Helicobacter Infection: Infection, Immunity and the Progression of Lesions to Invasive Gastric Cancer

  • Evelyn Kurt-Jones
  • Jean Marie Houghton


Many malignancies that arise in areas of inflammation progress through a series of architectural changes prior to becoming frankly malignant. These changes are often times linked to the acquisition of distinct genetic defects, and predictably the appearance of distinctive lesions depends upon these changes. Gastric cancer arising from Helicobacter infection is associated with architectural changes similar to those seen in other inflammatory driven malignancies. Tissue progresses from chronic active inflammation to atrophy. Within atrophic mucosa, metaplastic cell types begin to appear, and with long standing disease, adenocarcinoma can result. While temporally associated, it is not clear if the progression of changes from “premalignant” to malignant are causally related. Here we describe the sequence of events leading to the mucosal changes seen, and explore the data which relates these changes to the eventual appearance of gastric adenocarcinoma.


Gastric Cancer Gastric Adenocarcinoma Intestinal Metaplasia Parietal Cell Gastric Epithelial Cell 
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.


  1. 1.
    Marshall BJ, Armstrong JA, McGechie DB et al (1985) Attempt to fulfill Koch’s postulates for pyloric Campylobacter. Med J Aust 142(8):436–439PubMedGoogle Scholar
  2. 2.
    Peek RM Jr, Miller GG, Tham KT et al (1995) Heightened inflammatory response and cytokine expression in vivo to cagA+ Helicobacter pylori strains. Lab Invest 73:760–770PubMedGoogle Scholar
  3. 3.
    Eaton KA, Mefford M, Thevenot T (2001) The role of T cell subsets and cytokines in the pathogenesis of Helicobacter pylori gastritis in mice. J Immunol 66:7456–7461Google Scholar
  4. 4.
    Wang TC, Goldenring JR, Dangler C et al (1998) Mice lacking secretory phospholipase A2 show altered apoptosis and differentiation with Helicobacter felis infection. Gastroenterology 14:675–689CrossRefGoogle Scholar
  5. 5.
    Sutton P, Kolesnikov T, Danon S et al (2000) Dominant nonresponsiveness to Helicobacter pylori infection is associated with production of interleukin 10 but not gamma interferon. Infect Immun 68:4802–4804PubMedCrossRefGoogle Scholar
  6. 6.
    Roth KA, Kapadia SB, Martin SM et al (1999) Cellular immune responses are essential for the development of Helicobacterelis-associated gastric pathology. J Immunol 63:1490–1497Google Scholar
  7. 7.
    Smythies LE, Waites KB, Lindsey JR et al (2000) Helicobacter pylori-induced mucosal inflammation is Th1 mediated and exacerbated in IL-4 but not IFN-gamma, gene-deficient mice. J Immunol 165:1022–1029PubMedGoogle Scholar
  8. 8.
    Chen SY, Liu TY, Shun CT et al (2004) Modification effects of GSTM1, GSTT1 and CYP2E1 polymorphisms on associations between raw salted food and incomplete intestinal metaplasia in a high-risk area of stomach cancer. Int J Cancer 108:606–612PubMedCrossRefGoogle Scholar
  9. 9.
    Fox JG, Dangler CA, Taylor NS et al (1999) High-salt diet induces gastric epithelial hyperplasia and parietal cell loss, and enhances Helicobacter pylori colonization in C57BL/6 mice. Cancer Res 59:4823–4828PubMedGoogle Scholar
  10. 10.
    El-Omar EM, Oien K, Murray LS et al (2000) Increased prevalence of precancerous changes in relatives of gastric cancer patients: critical role of H. pylori. Gastroenterology 118:22–30PubMedCrossRefGoogle Scholar
  11. 11.
    Enders KW, Chan WY, Auyeung A et al (2002) Increased frequency of pre-malignant gastric lesions in first degree relatives of stomach cancer patients [abstract]. Gastroenterology 122(Suppl 1):136Google Scholar
  12. 12.
    El-Omar EM, Carrington M, Chow WH et al (2000) Interleukin 1 polymorphisms associated with increased risk of gastric cancer. Nature 404:398–402PubMedCrossRefGoogle Scholar
  13. 13.
    El-Omar EM, Rabkin CS, Gammon MD et al (2003) Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology 124:1193–1201PubMedCrossRefGoogle Scholar
  14. 14.
