Atrophy and Altered Mesenchymal—Epithelial Signaling Preceding Gastric Cancer

  • Juanita L. Merchant
  • Yana Zavros


Chronic inflammation in the stomach (gastritis) induces gastric atrophy characterized by the loss of the acid-secreting oxyntic glands. Although the initial report of pheno-typic changes that precede gastric cancer suggest that these steps occur sequentially (Correa et al. 1975), whether atrophy precedes metaplasia or occurs concurrently is unclear. Nevertheless, the metaplastic cell that begins to repopulate the gastric epithelium under hypochlorhydric conditions is a mucous cell of gastric or intestinal origin (Goldenring and Nomura 2006; Kang et al. 2005; Nomura et al. 2004; Oshima et al. 2006). Although Helicobacter pyloriinfection is the major reason chronic inflammation develops in the stomach, the molecular networks linking chronic inflammation to the atrophic/metaplastic changes are not well understood. This chapter reviews the causes of gastric atrophy and highlights the role that some activated signaling pathways have in committing the mucosa to neoplastic...


Gastric Cancer Intestinal Metaplasia Parietal Cell Chief Cell Gastric Atrophy 
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  1. Ahmed, S., and A. Nawshad. 2007. Complexity in interpretation of embryonic epithelial-mesenchymal transition in response to transforming growth factor-beta signaling. Cells issues Organs. 185:131–45.Google Scholar
  2. Altaba, R.R.I. 1997. Catching a Gli-mpse of Hedgehog. Cell. 90:193–6.Google Scholar
  3. Artavanis-Tsakonas, S., M.D. Rand, and R.J. Lake. 1999. Notch signaling: cell fate control and ignal integration in development. Science. 284:770–6.PubMedGoogle Scholar
  4. Bai, C.B., W. Auerbach, J.S. Lee, D. Stephen, and A.L. Joyner. 2002. Gli2, but not Gli1, is equired for initial Shh signaling and ectopic activation of the Shh pathway. Development. 129:4753–61.PubMedGoogle Scholar
  5. Bae, S.C., and J.K. Choi. 2004. Tumor suppressor activity of RUNX3. Oncogene. 23:4336–40.PubMedGoogle Scholar
  6. Bamford, K.B., X. Fan, S.E. Crowe, J.F. Leary, W.K. Gourley, G.K. Luthra, E.G. Brooks, D.Y. raham, V.E. Reyes, and P.B. Ernst. 1998. Lymphocytes in the human gastric mucosa during elicobacter pylori have a T helper cell 1 phenotype. Gastroenterology. 114:482–92.PubMedGoogle Scholar
  7. Barrett, S.P., P.A. Gleeson, H. de Silva, B.H. Toh, and I.R. van Driel. 1996. Interferon-gamma is equired during the initiation of an organ-specific autoimmune disease. Eur J Immunol. 26:1652–5.PubMedGoogle Scholar
  8. Barrett, S.P., B.H. Toh, F. Alderuccio, I.R. van Driel, and P.A. Gleeson. 1995. Organ-specific utoimmunity induced by adult thymectomy and cyclophosphamide-induced lymphopenia. Eur J Immunol. 25:238–44.PubMedGoogle Scholar
  9. Bataller, R., and D.A. Brenner. 2005. Liver fibrosis. J Clin Invest. 115:209–18.PubMedGoogle Scholar
  10. Baur, S., J.M. Fisher, R.G. Strickland, and K.B. Taylor. 1968. Autoantibody-containing cells in he gastric mucosa in pernicious anaemia. Lancet. 2:887–94.PubMedGoogle Scholar
