber N (2009) Inflammation and colorectal cancer. Curr Opin Pharmacol 9:405–410

    Article  PubMed  CAS  Google Scholar 

  51. Maltby S, Khazaie K, McNagny KM (2009) Mast cells in tumor growth: angiogenesis, tissue remodelling and immune-modulation. Biochim Biophys Acta 1796:19–26

    PubMed  CAS  Google Scholar 

  52. Conti P, Castellani ML, Kempuraj D, Salini V, Vecchiet J, Tete S, Mastrangelo F, Perrella A, De Lutiis MA, Tagen M, Theoharides TC (2007) Role of mast cells in tumor growth. Ann Clin Lab Sci 37:315–322

    PubMed  CAS  Google Scholar 

  53. Coussens LM, Raymond WW, Bergers G, Laig-Webster M, Behrendtsen O, Werb Z, Caughey GH, Hanahan D (1999) Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev 13:1382–1397

    Article  PubMed  CAS  Google Scholar 

  54. Gulubova M, Vlaykova T (2009) Prognostic significance of mast cell number and microvascular density for the survival of patients with primary colorectal cancer. J Gastroenterol Hepatol 24:1265–1275

    Article  PubMed  Google Scholar 

  55. Starkey JR, Crowle PK, Taubenberger S (1988) Mast-cell-deficient W/Wv mice exhibit a decreased rate of tumor angiogenesis. Int J Cancer 42:48–52

    Article  PubMed  CAS  Google Scholar 

  56. Suto H, Nakae S, Kakurai M, Sedgwick JD, Tsai M, Galli SJ (2006) Mast cell-associated TNF promotes dendritic cell migration. J Immunol 176:4102–4112

    PubMed  CAS  Google Scholar 

  57. Mizoguchi E, Mizoguchi A, Takedatsu H, Cario E, de Jong YP, Ooi CJ, Xavier RJ, Terhorst C, Podolsky DK, Bhan AK (2002) Role of tumor necrosis factor receptor 2 (TNFR2) in colonic epithelial hyperplasia and chronic intestinal inflammation in mice. Gastroenterology 122:134–144

    Article  PubMed  CAS  Google Scholar 

  58. Szlosarek P, Charles KA, Balkwill FR (2006) Tumour necrosis factor-alpha as a tumour promoter. Eur J Cancer 42:745–750

    Article  PubMed  CAS  Google Scholar 

  59. Yasui Y, Hosokawa M, Mikami N, Miyashita K, Tanaka T (2011) Dietary astaxanthin inhibits colitis and colitis-associated colon carcinogenesis in mice via modulation of the inflammatory cytokines. Chem Biol Interact 193:79–87

    Article  PubMed  CAS  Google Scholar 

  60. Yasui Y, Kim M, Oyama T, Tanaka T (2009) Colorectal carcinogenesis and suppression of tumor development by inhibition of enzymes and molecular targets. Curr Enzyme Inhibitio 5:1–26

    Article  CAS  Google Scholar 

  61. Kohno H, Takahashi M, Yasui Y, Suzuki R, Miyamoto S, Kamanaka Y, Naka M, Maruyama T, Wakabayashi K, Tanaka T (2007) A specific inducible nitric oxide synthase inhibitor, ONO-1714 attenuates inflammation-related large bowel carcinogenesis in male Apc(Min/+) mice. Int J Cancer 121:506–513

    Article  PubMed  CAS  Google Scholar 

  62. Dijkstra G, Moshage H, Jansen PL (2002) Blockade of NF-kappaB activation and donation of nitric oxide: new treatment options in inflammatory bowel disease? Scand J Gastroenterol Suppl: 37–41

  63. van der Woude CJ, Kleibeuker JH, Jansen PL, Moshage H (2004) Chronic inflammation, apoptosis and (pre-)malignant lesions in the gastro-intestinal tract. Apoptosis 9:123–130