  15. 15.
    Yamaoka Y, Alm R (2008) Helicobacter pylori: molecular genetics and cellular biology – Helicobacter pylori outer membrane proteins. Caister Academic Press, Linton, EnglandGoogle Scholar
  16. 16.
    Moran A, Trent S (2008) Helicobacter pylori: molecular genetics and cellular biology – Helicobacter pylori lipopolysaccharides and Lewis antigens. Caister Academic Press, Linton, EnglandGoogle Scholar
  17. 17.
    Rust M, Schweinitzer T, Josenhans C (2008) Helicobacter pylori: molecular genetics and cellular biology – Helicobacter flagella, motility and chemotaxis. Caister Academic Press, Linton, EnglandGoogle Scholar
  18. 18.
    Covacci A, Rappuoli R (2003) Helicobacter pylori: after the genomes, back to biology. J Exp Med 197:807–811PubMedCrossRefGoogle Scholar
  19. 19.
    Schmitz JM, Durham CG, Ho SB et al (2009) Gastric mucus alterations associated with murine Helicobacter infection. J Hisotochem Cytochem 57:457–467CrossRefGoogle Scholar
  20. 20.
    Guruge JL, Falk PG, Lorenz RG et al (1998) Epithelial attachment alters the outcome of Helicobacter pylori infection. Proc Natl Acad Sci U S A 95:3925–3930PubMedCrossRefGoogle Scholar
  21. 21.
    Peek RM Jr, Blaser MJ (2002) Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat Rev Cancer 2:28–37PubMedCrossRefGoogle Scholar
  22. 22.
    Suerbaum S, Michetti P (2002) Helicobacter pylori infection. N Engl J Med 347:1175–1186PubMedCrossRefGoogle Scholar
  23. 23.
    Dixon MF (2001) Prospects for intervention in gastric carcinogenesis: reversibility of gastric atrophy and intestinal metaplasia. Gut 49:2–4PubMedCrossRefGoogle Scholar
  24. 24.
    Lauren P (1965) The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. Acta Pathol Microbiol Scand 64:31–49PubMedGoogle Scholar
  25. 25.
    Fuchs CS, Mayer RJ (1995) Gastric carcinoma. N Engl J Med 333:32–41PubMedCrossRefGoogle Scholar
  26. 26.
    Correa P (1992) Human gastric carcinogenesis: a multistep and multifactorial process – first American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 52:6735–6740PubMedGoogle Scholar
  27. 27.
    Sipponen P, Marshall BJ (2000) Gastritis and gastric cancer. Western countries. Gastroenterol Clin North Am 29:579–592PubMedCrossRefGoogle Scholar
  28. 28.
    Mandell L, Moran AP, Cocchiarella A et al (2004) Intact Gram-negative Helicobacter hepaticus, Helicobacter pylori and Helicobacter felis bacteria activate innate immunity via Toll-like receptor-2 not Toll-like receptor 4. Infect Immun 72(11):6446–6454PubMedCrossRefGoogle Scholar
  29. 29.
    Smith MF Jr, Mitchell A, Li G et al (2003) Toll-like receptor (TLR) 2 and TLR5, but not TLR4, are required for Helicobacter pylori-induced NF-kappa B activation and chemokine expression by epithelial cells. J Biol Chem 278:32552–32560PubMedCrossRefGoogle Scholar
  30. 30.
    Chaouche-Drider N, Kaparakis M, Karrar A et al (2009) A commensal Helicobacter sp. Of the rodent intestinal flora activates TLR2 and NOD1 responses in epithelial cells. PLos One 4(4):e5396PubMedCrossRefGoogle Scholar
  31. 31.
    Rad R, Ballhorn W, Voland P et al (2009) Extracellular and intracellular pattern recognition receptors cooperate in the recognition of Helicobacter pylori. Gastroenterology 136: 2247–2257PubMedCrossRefGoogle Scholar
  32. 32.
    Moran AP, Lindner B, Walsh EJ (1997) Structural characterization of the lipid A component of Helicobacter pylori rough- and smooth-form lipopolysaccharides. J Bacteriol 179: 6453–6463PubMedGoogle Scholar
  33. 33.
    Muotiala A, Helander IM, Pyhala L et al (1992) Low biological activity of Helicobacter pylori lipopolysaccharide. Infect Immun 60:1714–1716PubMedGoogle Scholar
  34. 34.
