Skip to main content

Advertisement

SpringerLink
Log in

The inflammatory network in the gastrointestinal tumor microenvironment: lessons from mouse models

  • Review
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Accumulating evidence has indicated that inflammatory responses are important for cancer development. Epidemiological studies have shown that regular use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of colon cancer development. Subsequently, mouse genetic studies have shown that cyclooxygenase (COX)-2, one of the target molecules of NSAIDs, and its downstream product, prostaglandin E2 (PGE2), play an important role in gastrointestinal tumorigenesis. Bacterial infection stimulates the Toll-like receptor (TLR)/MyD88 pathway in tumor tissues, which leads to the induction of COX-2 in stromal cells, including macrophages. Induction of the COX-2/PGE2 pathway in tumor stroma is important for the development and maintenance of an inflammatory microenvironment in gastrointestinal tumors. In such a microenvironment, tumor-associated macrophages express proinflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-6, and these cytokines, respectively, activate the nuclear factor (NF)-κB and Stat3 transcription factors in epithelial cells, as well as in stromal cells. Recent mouse studies have uncovered the role of such an inflammatory network in the promotion of gastrointestinal tumor development. Genetically engineered and chemically induced mouse tumor models which mimic sporadic or inflammation-associated tumorigenesis were used in these studies. In this review article, we focus on mouse genetic studies using these tumor models, which have contributed to the elucidation of the molecular mechanisms associated with the inflammatory network in gastrointestinal tumors, and we also discuss the role of each pathway in cancer development. The involvement of immune cells such as macrophages, mast cells, and regulatory T cells in tumor promotion is also discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Kuper H, Adami HO, Trichopoulos D. Infections as a major preventable cause of human cancer. J Intern Med. 2000;248:171–83.

    Article  PubMed  CAS  Google Scholar 

  2. Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer. 2006;118:3030–44.

    Article  PubMed  CAS  Google Scholar 

  3. Aggarwal BB, Vijayalekshmi RV, Sung B. Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res. 2009;15:425–30.

    Article  PubMed  CAS  Google Scholar 

  4. Takahashi H, Ogata H, Nishigaki R, Broide DH, Karin M. Tobacco smoke promotes lung tumorigenesis by triggering IKKβ-and JNK1-dependent inflammation. Cancer Cell. 2010;17:89–97.

    Article  PubMed  CAS  Google Scholar 

  5. Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140:197–208.

    Article  PubMed  CAS  Google Scholar 

  6. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7.

    Article  PubMed  CAS  Google Scholar 

  7. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44.

    Article  PubMed  CAS  Google Scholar 

  8. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99.

    Article  PubMed  CAS  Google Scholar 

  9. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  PubMed  CAS  Google Scholar 

  10. Thun MJ, Namboodiri MM, CW Jr Heath. Aspirin use and reduced risk of fatal colon cancer. N Engl J Med. 1991;325:1593–6.

    Article  PubMed  CAS  Google Scholar 

  11. Giovannucci E, Egan KM, Hunter DJ, Stampfer MJ, Colditz GA, Willett WC, Speizer FE. Aspirin and the risk of colorectal cancer in women. N Engl J Med. 1995;333:609–14.

    Article  PubMed  CAS  Google Scholar 

  12. Wang D, DuBois RN. Eicosanoids and cancer. Nat Rev Cancer. 2010;10:181–93.

    Article  PubMed  CAS  Google Scholar 

  13. Wang D, DuBois RN. The role of COX-2 in intestinal inflammation and colorectal cancer. Oncogene. 2010;29:781–8.

    Article  PubMed  CAS  Google Scholar 

  14. Oshima M, Oshima H, Kitagawa K, Kobayashi M, Itakura C, Taketo M. Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Apc gene. Proc Natl Acad Sci USA. 1995;92:4482–6.

    Article  PubMed  CAS  Google Scholar 

  15. Moser AR, Pitot HC, Dove WF. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science. 1989;247:322–4.

    Article  Google Scholar 

  16. Miyoshi Y, Nagase H, Ando H, Horii A, Ichii S, Nakatsuru S, et al. Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet. 1992;1:229–33.

    Article  PubMed  CAS  Google Scholar 

  17. Powell SM, Zilz N, Beazer-Barclay Y, Bryan TM, Hamilton SR, Thibodeau SN, et al. APC mutations occur early during colorectal tumorigenesis. Nature. 1992;359:235–7.