  11. Bayerdorffer, E., N. Lehn, R. Hatz, G.A. Mannes, H. Oertel, T. Sauerbruch, and M. Stolte. 1992. Difference in expression of Helicobacter pylori gastritis in antrum and body. Gastroenterology. 102:1575–82.PubMedGoogle Scholar
  12. Beales, I.L. 2000. Effects of pro-inflammatory cytokines on acid secretion. Dig Dis Sci.45:289–90.Google Scholar
  13. Beales, I.L., and J. Calam. 1998. Interleukin 1 beta and tumour necrosis factor alpha inhibit acid secretion in cultured rabbit parietal cells by multiple pathways. Gut. 42:227–34.PubMedGoogle Scholar
  14. Beauchamp, R.D., J.A. Barnard, C.M. McCutchen, J.A. Cherner, and R.J. Coffey, Jr. 1989. Localization of transforming growth factor a and its receptor in gastric mucosal cells. J Clin Invest. 84:1017–23.PubMedGoogle Scholar
  15. Berman, D.M., S.S. Karhadkar, A.R. Hallahan, J.I. Pritchard, C.G. Eberhart, D.N. Watkins, J.K. Chen, M.K. Cooper, J. Taipale, J.M. Olson, and P.A. Beachy. 2002. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science. 297:1559–61.PubMedGoogle Scholar
  16. Berman, D.M., S.S. Karhadkar, A. Maitra, R. Montes De Oca, M.R. Gerstenblith, K. Briggs, A.R. Parker, Y. Shimada, J.R. Eshleman, D.N. Watkins, and P.A. Beachy. 2003. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature. 425:846–51.PubMedGoogle Scholar
  17. Bertario, L., A. Russo, P. Sala, L. Varesco, R. Crucianelli, M. Frattini, M.A. Pierotti, and P. Radice. 2004. APC genotype is not a prognostic factor in familial adenomatous polyposis patients with colorectal cancer. Dis Colon Rectum. 47:1662–9.PubMedGoogle Scholar
  18. Blair, V., I. Martin, D. Shaw, I. Winship, D. Kerr, J. Arnold, P. Harawira, M. McLeod, S. Parry, A. Charlton, M. Findlay, B. Cox, B. Humar, H. More, and P. Guilford. 2006. Hereditary diffuse gastric cancer: diagnosis and management. Clin Gastroenterol Hepatol. 4:262–75.PubMedGoogle Scholar
  19. Blaser, M.J., and J. Parsonnet. 1994. Parasitism by the ‘slow’ bacterium Helicobacter pylori leads to altered gastric homeostasis and neoplasia. J Clin Invest. 94:4–8.PubMedGoogle Scholar
  20. Bleuming, S.A., L.L. Kodach, M.J. Garcia Leon, D.J. Richel, M.P. Peppelenbosch, P.H. Reitsma, J.C. Hardwick, and G.R. van den Brink. 2006. Altered bone morphogenetic protein signalling in the Helicobacter pylori-infected stomach. J Pathol. 209:190–7.PubMedGoogle Scholar
  21. Bumcrot, D.A., R. Takada, and A.P. McMahon. 1995. Proteolytic processing yields two secreted forms of sonic hedgehog. Mol Cell Biol. 15:2294–303.PubMedGoogle Scholar
  22. Carlson, M.E., and I.M. Conboy. 2007. Regulating the Notch pathway in embryonic, adult and old stem cells. Curr Opin Pharmacol. 7:303–9.PubMedGoogle Scholar
  23. Caruso, R., F. Pallone, D. Fina, V. Gioia, I. Peluso, F. Caprioli, C. Stolfi, A. Perfetti, L.G. Spagnoli, G. Palmieri, T.T. Macdonald, and G. Monteleone. 2006. Protease-activated receptor-2 activation in gastric cancer cells promotes epidermal growth factor receptor trans-activation and proliferation. Am J Pathol. 169:268–78.PubMedGoogle Scholar