    Bliss CM Jr, Golenbock DT, Keates S et al (1998) Helicobacter pylori lipopolysaccharide binds to CD14 and stimulates release of interleukin-8, epithelial neutrophil-activating peptide 78, and monocyte chemotactic protein 1 by human monocytes. Infect Immun 66:5357–5363PubMedGoogle Scholar
  35. 35.
    Martin M, Katz J, Vogel SN et al (2001) Differential induction of endotoxin tolerance by lipopolysaccharides derived from Porphyromonas gingivalis and Escherichia coli. J Immunol 167:5278–5285PubMedGoogle Scholar
  36. 36.
    Kawahara T, Kuwano Y, Teshima-Kondo S et al (2001) Helicobacter pylori lipopolysaccharide from type I, but not type II strains, stimulates apoptosis of cultured gastric mucosal cells. J Med Invest 48:167–174PubMedGoogle Scholar
  37. 37.
    Kawahara T, Teshima S, Oka A et al (2001) Type I Helicobacter pylori lipopolysaccharide stimulates toll-like receptor 4 and activates mitogen oxidase 1 in gastric pit cells. Infect Immun 69:4382–4389PubMedCrossRefGoogle Scholar
  38. 38.
    Lee SK, Stack A, Katzowitsch E et al (2003) Helicobacter pylori flagellins have very low intrinsic activity to stimulate human gastric epithelial cells via TLR5. Microbes Infect 5:45–56Google Scholar
  39. 39.
    Haas T, Metzger J, Schmitz F et al (2008) The DNA sugar backbone 2’ deoxyribose determines toll-like receptor 9 activation. Immunity 28:315–323PubMedCrossRefGoogle Scholar
  40. 40.
    Latz E, Verma A, Visintin A (2007) Ligand-induced conformational changes allosterically activate Toll-like receptor 9. Nat Immunol 8:772–779PubMedCrossRefGoogle Scholar
  41. 41.
    Raghavan S, Nystrom J, Fredriksson M et al (2003) Orally administered CpG oligodeoxynucleotide induces production of CXC and CC chemokines in the gastric mucosa and suppresses bacterial colonization in a mouse model of Helicobacter pylori infection. Infect Immun 71:7014–7022PubMedCrossRefGoogle Scholar
  42. 42.
    Ortega-Cava CF, Ishihara S, Rumi MA et al (2003) Strategic compartmentalization of Toll-like receptor 4 in the mouse gut. J Immunol 170:3977–3985PubMedGoogle Scholar
  43. 43.
    Chen ZT, Li SL, Cai EQ et al (2003) LPS induces pulmonary intravascular macrophages producing inflammatory mediators via activating NF-kappaB. J Cell Biochem 89: 1206–1214PubMedCrossRefGoogle Scholar
  44. 44.
    Rad R et al (2007) Toll-like receptor-dependent activation of antigen-presenting cells affects adaptive immunity to Helicobacter pylori. Gastroenterology 133:150–163PubMedCrossRefGoogle Scholar
  45. 45.
    Liu T, Matsuguchi T, Tsuboi N et al (2002) Differences in expression of toll-like receptors and their reactivities in dendritic cells in BALB/c and C57BL/6 mice. Infect Immun 70:6638–6645PubMedCrossRefGoogle Scholar
  46. 46.
    Visintin A, Mazzoni A, Spitzer JH et al (2001) Regulation of Toll-like receptors in human monocytes and dendritic cells. J Immunol 166:249–255PubMedGoogle Scholar
  47. 47.
    Schnare M, Barton GM, Holt AC et al (2001) Toll-like receptors control activation of adaptive immune responses. Nat Immunol 2:947–950PubMedCrossRefGoogle Scholar
  48. 48.
    Kuroda E, Yamashita U (2003) Mechanisms of enhanced macrophage-mediated prostaglandin E2 production and its suppressive role in Th1 activation in Th2-dominant BALB/c mice. J Immunol 170:757–764PubMedGoogle Scholar
  49. 49.
    Roth KA, Kapadia SB, Martin SM et al (1999) Cellular immune responses are essential for the development of Helicobacter felis-associated gastric pathology. J Immunol 163: 1490–1497PubMedGoogle Scholar
  50. 50.