    Article  PubMed  CAS  Google Scholar 

  18. Sparks AB, Morin PJ, Vogelstein B, Kinzler KW. Mutational analysis of the APC/β-catenine/TCF pathway in colorectal cancer. Cancer Sci. 1998;58:1130–4.

    CAS  Google Scholar 

  19. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001;48:526–35.

    Article  PubMed  CAS  Google Scholar 

  20. van Hogezand RA, Eichhorn RF, Choudry A, Veenendaal RA, Lamers BHW. Malignancies in inflammatory bowel disease: fact or fiction? Scand J Gastroenterol. 2002;235:48–53.

    Article  Google Scholar 

  21. Tanaka T, Kohno H, Suzuki R, Yamada Y, Sugie S, Mori H. A novel inflammation-related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate. Cancer Sci. 2003;94:965–73.

    Article  PubMed  CAS  Google Scholar 

  22. Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y, Nakaya R. Novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology. 1990;98:694–702.

    PubMed  CAS  Google Scholar 

  23. Erdman SE, Poutahidis T, Tomczak M, Rogers AB, Cormier K, Plank B, et al. CD4+ CD25+ regulatory T lymphocytes inhibit microbially induced colon cancer in Rag2-deficient mice. Am J Pathol. 2003;162:691–702.

    Article  PubMed  CAS  Google Scholar 

  24. Erdman SE, Rao VP, Poutahidis T, Ihrig MM, Ge Z, Feng Y, et al. CD4+ CD25+ regulatory T lymphocytes require interleukin 10 to interrupt colon carcinogenesis in mice. Cancer Res. 2003;63:6042–50.

    PubMed  CAS  Google Scholar 

  25. Clements WM, Wang J, Saranaik A, Kim OJ, MacDonald J, Fenoglio-Preiser C, et al. β-Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Cancer Res. 2002;62:3503–6.

    PubMed  CAS  Google Scholar 

  26. Oshima H, Matusnaga A, Fujimura T, Tsukamoto T, Taketo MM, Oshima M. Carcinogenesis in mouse stomach by simultaneous activation of the Wnt signaling and prostaglandin E2 pathway. Gastroenterology. 2006;131:1086–95.

    Article  PubMed  CAS  Google Scholar 

  27. Correa P. Helicobactor pylori infection and gastric cancer. Cancer Epidemiol Biomark Prev. 2003;12:238s–41s.

    Google Scholar 

  28. Fu S, Ramanujam KS, Wong A, Fantry GT, Drachenberg CB, James SP, et al. Increased expression and cyclooxygenase 2 in Helicobactor pylori gastritis. Gastroenterology. 1999;116:1319–29.

    Article  PubMed  CAS  Google Scholar 

  29. Oshima H, Oshima M, Inaba K, Taketo MM. Hyperplastic gastric tumors induced by activated macrophages in COX-2/mPGES-1 transgenic mice. EMBO J. 2004;23:1669–78.

    Article  PubMed  CAS  Google Scholar 

  30. Oshima H, Oguma K, Du YC, Oshima M. Prostaglandin E2, Wnt, and BMP in gastric tumor mouse models. Cancer Sci. 2009;100:1779–85.

    Article  PubMed  CAS  Google Scholar 

  31. Oshima H, Oshima M. Mouse models of gastric tumors: Wnt activation and PG E2 induction. Pathol Int. 2010;60:599–607.

    Article  PubMed  CAS  Google Scholar 

  32. Giardiello FM, Hamilton SR, Krush AJ, Piantadosi S, Hylind LM, Celano P, et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med. 1993;328:1313–6.

    Article  PubMed  CAS  Google Scholar 

  33. Oshima M, Taketo MM. COX selectivity and animal models for colon cancer. Curr Pharm Des. 2002;8:1021–34.

    Article  PubMed  CAS  Google Scholar 

  34. Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B, Kwong E, et al. Suppression of intestinal polyposis in Apc Δ716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell. 1996;87:803–9.

    Article  PubMed  CAS  Google Scholar 

  35. Chulada PC, Thompson MB, Mahler JF, Doyle CM, Gaul BW, Lee C, et al. Genetic disruption of Ptgs-1, as well as of Ptgs-2, reduces intestinal tumorigenesis in Min mice. Cancer Res. 2000;60:4705–8.