  24. Chen, M.C., A.T. Lee, W.E. Karnes, D. Avedian, M. Martin, J.M. Sorvillo, and A.H. Soll. 1993. Paracrine control of gastric epithelial cell growth in culture by transforming growth factor- α.Am J Physiol. 264:G390–6.PubMedGoogle Scholar
  25. Chen, J.K., J. Taipale, K.E. Young, T. Maiti, and P.A. Beachy. 2002. Small molecule modulation of Smoothened activity. Proc Natl Acad Sci USA 99:14071–6.Google Scholar
  26. Chey, W.D., and B.C. Wong. 2007. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. 102(8):1808–25.PubMedGoogle Scholar
  27. Corley, D.A., and A. Kubo. 2004. Influence of site classification on cancer incidence rates: an analysis of gastric cardia carcinomas. J Natl Cancer Inst. 96:1383–7.PubMedGoogle Scholar
  28. Correa, P. 1992. Human gastric carcinogenesis: a multistep and multifactorial process—first American Cancer Society award lecture on cancer epidemiology and prevention. Cancer Res. 52:6735–40.PubMedGoogle Scholar
  29. Correa, P. 1995. Helicobacter pylori and gastric carcinogenesis. Am J Surg Pathol. 19(Suppl 1): S37–43.PubMedGoogle Scholar
  30. Correa, P., W. Haenszel, C. Cuello, S. Tannenbaum, and M. Archer. 1975. A model for gastric cancer epidemiology. Lancet. 2:58–60.PubMedGoogle Scholar
  31. Coste, I., J.N. Freund, S. Spaderna, T. Brabletz, and T. Renno. 2007. Precancerous lesions upon sporadic activation of beta-catenin in mice. Gastroenterology. 132:1299–308.PubMedGoogle Scholar
  32. Coughlin, S.R., and E. Camerer. 2003. PARticipation in inflammation. J Clin Invest. 111:25–7.PubMedGoogle Scholar
  33. Daub, H., F.U. Weiss, C. Wallasch, and A. Ullrich. 1996. Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature. 379:557–60.PubMedGoogle Scholar
  34. Davidson, N.O. 2007. Genetic testing in colorectal cancer: who, when, how and why. Keio J Med. 56:14–20.PubMedGoogle Scholar
  35. Dimmler, A., T. Brabletz, F. Hlubek, M. Hafner, T. Rau, T. Kirchner, and G. Faller. 2003. Transcription of sonic hedgehog, a potential factor for gastric morphogenesis and gastric mucosa maintenance, is up-regulated in acidic conditions. Lab Invest. 83:1829–37.PubMedGoogle Scholar
  36. El-Omar, E.M., M. Carrington, W.H. Chow, K.E. McColl, J.H. Bream, H.A. Young, J. Herrera, J. Lissowska, C.C. Yuan, N. Rothman, G. Lanyon, M. Martin, J.F. Fraumeni, Jr., and C.S. Rabkin. 2000. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 404:398–402.PubMedGoogle Scholar
  37. El-Omar, E.M., C.S. Rabkin, M.D. Gammon, T.L. Vaughan, H.A. Risch, J.B. Schoenberg, J.L. Stanford, S.T. Mayne, J. Goedert, W.J. Blot, J.F. Fraumeni, Jr., and W.H. Chow. 2003. Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology. 124:1193–201.PubMedGoogle Scholar
  38. El-Zaatari, M., A. Tobias, A.M. Grabowska, R. Kumari, P.J. Scotting, P. Kaye, J. Atherton, P.A. Clarke, D.G. Powe, and S.A. Watson. 2007. De-regulation of the sonic hedgehog pathway in the InsGas mouse model of gastric carcinogenesis. Br J Cancer. 96:1855–61.PubMedGoogle Scholar
  39. El-Zimaity, H.M., H. Ota, D.Y. Graham, T. Akamatsu, and T. Katsuyama. 2002. Patterns of gastric atrophy in intestinal type gastric carcinoma. Cancer. 94:1428–36.PubMedGoogle Scholar