    Cui G, Houghton J, Finkel N et al (2003) IFN-gamma infusion induces gastric atrophy, metaplasia and dysplasia in the absence of Helicobacter infection – a role for immune response in Helicobacter disease [abstract]. Gastroenterology 24:A19CrossRefGoogle Scholar
  51. 51.
    Fox JG, Beck P, Dangler CA et al (2000) Concurrent enteric helminth infection modulates inflammation and gastric immune responses and reduces helicobacter-induced gastric atrophy. Nat Med 6:536–542PubMedCrossRefGoogle Scholar
  52. 52.
    Stoicov C, Whary M, Rogers AB et al (2004) Co-infection modulates inflammatory response and clinical outcomes of Helicobacter felis and Toxoplasma gondii infection. J Immunol 173(5):3329–3336PubMedGoogle Scholar
  53. 53.
    Szabo SJ, Kim ST, Costa GL (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100:655–669PubMedCrossRefGoogle Scholar
  54. 54.
    Stoicov C, Fan X, Liu JH et al (2009) T-bet knockout prevents Helicobacter felis induced gastric cancer. J Immunol 183:642–649PubMedCrossRefGoogle Scholar
  55. 55.
    Macarthur M, Hold LG, El-Omar EM (2004) Inflammation and Cancer II. Role of chronic inflammation and cytokine gene polymorphisms in the pathogenesis of gastrointestinal malignancy. Am J Physiol Gastrointest Liver Physiol 286:515–520CrossRefGoogle Scholar
  56. 56.
    Wagner S, Beil W, Westermann J et al (1997) Regulation of gastric epithelial cell growth by Helicobacter pylori: evidence for a major role of apoptosis. Gastroenterology 113:1836–1847PubMedCrossRefGoogle Scholar
  57. 57.
    Jones NL, Shannon PT, Cutz E et al (1997) Increase in proliferation and apoptosis of gastric epithelial cells early in the natural history of Helicobacter pylori infection. Am J Pathol 151:1695–1703PubMedGoogle Scholar
  58. 58.
    Rudi J, Kuck D, Strand S et al (1998) Involvement of the CD95 (APO-1/Fas) receptor and ligand system in Helicobacter pylori-induced gastric epithelial apoptosis. J Clin Invest 102:1506–1514PubMedCrossRefGoogle Scholar
  59. 59.
    Houghton J, Korah RM, Kim CMR et al (1999) Apoptosis in Helicobacter pylori-associated gastric and duodenal ulcer disease is mediated via the Fas antigen pathway. Dig Dis Sci 44:465–478PubMedCrossRefGoogle Scholar
  60. 60.
    Houghton JM, Bloch LM, Goldstein M et al (2000) In vivo disruption of the Fas pathway abrogates gastric growth alterations secondary to Helicobacter infection. J Infect Dis 182:856–864PubMedCrossRefGoogle Scholar
  61. 61.
    Houghton J, Macera-Bloch LS, Harrison L et al (2000) Tumor necrosis factor alpha and interleukin 1beta up-regulate gastric mucosal Fas antigen expression in Helicobacter pylori infection. Infect Immun 68:1189–1195PubMedCrossRefGoogle Scholar
  62. 62.
    Li H, Stoicov C, Houghton J (2003) Fas antigen ligation signal for apoptosis or proliferation in gastric mucosal cells – the importance of receptor abundance [abstract]. Gastroenterology 124:A595CrossRefGoogle Scholar
  63. 63.
    Cai X, Stoicov C, Li H et al (2005) Overcoming Fas mediated apoptosis accelerates Helicobacter induced gastric cancer in the mouse. Cancer Res 65(23):10912–10919PubMedCrossRefGoogle Scholar
  64. 64.
    Jones NL, Day AS, Jennings H et al (2002) Enhanced disease severity in Helicobacter pylori-infected mice deficient in Fas signaling. Infect Immun 70:2591–2597PubMedCrossRefGoogle Scholar
  65. 65.
    Lee SH, Shin MS, Park WS et al (1999) Immunohistochemical localization of FAP-1, an inhibitor of Fas mediated apoptosis, in normal and neoplastic human tissues. APMIS 107:1101–1108PubMedCrossRefGoogle Scholar
  66. 66.