    PubMed  CAS  Google Scholar 

  36. Myung S, Rerko RM, Yan M, Platzer P, Guda K, Dotson A, et al. 15-Hydroxyprostaglandin dehydrogenase is an in vivo suppressor of colon tumorigenesis. Proc Natl Acad Sci USA. 2006;103:12098–102.

    Article  PubMed  CAS  Google Scholar 

  37. Al-Salihi MA, Pearman AT, Doan T, Reichert EC, Rosenberg DW, Prescott SM, et al. Transgenic expression of cyclooxygenase-2 in mouse intestine epithelium is insufficient to initiate tumorigenesis but promotes tumor progression. Cancer Lett. 2009;273:225–32.

    Article  PubMed  CAS  Google Scholar 

  38. Sonoshita M, Takaku K, Sasaki N, Sugimoto Y, Ushikubi F, Natumiya S, et al. Acceleration of intestinal polyposis through prostaglandin receptor EP2 in Apc Δ716 knockout mice. Nat Med. 2001;7:1048–51.

    Article  PubMed  CAS  Google Scholar 

  39. Seno H, Oshima M, Ishikawa TO, Oshima H, Takaku K, Chiba T, et al. Cyclooxygenase 2- and prostaglandin E2 receptor EP2-dependent angiogenesis in Apc Δ716 mouse intestinal polyps. Cancer Res. 2002;62:506–11.

    PubMed  CAS  Google Scholar 

  40. Wang D, Wang H, Shi Q, Katkuri S, Walhi W, Desvergne B, et al. Prostaglandin E2 promotes colorectal adenoma growth via transactivation of the nuclear peroxisome proliferators-activated receptor δ. Cancer Cell. 2004;6:285–95.

    Article  PubMed  CAS  Google Scholar 

  41. Castellone MD, Teramoto H, Williams BO, Druey KM, Gutkind JS. Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-β-catenin signaling axis. Science. 2005;310:1504–10.

    Article  PubMed  CAS  Google Scholar 

  42. van Rees BP, Sivula A, Thoren S, Yokozaki H, Jalobsson PJ, Offerhaus GJ, Ristimaki A. Expression of microsomal prostaglandin E synthase-1 in intestinal gastric adenocarcinoma and in gastric cancer cell lines. Int J Cancer. 2003;107:551–6.

    Article  PubMed  Google Scholar 

  43. Yoshimatsu K, Altorki NK, Golijanin D, Zhang F, Jakobsson PJ, Dannenberg AJ, Subbaramaiah K. Inducible prostaglandin E synthase is overexpressed in non-small cell lung cancer. Clin Cancer Res. 2001;7:2669–74.

    PubMed  CAS  Google Scholar 

  44. Nakanishi M, Montrose DC, Clark P, Nambiar PR, Belinsky GS, Claffey KP, et al. Genetic deletion of mPGES-1 suppresses intestinal tumorigenesis. Cancer Res. 2008;68:3251–9.

    Article  PubMed  CAS  Google Scholar 

  45. Nakanishi M, Menoret A, Tanaka T, Miyamoto S, Montrose DC, Vella AT, Rosenberg DW. Selective PGE2 suppression inhibits colon carcinogenesis and modifies local mucosal immunity. Cancer Prev Res. 2011;4:1198–208.

    Article  CAS  Google Scholar 

  46. Ristimaki A, Honkanen N, Jankaka H, Sipponen P, Harkonen M. Expression of cyclooxygenase-2 in human gastric carcinoma. Cancer Res. 1997;57:1276–80.

    PubMed  CAS  Google Scholar 

  47. Saukkonen K, Rintahaka J, Sivula A, Buskens CJ, van Rees BP, Rio MC, et al. Cyclooxygenase-2 and gastric carcinogenesis. APMIS. 2003;111:915–25.

    Article  PubMed  CAS  Google Scholar 

  48. Oshima H, Popivanova BK, Oguma K, Kong D, Ishikawa TO, Oshima M. Activation of epidermal growth factor receptor signaling by the prostaglandin E2 receptor EP4 pathway during gastric tumorigenesis. Cancer Sci. 2011;102:713–9.