  40. Faller, G., A. Dimmler, T. Rau, S. Spaderna, F. Hlubek, A. Jung, T. Kirchner, and T. Brabletz. 2004. Evidence for acid-induced loss of Cdx2 expression in duodenal gastric metaplasia. J Pathol. 203:904–8.PubMedGoogle Scholar
  41. Fietz, M.J., J.P. Concordet, R. Barbosa, R. Johnson, S. Krauss, A.P. McMahon, C. Tabin, and P.W. Ingham. 1994. The hedgehog gene family in Drosophila and vertebrate development. Dev Suppl 43–51.Google Scholar
  42. Ford, M.G., J.D. Valle, C.J. Soroka, and J.L. Merchant. 1997. EGF receptor activation stimulates endogenous gastrin gene expression in canine G cells and human gastric cell cultures. J Clin Invest. 99:2762–71.PubMedGoogle Scholar
  43. Fox, J.G., X. Li, R.J. Cahill, K. Andrutis, A.K. Rustgi, R. Odze, and T.C. Wang. 1996. Hypertrophic gastropathy in Helicobacter felis-infected wild-type C57BL/6 mice and p53 hemizygous transgenic mice. Gastroenterology. 110:155–66.PubMedGoogle Scholar
  44. Fox, J.G., and T.C. Wang. 2007. Inflammation, atrophy, and gastric cancer. J Clin Invest. 117:60–9.PubMedGoogle Scholar
  45. Friedrich, M.J., R. Rad, R. Langer, P. Voland, H. Hoefler, R.M. Schmid, C. Prinz, and M. Gerhard. 2006. Lack of RUNX3 regulation in human gastric cancer. J Pathol. 210:141–6.PubMedGoogle Scholar
  46. Friis-Hansen, L., K. Rieneck, H.O. Nilsson, T. Wadstrom, and J.F. Rehfeld. 2006. Gastric inflammation, metaplasia, and tumor development in gastrin-deficient mice. Gastroenterology. 131:246–58.PubMedGoogle Scholar
  47. Fukaya, M., N. Isohata, H. Ohta, K. Aoyagi, T. Ochiya, N. Saeki, K. Yanagihara, Y. Nakanishi, H. Taniguchi, H. Sakamoto, T. Shimoda, Y. Nimura, T. Yoshida, and H. Sasaki. 2006. Hedgehog signal activation in gastric pit cell and in diffuse-type gastric cancer. Gastroenterology. 131:14–29.PubMedGoogle Scholar
  48. Furuta, T., E.M. El-Omar, F. Xiao, N. Shirai, M. Takashima, H. Sugimura, and H. Sugimurra. 2002. Interleukin 1beta polymorphisms increase risk of hypochlorhydria and atrophic gastritis and reduce risk of duodenal ulcer recurrence in Japan. Gastroenterology. 123:92–105.PubMedGoogle Scholar
  49. Giraud, A.S., C. Jackson, T.R. Menheniott, and L.M. Judd. 2007. Differentiation of the gastric mucosa. IV. Role of trefoil peptides and IL-6 cytokine family signaling in gastric homeostasis. Am J Physiol Gastrointest Liver Physiol. 292:G1–5.PubMedGoogle Scholar
  50. Gisbert, J.P., M. Fernandez-Bermejo, J. Molina-Infante, B. Perez-Gallardo, A.B. Prieto-Bermejo, J.M. Mateos-Rodriguez, P. Robledo-Andres, and G. Gonzalez-Garcia. 2007. First-line triple therapy with levofloxacin for Helicobacter pylori eradication. Aliment Pharmacol Ther. 26:495–500.PubMedGoogle Scholar
  51. Gleeson, P.A., B.H. Toh, and I.R. van Driel. 1996. Organ-specific autoimmunity induced by lymphopenia. Immunol Rev. 149:97–125.PubMedGoogle Scholar
  52. Goetz, J.A., S. Singh, L.M. Suber, F.J. Kull, and D.J. Robbins. 2006. A highly conserved amino-terminal region of sonic hedgehog is required for the formation of its freely diffusible mul-timeric form. J Biol Chem. 281:4087–93.PubMedGoogle Scholar