    Lee SH, Kim HS, Kim SY et al (2003) Increased expression of FLIP, an inhibitor of Fas mediated apoptosis, in stomach cancer. APMIS 111:309–314PubMedCrossRefGoogle Scholar
  67. 67.
    Li H, Stoicov C, Houghton J et al (2003) Hyperosmolarity shifts signaling pathway from apoptosis to proliferation by activation of p38 in gastric mucosal cell [abstract]. Gastroenterology 124:A460CrossRefGoogle Scholar
  68. 68.
    Stoicov C, Cai X, Li H et al (2005) Major histocompatibility complex class II inhibits Fas antigen-mediated gastric mucosal cell apoptosis through actin-dependent inhibition of receptor aggregation. Infect Immun 73(10):6311–6321PubMedCrossRefGoogle Scholar
  69. 69.
    Kim R, Emi M, Tanabe K et al (2004) The role of Fas ligand and transforming growth factor beta in tumor progression. Cancer 100:2281–2291PubMedCrossRefGoogle Scholar
  70. 70.
    Zheng HC, Sun JM, Wei ZL et al (2003) Expression of Fas ligand and caspase-3 contributes to formation of immune escape in gastric cancer. World J Gastroenterol 9:1415–1420PubMedGoogle Scholar
  71. 71.
    Bennett MW, O’connell J, O’sullivan GC, Roche D et al (1999) Expression of Fas ligand by human gastric adenocarcinomas: a potential mechanism of immune escape in stomach cancer. Gut 44:156–162PubMedCrossRefGoogle Scholar
  72. 72.
    Furuta S, Goto H, Niwa Y et al (2002) Interferon-gamma regulates apoptosis by releasing soluble tumor necrosis factor receptors in a gastric epithelial cell line. J Gastroenterol Hepatol 17:1283–1290PubMedCrossRefGoogle Scholar
  73. 73.
    Lehmann FS, Terracciano L, Carena I et al (2002) In situ correlation of cytokine secretion and apoptosis in Helicobacter pylori-associated gastritis. Am J Physiol Gastrointest Liver Physiol 283:481–488Google Scholar
  74. 74.
    Huber C, Zanner R, Pohlinger A et al (2002) Tumor necrosis factor-alpha effects on rat gastric enterochromaffin-like cells. Digestion 65:87–102PubMedCrossRefGoogle Scholar
  75. 75.
    Shimada M, Ina K, Kyokane K et al (2002) Upregulation of mucosal soluble Fas ligand and interferon-gamma may be involved in ulcerogenesis in patients with Helicobacter pylori-positive gastric ulcer. Scand J Gastroenterol 37:501–511PubMedCrossRefGoogle Scholar
  76. 76.
    Mannick JB, Hausladen A, Liu L et al (1999) Fas-induced caspase denitrosylation. Science 284:651–654PubMedCrossRefGoogle Scholar
  77. 77.
    Archimandritis A, Sougioultzis S, Foukas PG et al (2000) Expression of HLA-DR, costimulatory molecules B7-1, B7-2, intercellular adhesion molecule-1 (ICAM-1) and Fas ligand (FasL) on gastric epithelial cells in Helicobacter pylori gastritis; influence of H. pylori eradication. Clin Exp Immunol 119:464–471PubMedCrossRefGoogle Scholar
  78. 78.
    Fan X, Crowe SE, Behar S et al (1998) The effect of class II major histocompatibility complex expression on adherence of Helicobacter pylori and induction of apoptosis in gastric epithelial cells: a mechanism for T helper cell type 1-mediated damage. J Exp Med 187:1659–1669PubMedCrossRefGoogle Scholar
  79. 79.
    Fan X, Gunasena H, Cheng Z et al (2000) Helicobacter pylori urease binds to class II MHC on gastric epithelial cells and induces their apoptosis. J Immunol 165:1918–1924PubMedGoogle Scholar
  80. 80.
    Ye G, Barrera C, Fan X et al (1997) Expression of B7-1 and B7-2 costimulatory molecules by human gastric epithelial cells: potential role in CD4+ T cell activation during Helicobacter pylori infection. J Clin Invest 99:1628–1636PubMedCrossRefGoogle Scholar
  81. 81.
    Barrera C, Ye G, Espejo R et al (2001) Expression of cathepsins B, L, S, and D by gastric epithelial cells implicates them as antigen presenting cells in local immune responses. Hum Immunol 62:1081–1091PubMedCrossRefGoogle Scholar
  82. 82.