    Article  PubMed  Google Scholar 

  64. Oshima H, Oshima M (2012) The inflammatory network in the gastrointestinal tumor microenvironment: lessons from mouse models. J Gastroenterol 47:97–106

    Article  PubMed  CAS  Google Scholar 

  65. Beck PL, Li Y, Wong J, Chen CW, Keenan CM, Sharkey KA, McCafferty DM (2007) Inducible nitric oxide synthase from bone marrow-derived cells plays a critical role in regulating colonic inflammation. Gastroenterology 132:1778–1790

    Article  PubMed  CAS  Google Scholar 

  66. Kobayashi Y (2010) The regulatory role of nitric oxide in proinflammatory cytokine expression during the induction and resolution of inflammation. J Leukoc Biol 88:1157–1162

    Article  PubMed  CAS  Google Scholar 

  67. Uronis JM, Muhlbauer M, Herfarth HH, Rubinas TC, Jones GS, Jobin C (2009) Modulation of the intestinal microbiota alters colitis-associated colorectal cancer susceptibility. PLoS One 4:e6026

    Article  PubMed  Google Scholar 

  68. Gerling M, Glauben R, Habermann JK, Kuhl AA, Loddenkemper C, Lehr HA, Zeitz M, Siegmund B (2011) Characterization of chromosomal instability in murine colitis-associated colorectal cancer. PLoS One 6:e22114

    Article  PubMed  CAS  Google Scholar 

  69. Guda K, Upender MB, Belinsky G, Flynn C, Nakanishi M, Marino JN, Ried T, Rosenberg DW (2004) Carcinogen-induced colon tumors in mice are chromosomally stable and are characterized by low-level microsatellite instability. Oncogene 23:3813–3821

    Article  PubMed  CAS  Google Scholar 

  70. Araujo SE, Bernardo WM, Habr-Gama A, Kiss DR, Cecconello I (2007) DNA ploidy status and prognosis in colorectal cancer: a meta-analysis of published data. Dis Colon Rectum 50:1800–1810

    Article  PubMed  Google Scholar 

  71. Gerling M, Meyer KF, Fuchs K, Igl BW, Fritzsche B, Ziegler A, Bader F, Kujath P, Schimmelpenning H, Bruch HP, Roblick UJ, Habermann JK (2010) High frequency of aneuploidy defines ulcerative colitis-associated carcinomas: a comparative prognostic study to sporadic colorectal carcinomas. Ann Surg

  72. Habermann J, Lenander C, Roblick UJ, Kruger S, Ludwig D, Alaiya A, Freitag S, Dumbgen L, Bruch HP, Stange E, Salo S, Tryggvason K, Auer G, Schimmelpenning H (2001) Ulcerative colitis and colorectal carcinoma: DNA-profile, laminin-5 gamma2 chain and cyclin A expression as early markers for risk assessment. Scand J Gastroenterol 36:751–758

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was partly supported by a Grant-in-Aid for the 2nd and 3rd Terms Comprehensive 10-year Strategy for Cancer Control, Cancer Prevention, from the Ministry of Health and Welfare of Japan; a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare of Japan; and a Grant-in-Aid (no. 13671986 and no. 23501324) from the Ministry of Education, Science, Sports, and Culture of Japan.

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  1. The Tohkai Cytopathology Institute: Cancer Research and Prevention (TCI-CaRP), 5-1-2 Minami-uzura, Gifu, 500-8285, Japan

    Takuji Tanaka

  2. Department of Tumor Pathology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan

    Takuji Tanaka

  3. Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan

    Hideki Ishikawa

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Correspondence to Takuji Tanaka.

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This article is a contribution to the special issue on Inflammation and Cancer - Guest Editor: Takuji Tanaka

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Tanaka, T., Ishikawa, H. Mast cells and inflammation-associated colorectal carcinogenesis. Semin Immunopathol 35, 245–254 (2013). https://doi.org/10.1007/s00281-012-0343-7

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