  53. Goetz, J.A., L.M. Suber, X. Zeng, and D.J. Robbins. 2002. Sonic hedgehog as a mediator of long-range signaling. Bioessays. 24:157–65.PubMedGoogle Scholar
  54. Goldenring, J.R., and S. Nomura. 2006. Differentiation of the gastric mucosa. III. Animal models of oxyntic atrophy and metaplasia. Am J Physiol Gastrointest Liver Physiol. 291:G999–1004.PubMedGoogle Scholar
  55. Goodrich, L.V., L. Milenkovic, K.M. Higgins, and M.P. Scott. 1997. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science. 277:1109–13.PubMedGoogle Scholar
  56. Graham, D.Y. 1998. Antibiotic resistance in Helicobacter pylori: implications for therapy. Gastroenterology. 115:1272–7.PubMedGoogle Scholar
  57. Gritli-Linde, A., P. Lewis, A.P. McMahon, and A. Linde. 2001. The whereabouts of a morphogen:direct evidence for short- and graded long-range activity of hedgehog signaling peptides. Dev Biol. 236:364–86.PubMedGoogle Scholar
  58. Halldorsdottir, A.M., M. Sigurdardottrir, J.G. Jonasson, M. Oddsdottir, J. Magnusson, J.R. Lee, and J.R. Goldenring. 2003. Spasmolytic polypeptide-expressing metaplasia (SPEM) associated with gastric cancer in Iceland. Dig Dis Sci. 48:431–41.PubMedGoogle Scholar
  59. Hammerschmidt, M., A. Brook, and A.P. McMahon. 1997. The world according to hedgehog. Trends Genet. 13:14–21.PubMedGoogle Scholar
  60. He, J., T. Sheng, A.A. Stelter, C. Li, X. Zhang, M. Sinha, B.A. Luxon, and J. Xie. 2006. Suppressing Wnt signaling by the hedgehog pathway through sFRP-1. J Biol Chem. 281:35598–602.PubMedGoogle Scholar
  61. Hirayama, F., S. Takagi, E. Iwao, Y. Yokoyama, K. Haga, and S. Hanada. 1999. Development of poorly differentiated adenocarcinoma and carcinoid due to long-term Helicobacter pylori colonization in Mongolian gerbils. J Gastroenterol. 34:450–4.PubMedGoogle Scholar
  62. Hofman, P., B. Waidner, V. Hofman, S. Bereswill, P. Brest, and M. Kist. 2004. Pathogenesis of Helicobacter pylori infection. Helicobacter. 9(Suppl 1):15–22.PubMedGoogle Scholar
  63. Honda, S., T. Fujioka, M. Tokieda, R. Satoh, A. Nishizono, and M. Nasu. 1998. Development of Helicobacter pylori-induced gastric carcinoma in Mongolian gerbils. Cancer Res. 58:4255–9.PubMedGoogle Scholar
  64. Hou, L., E.M. El-Omar, J. Chen, P. Grillo, C.S. Rabkin, A. Baccarelli, M. Yeager, S.J. Chanock, W. Zatonski, L.H. Sobin, J. Lissowska, J.F. Fraumeni, Jr., and W.H. Chow. 2007. Polymorphisms in Th1-type cell-mediated response genes and risk of gastric cancer. Carcinogenesis. 28:118–23.PubMedGoogle Scholar
  65. Houghton, J., C. Stoicov, S. Nomura, A.B. Rogers, J. Carlson, H. Li, X. Cai, J.G. Fox, J.R. Goldenring, and T.C. Wang. 2004. Gastric cancer originating from bone marrow-derived cells. Science. 306:1568–71.PubMedGoogle Scholar
  66. Howlett, M., L.M. Judd, B. Jenkins, N.L. La Gruta, D. Grail, M. Ernst, and A.S. Giraud. 2005. Differential regulation of gastric tumor growth by cytokines that signal exclusively through the coreceptor gp130. Gastroenterology. 129:1005–18.PubMedGoogle Scholar