    Azuma T, Ito S, Sato F et al (1998) The role of the HLA-DQA1 gene in resistance to atrophic gastritis and gastric adenocarcinoma induced by Helicobacter pylori infection. Cancer 82:1013–1018PubMedCrossRefGoogle Scholar
  83. 83.
    Galmiche A, Rassow J, Doye A et al (2000) The N-terminal 34 kDa fragment of Helicobacter pylori vacuolating cytotoxin targets mitochondria and induces cytochrome c release. EMBO J 19:6361–6370PubMedCrossRefGoogle Scholar
  84. 84.
    Goldenring J, Nomura S (2006) Differentiation of the gastric mucosa III animal models of oxyntic atrophy and metaplasia. Am J Physiol Gastrointest Liver Physiol 291:G999–G1004PubMedCrossRefGoogle Scholar
  85. 85.
    Houghton J, Stoicov C, Nomura S et al (2004) Gastric cancer originating from bone marrow-derived cells. Science 306(5701):1568–1571PubMedCrossRefGoogle Scholar
  86. 86.
    Mimuro H, Suzuki T, Tanaka J et al (2002) Grb2 is a key mediator of Helicobacter pylori CagA protein activities. Mol Cell 10:745–755PubMedCrossRefGoogle Scholar
  87. 87.
    Tsutsumi R, Higashi H, Higuchi M et al (2003) Attenuation of Helicobacter pylori CagA × SHP-2 signaling by interaction between CagA and C-terminal Src kinase. J Biol Chem 278:3664–3670PubMedCrossRefGoogle Scholar
  88. 88.
    Moss SF, Calam J, Agarwal B et al (1996) Induction of gastric epithelial apoptosis by Helicobacter pylori. Gut 38:498–501PubMedCrossRefGoogle Scholar
  89. 89.
    Kohda K, Tanaka K, Aiba Y et al (1999) Role of apoptosis induced by Helicobacter pylori infection in the development of duodenal ulcer. Gut 44:456–462PubMedCrossRefGoogle Scholar
  90. 90.
    Peek RM Jr, Moss SF, Tham KT et al (1997) Helicobacter pylori cagA+ strains and dissociation of gastric epithelial cell proliferation from apoptosis. J Natl Cancer Inst 89:863–868PubMedCrossRefGoogle Scholar
  91. 91.
    Rokkas T, Ladas S, Liatsos C et al (1999) Relationship of Helicobacter pylori CagA status to gastric cell proliferation and apoptosis. Dig Dis Sci 44:487–493PubMedCrossRefGoogle Scholar
  92. 92.
    Li H, Cai X, Fan X et al (2008) Fas Ag-FasL coupling leads to ERK1/2-mediated proliferation of gastric mucosal cells. Am J Physiol Gastrointestintest Liver Physiol 294(1): G263–G275CrossRefGoogle Scholar
  93. 93.
    Kidd M, Hauso Ø, Drozdov I et al (2009) Delineation of the chemomechanosensory regulation of gastrin secretion using pure rodent G cells. Gastroenterology 137:231–241PubMedCrossRefGoogle Scholar
  94. 94.
    Schubert ML, Peura DA (2008) Control of gastric acid secretion in health and disease. Gastroenterology 134:1842–1860PubMedCrossRefGoogle Scholar
  95. 95.
    Wang TC, Dangler CA, Chen D et al (2000) Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer. Gastroenterology 118:36–47PubMedCrossRefGoogle Scholar
  96. 96.
    Fu S, Ramanujam KS, Wong A et al (1999) Increased expression and cellular localization of inducible nitric oxide synthase and cyclooxygenase 2 in Helicobacter pylori gastritis. Gastroenterology 116:1319–1329PubMedCrossRefGoogle Scholar
  97. 97.
    Baik SC, Youn HS, Chung MH et al (1996) Increased oxidative DNA damage in Helicobacter pylori-infected human gastric mucosa. Cancer Res 56:1279–1282PubMedGoogle Scholar
  98. 98.
    Williams GM, Weisburger JH (1983) Carcinogen risk assessment. Science 221:4605–4606Google Scholar
  99. 99.
    Pitot HC, Goldsworthy T, Moran S (1981) The natural history of carcinogenesis: implications of experimental carcinogenesis in the genesis of human cancer. J Supramol Struct Cell Biochem 17:133–146PubMedCrossRefGoogle Scholar
  100. 100.