    Article  PubMed  CAS  Google Scholar 

  49. Oshima H, Hioki K, Popivanova BK, Oguma K, van Rooijen N, Ishikawa TO, Oshima M. Prostaglandin E2 signaling and bacterial infection recruit tumor-promoting macrophages to mouse gastric tumors. Gastroenterology. 2011;140:596–607.

    Article  PubMed  CAS  Google Scholar 

  50. Sonoshita M, Takaku K, Oshima M, Sugihara K, Taketo MM. Cyclooxygenase-2 expression in fibroblasts and endothelial cells of intestinal polyps. Cancer Res. 2002;62:6846–9.

    PubMed  CAS  Google Scholar 

  51. Hull MA, Booth JK, Tisbury A, Scott N, Bonifer C, Markham AF, Coletta PL. Cyclooxygenase 2 is up-regulated and localized to macrophages in the intestine of Min mice. Br J Cancer. 1999;79:1399–405.

    Article  PubMed  CAS  Google Scholar 

  52. Takeda H, Sonoshita M, Oshima H, Sugihara K, Chulada PC, Langenbach R, et al. Cooperation of cyclooxygenase 1 and cyclooxygenase 2 in intestinal polyposis. Cancer Res. 2003;63:4872–7.

    PubMed  CAS  Google Scholar 

  53. Miyoshi H, Nakau M, Ishikawa T, Seldin FM, Oshima M, Taketo MM. Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice. Cancer Res. 2002;62:2261–6.

    PubMed  CAS  Google Scholar 

  54. Tamai Y, Nakajima R, Ishikawa T, Takaku K, Seldin MF, Taketo MM. Colonic hamartoma development by anomalous duplication in Cdx2 knockout mice. Cancer Res. 1999;59:2965–70.

    PubMed  CAS  Google Scholar 

  55. Kitamura T, Kometani K, Hashida H, Matsunaga A, Miyoshi H, Hosogi H, et al. SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion. Nat Genet. 2007;39:467–75.

    Article  PubMed  CAS  Google Scholar 

  56. Takeda H, Miyoshi H, Tamai Y, Oshima M, Taketo MM. Simultaneous expression of COX-2 and mPGES-1 in mouse gastrointestinal hamartomas. Br J Cancer. 2004;90:701–4.

    Article  PubMed  CAS  Google Scholar 

  57. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 2004;118:229–41.

    Article  PubMed  CAS  Google Scholar 

  58. Pull SL, Doherty JM, Mills JC, Gordon JI, Stappenbeck TS. Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc Natl Acad Sci USA. 2005;102:99–104.

    Article  PubMed  CAS  Google Scholar 

  59. Fukuta M, Chen A, Klepper A, Krishnareddy S, Vamadevan AS, Thomas LS, et al. Cox-2 is regulated by toll like receptor-4 (TLR-4) signaling: role in proliferation and apoptosis in the intestine. Gastroenterology. 2006;131:862–77.

    Article  Google Scholar 

  60. Fukuta M, Chen A, Vamadevan AS, Cohen J, Breglio K, Krishnareddy S, et al. Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology. 2007;133:1869–81.

    Article  Google Scholar 

  61. Hernandez Y, Sotolongo J, Breglio K, Conduah D, Chen A, Xu R, et al. The role of prostaglandin E2 (PGE2) in toll-like receptor 4 (TLR4)-mediated colitis-associated neoplasia. BMC Gastroenterol. 2010;10:82.

    Google Scholar 

  62. Fukata M, Hernandez Y, Conduah D, Cohen J, Chen A, Breglio K, et al. Innate immune signaling by toll-like receptor-4 (TLR-4) shapes the inflammatory microenvironment in colitis-associated tumors. Inflamm Bowel Dis. 2009;15:997–1006.

    Article  PubMed  Google Scholar 

  63. Rakoff-Nahoum S, Medzhitov R. Regulation of spontaneous intestinal tumorigenesis through the adaptor protein Myd88. Science. 2007;317:124–7.

    Article  PubMed  CAS  Google Scholar 

  64. Lee SH, Hu LL, Gonzalez-Navajas J, Seo GS, Shen C, Brick J, et al. ERK activation drives intestinal tumorigenesis in Apc Min/+ mice. Nat Med. 2010;16:665–70.