    Kolaja KL, Stevenson DE, Walborg EF Jr et al (1996) Selective dieldrin promotion of hepatic focal lesions in mice. Carcinogenesis 17:1243–1250PubMedCrossRefGoogle Scholar
  101. 101.
    Rokkas T, Liatsos C, Petridou E et al (1999) Relationship of Helicobacter pylori CagA(+) status to gastric juice vitamin C levels. Eur J Clin Invest 29:56–62PubMedCrossRefGoogle Scholar
  102. 102.
    van den Brink GR, Hardwick JC, Tytgat GN et al (2001) Sonic hedgehog regulates gastric gland morphogenesis in man and mouse. Gastroenterology 121:317–328PubMedCrossRefGoogle Scholar
  103. 103.
    Beales ILP (2004) Gastrin and interleukin-1β stimulate growth factor secretion from cultured rabbit gastric parietal cells. Life Sci 75:2983–2995PubMedCrossRefGoogle Scholar
  104. 104.
    Stepan V, Ramamoorthy S, Nitsche H et al (2005) Regulation and function the sonic hedgehog signal transduction pathway in isolated gastric parietal cells. J Biol Chem 280:15700–15708PubMedCrossRefGoogle Scholar
  105. 105.
    Mashimo H, Wu DC, Podolsky DK et al (1996) Impaired defense of intestinal mucosa in mice lacking intestinal trefoil factor. Science 274:262–265PubMedCrossRefGoogle Scholar
  106. 106.
    Farrell JJ, Taupin D, Koh TJ et al (2002) TFF2/SP-deficient mice show decreased gastric proliferation, increased acid secretion, and increased susceptibility to NSAID injury. J Clin Invest 109:193–204PubMedGoogle Scholar
  107. 107.
    Maesawa C, Tamura G, Suzuki Y et al (1995) The sequential accumulation of genetic alterations characteristic of the colorectal adenoma-carcinoma sequence does not occur between gastric adenoma and adenocarcinoma. J Pathol 176:249–258PubMedCrossRefGoogle Scholar
  108. 108.
    Kim JH, Takahashi T, Chiba I et al (1991) Occurrence of p53 gene abnormalities in gastric carcinoma tumors and cell lines. J Natl Cancer Inst 83:938–943PubMedCrossRefGoogle Scholar
  109. 109.
    Victor T, Du Toit R, Jordaan AM et al (1990) No evidence for point mutations in codons 12, 13, and 61 of the ras gene in a high-incidence area for esophageal and gastric cancers. Cancer Res 50:4911–4914PubMedGoogle Scholar
  110. 110.
    Stemmermann G, Heffelfinger SC, Noffsinger A et al (1994) The molecular biology of esophageal and gastric cancer and their precursors: oncogenes, tumor suppressor genes, and growth factors. Hum Pathol 25:968–981PubMedCrossRefGoogle Scholar
  111. 111.
    Farinati F, Cardin F, Di Mario F et al (1987) Early and advanced gastric cancer during follow-up of apparently benign gastric ulcer: significance of the presence of epithelial dysplasia. J Surg Oncol 36:263–267PubMedCrossRefGoogle Scholar
  112. 112.
    Park WS, Oh RR, Park JY et al (2000) Somatic mutations of the trefoil factor family 1 gene in gastric cancer. Gastroenterology 119:691–698PubMedCrossRefGoogle Scholar
  113. 113.
    Li QL, Ito K, Sakakura C et al (2002) Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell 109:113–124PubMedCrossRefGoogle Scholar
  114. 114.
    Karam SM, Tomasetto C, Rio MC (2008) Amplification and invasiveness of epithelial progenitors during gastric carcinogenesis in trefoil factor 1 knockout mice. Cell Proliferation 41(6):923–935PubMedCrossRefGoogle Scholar
  115. 115.
    Ito K, Liu Q, Salto-Tellez M et al (2005) RUNX3 a novel tumor suppressor is frequently inactivated in gastric cancer by protein mislocalization. Cancer Res 65:7743–7750PubMedCrossRefGoogle Scholar
  116. 116.
    Yuasa Y (2003) Control of gut differentiation and intestinal-type gastric carcinogenesis. Nat Rev Cancer 3:592–600PubMedCrossRefGoogle Scholar
  117. 117.
    Silberg DG, Sullivan J, Kang E et al (2002) Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice. Gastroenterology 122:689–696PubMedCrossRefGoogle Scholar
  118. 118.
    Rawat VP, Cusan M, Deshpande A et al (2004) Ectopic expression of the homeobox gene Cdx2 is the transforming event in a mouse model of t(12;13)(p13;q12) acute myeloid leukemia. Proc Natl Acad Sci U S A. doi:10.1073/pnas.0305555101Google Scholar
  119. 119.
    Scholl C, Bansal D, Döhner K et al (2007) The homeobox gene CDX2 is aberrantly expressed in most cases of acute myeloid leukemia and promotes leukemogenesis. J Clin Invest. doi:10.1172/JCI30182PubMedGoogle Scholar
  120. 120.
    Hansson LE, Nyren O, Hsing AW et al (1996) The risk of stomach cancer in patients with gastric or duodenal ulcer disease. N Engl J Med 335:242PubMedCrossRefGoogle Scholar
  121. 121.
    Dixon MF, Genta RM, Yardley JH et al (1994) Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis. Am J Surg Pathol 20:1161–1181CrossRefGoogle Scholar
  122. 122.
    Cai X, Carlson J, Stoicov C et al (2005) Helicobacter felis eradication restores normal architecture and inhibits gastric cancer progression in C57BL/6 mice. Gastroenterology 128:1937–1952PubMedCrossRefGoogle Scholar
  123. 123.
    Matsukura N, Suzuki K, Kawachi T et al (1980) Distribution of marker enzymes and mucin in intestinal metaplasia in human stomach and relation to complete and incomplete types of intestinal metaplasia to minute gastric carcinomas. J Natl Cancer Inst 65:231–240PubMedGoogle Scholar
  124. 124.
    Reis CA, David L, Correa P et al (1999) Intestinal metaplasia of human stomach displays distinct patterns of mucin (MUC1, MUC2, MUC5AC, and MUC6) expression. Cancer Res 59:1003–1007PubMedGoogle Scholar
  125. 125.
    de Vries AC, Haringsma J, Kuipers EJ (2007) The detection, surveillance and treatment of premalignant gastric lesions related to Helicobacter pylori infection. Helicobacter 12:1–15PubMedGoogle Scholar
  126. 126.
    Uemura N, Okamoto S, Yamamoto S et al (2001) Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 345:784–789PubMedCrossRefGoogle Scholar
  127. 127.
    Kato M, Asaka M, Nakamura T et al (2006) Helicobacter pylori eradication prevents the development of gastric cancer - results of a long-term retrospective study in Japan. Aliment Pharmacol Ther 24:203–206CrossRefGoogle Scholar
  128. 128.
    Ley C, Mohar A, Guarner J et al (2004) Helicobacter pylori eradication and gastric preneoplastic conditions: a randomized, double-blind, placebo-controlled trial. Cancer Epidemiol Biomarkers Prev 13:4–10PubMedCrossRefGoogle Scholar
  129. 129.
    Wong BC, Lam SK, Wong WM, China Gastric Cancer Study Group et al (2004) Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA 291:187–194PubMedCrossRefGoogle Scholar
  130. 130.
    Leung WK, Lin SR, Ching JY et al (2004) Factors predicting progression of gastric intestinal metaplasia: results of a randomised trial on Helicobacter pylori eradication. Gut 53:1244–1249PubMedCrossRefGoogle Scholar
  131. 131.
    You WC, Brown LM, Zhang L et al (2006) Randomized double-blind factorial trial of three treatments to reduce the prevalence of precancerous gastric lesions. J Natl Cancer Inst 98:974–983PubMedCrossRefGoogle Scholar
  132. 132.
    Yamaguchi H, Goldenring JR, Kaminishi M et al (2002) Association of spasmolytic polypeptide − expressing metaplasia with carcinogen administration and oxyntic atrophy in rats. Lab Invest 82:1045–1052PubMedGoogle Scholar
  133. 133.
    Hamilton SR, Aaltonen LA (2000) World Health Organization Classification of Tumours. Pathology and genetics. Tumours of the digestive system. IARC, Lyon, FranceGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Cancer BiologyUniversity of Massachusetts Medical SchoolWorcesterUSA

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