    Article  PubMed  CAS  Google Scholar 

  65. Rakoff-Nahoum S, Medzhitov R. Toll-like receptors and cancer. Nat Rev Cancer. 2009;9:57–63.

    Article  PubMed  CAS  Google Scholar 

  66. Reuter BK, Asfaha S, Buret A, Sharkey KA, Wallace JL. Exacerbation of inflammation-associated colonic injury in rat through inhibition of cyclooxygenase-2. J Clin Invest. 1996;98:2076–85.

    Article  PubMed  CAS  Google Scholar 

  67. Morteau O, Morham SG, Sellon R, Dieleman LA, Langenbach R, Smithies O, et al. Impaired mucosal defense to acute colonic injury in mice lacking cyclooxygenase-1 or cyclooxygenase-2. J Clin Invest. 2000;105:469–78.

    Article  PubMed  CAS  Google Scholar 

  68. Ishikawa TO, Herschman HR. Tumor formation in a mouse model of colitis-associated colon cancer does not require COX-1 or COX-2 expression. Carcinogenesis. 2010;31:729–36.

    Article  PubMed  CAS  Google Scholar 

  69. Ishikawa TO, Oshima M, Herschman HR. Cox-2 deletion in myeloid and endothelial cells, but not in epithelial cells, exacerbates murine colitis. Carcinogenesis. 2011;32:417–26.

    Article  PubMed  CAS  Google Scholar 

  70. Balkwill F. Tumor necrosis factor and cancer. Nat Rev Cancer. 2009;9:361–71.

    Article  PubMed  CAS  Google Scholar 

  71. Karin M, Greten FR. NF-κB: Linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005;5:749–59.

    Article  PubMed  CAS  Google Scholar 

  72. Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, et al. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 2004;118:285–96.

    Article  PubMed  CAS  Google Scholar 

  73. Popivanova BK, Kitamura K, Wu Y, Kondo T, Kagaya T, Kaneko S, et al. Blocking TNF-α in mice reduces colorectal carcinogenesis associated with chronic colitis. 2008;118:560–70.

  74. Popivanova BK, Kostadinova FI, Furuichi K, Shamekh MM, Kondo T, Wada T, et al. Blocking of a chemokine, CCL2, reduces chronic colitis-associated carcinogenesis in mice. Cancer Res. 2009;69:7884–92.

    Article  PubMed  CAS  Google Scholar 

  75. Matsushima K, Larsen CG, DuBois GC, Oppenheim JJ. Purification and characterization of a novel monocyte chemotactic and activating factor produced by a human myelomonocytic cell line. J Exp Med. 1989;169:1485–90.

    Article  PubMed  CAS  Google Scholar 

  76. Gounaris E, Erdman SE, Restaino C, Gurish MF, Friend DS, Gounairi F, et al. Mast cells are an essential hematopoietic component for polyp development. Proc Natl Acad Sci USA. 2007;104:19977–82.

    Article  PubMed  CAS  Google Scholar 

  77. Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, et al. NF-κB functions as a tumor promoter in inflammation-associated cancer. Nature. 2004;431:461–6.

    Article  PubMed  CAS  Google Scholar 

  78. Oshima M, Oshima H, Matsunaga A, Taketo MM. Hyperplastic gastric tumors with spasmolytic polypeptide-expressing metaplasia caused by tumor necrosis factor-α-dependent inflammation in cyclooxygenase-2/microsomal prostaglandin E synthase-1 transgenic mice. Cancer Res. 2005;65:9147–51.

    Article  PubMed  CAS  Google Scholar 

  79. Kishimoto T. Interleukin-6: from basic science to medicine—40 years in immunology. Annu Rev Immunol. 2005;23:1–21.

    Article  PubMed  CAS  Google Scholar 

  80. Heikkila K, Ebrahim S, Lawlor DA. Systematic review of the association between circulating interleukin-6 (IL-6) and cancer. Eur J Cancer. 2008;44:937–45.

    Article  PubMed  CAS  Google Scholar 

  81. Bollrath J, Phesse TJ, von Burstin VA, Putoczki T, Bennecke M, Bateman T, et al. gp130-mediated STAT3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell. 2009;15:91–102.

    Article  PubMed  CAS  Google Scholar 

  82. Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, et al. IL-6 and STAT3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 2009;15:103–13.

    Article  PubMed  CAS  Google Scholar 

  83. He G, Karin M. NF-κB and STAT3-key players in liver inflammation and cancer. Cell Res. 2011;21:159–68.

    Article  PubMed  CAS  Google Scholar 

  84. Li N, Grivennikov SI, Karin M. The unholy trinity: inflammation, cytokines, and STAT3 shape the cancer microenvironment. Cancer Cell. 2011;19:429–31.

    Article  PubMed  CAS  Google Scholar 

  85. Tebbutt NC, Giraud AS, Inglese M, Jennkins B, Waring P, Clay FJ, et al. Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nat Med. 2002;8:1089–97.

    Article  PubMed  CAS  Google Scholar 

  86. Jenkins BJ, Grail D, Nheu T, Najdovska M, Wang B, Waring P, et al. Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-β signaling. Nat Med. 2005;11:845–52.

    Article  PubMed  CAS  Google Scholar 

  87. Judd LM, Bredin K, Kalantzis A, Jenkins BJ, Ernst M, Giraud AS. STAT3 activation regulates growth, inflammation, and vascularization in a mouse model of gastric tumorigenesis. Gastroenterology. 2006;131:1073–85.

    Article  PubMed  CAS  Google Scholar 

  88. Howlett M, Giraud AS, Lescesen H, Jackson CB, Kalantzis A, van Driel IR, et al. The interleukin-6 family cytokine interleukin-11 regulates homeostatic epithelial cell turnover and promotes gastric tumor development. Gastroenterology. 2009;136:976–77.

    Google Scholar 

  89. Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141:39–51.

    Article  PubMed  CAS  Google Scholar 

  90. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010;11:889–85

    Google Scholar 

  91. DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D, Kolhatkar N, et al. CD4+ T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell. 2009;16:91–102.

    Article  PubMed  CAS  Google Scholar 

  92. Nakanishi Y, Nakatsuji M, Seno H, Ishizu S, Akitake-kawano R, Kanda K, et al. COX-2 inhibition alters the phenotype of tumor-associated macrophages from M2 to M1 in Apc Min/+ mouse polyps. Carcinogenesis. 2011;32:1333–9.

    Article  PubMed  CAS  Google Scholar 

  93. Oguma K, Oshima H, Aoki M, Uchio R, Naka K, Nakamura S, et al. Activated macrophages promote Wnt signaling through tumour necrosis factor-a in gastric tumour cells. EMBO J. 2008;27:1671–81.

    Article  PubMed  CAS  Google Scholar 

  94. Erdman SE, Sohn JJ, Rao VP, Nambiar PR, Ge Z, Fox JG, Schauer DB. CD4+CD25+ regulatory lymphocytes induce regression of intestinal tumors in Apc Min/+ mice. Cancer Res. 2005;65:3998–4004.

    Article  PubMed  CAS  Google Scholar 

  95. Gounaris E, Blatner NR, Dennis K, Magnusson F, Gurish MF, Strom TB, et al. T-regulatory cells shift from a protective anti-inflammatory to a cancer-promoting proinflammatory phenotype in polyposis. Cancer Res. 2009;69:5490–6.

    Article  PubMed  CAS  Google Scholar 

  96. Colombo MP, Piconese S. Polyps wrap mast cells and Treg within tumorigenic tentacles. Cancer Res. 2009;69:5619–22.

    Article  PubMed  CAS  Google Scholar 

  97. Chae WJ, Gibson TF, Zelterman D, Hao L, Henegariu O, Bothwell ALM. Ablation of IL-17A abrogates progression of spontaneous intestinal tumorigenesis. Proc Natl Acad Sci USA. 2010;107:5540–4.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Manami Watanabe for her helpful work with the papers of the Gan mouse studies.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Division of Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan

    Hiroko Oshima & Masanobu Oshima

Authors
  1. Hiroko Oshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masanobu Oshima
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masanobu Oshima.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Oshima, H., Oshima, M. The inflammatory network in the gastrointestinal tumor microenvironment: lessons from mouse models. J Gastroenterol 47, 97–106 (2012). https://doi.org/10.1007/s00535-011-0523-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-011-0523-6

Keywords

Search

Navigation