  67. Iijima, K., H. Sekine, T. Koike, A. Imatani, S. Ohara, and T. Shimosegawa. 2005. Serum pepsino-gen concentrations as a measure of gastric acid secretion in Helicobacter pylori-negative and -positive Japanese subjects. J Gastroenterol. 40:938–44.PubMedGoogle Scholar
  68. Ingram, W.J., C.A. Wicking, S.M. Grimmond, A.R. Forrest, and B.J. Wainwright. 2002. Novel genes regulated by sonic hedgehog in pluripotent mesenchymal cells. Oncogene. 21:8196–205.PubMedGoogle Scholar
  69. James, L.F., K.E. Panter, W. Gaffield, and R.J. Molyneux. 2004. Biomedical applications of poisonous plant research. J Agric Food Chem. 52:3211–30.PubMedGoogle Scholar
  70. Jass, J.R. 2006. Colorectal cancer: a multipathway disease. Crit Rev Oncog. 12:273–87.PubMedGoogle Scholar
  71. Jenkins, B.J., D. Grail, T. Nheu, M. Najdovska, B. Wang, P. Waring, M. Inglese, R.M. McLoughlin, S.A. Jones, N. Topley, H. Baumann, L.M. Judd, A.S. Giraud, A. Boussioutas, H.J. Zhu, and M. Ernst. 2005. Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperprolif-eration and desensitizes TGF-beta signaling. Nat Med. 11:845–52.PubMedGoogle Scholar
  72. Johnson, C.L., A.S. Kowalik, N. Rajakumar, and C.L. Pin. 2004. Mist1 is necessary for the establishment of granule organization in serous exocrine cells of the gastrointestinal tract. Mech Dev. 121:261–72.PubMedGoogle Scholar
  73. Judd, L.M., B.M. Alderman, M. Howlett, A. Shulkes, C. Dow, J. Moverley, D. Grail, B.J. Jenkins, M. Ernst, and A.S. Giraud. 2004. Gastric cancer development in mice lacking the SHP2 binding site on the IL-6 family co-receptor gp130. Gastroenterology. 126:196–207.PubMedGoogle Scholar
  74. Judd, L.M., K. Bredin, A. Kalantzis, B.J. Jenkins, M. Ernst, and A.S. Giraud. 2006. STAT3 activation regulates growth, inflammation, and vascularization in a mouse model of gastric tumori-genesis. Gastroenterology. 131:1073–85.PubMedGoogle Scholar
  75. Kang, W., S. Rathinavelu, L.C. Samuelson, and J.L. Merchant. 2005. Interferon gamma induction of gastric mucous neck cell hypertrophy. Lab Invest. 85(5):702–15.PubMedGoogle Scholar
  76. Karam, S.M. 1993. Dynamics of epithelial cells in the corpus of the mouse stomach. I V. Bidirectional migration of parietal cells ending in their gradual degeneration and loss. Anat Rec. 236:314–32.PubMedGoogle Scholar
  77. Karam, S.M., and C.P. Leblond. 1993a. Dynamics of epithelial cells in the corpus of the mouse stomach. II. Outward migration of pit cells. Anat Rec. 236:280–96.Google Scholar
  78. Karam, S.M., and C.P. Leblond. 1993b. Dynamics of epithelial cells in the corpus of the mouse stomach. III. Inward migration of neck cells followed by progressive transformation into zymogenic cells. Anat Rec. 236:297–313.Google Scholar
  79. Katoh, Y., and M. Katoh. 2005. Comparative genomics on sonic hedgehog orthologs. Oncol Rep. 14:1087–90.PubMedGoogle Scholar
  80. Katoh, M., and M. Katoh. 2007. Notch signaling in gastrointestinal tract [review]. Int J Oncol. 30:247–51.PubMedGoogle Scholar
  81. Kawachi, T., K. Kogure, N. Tanaka, A. Tokunaga, and T. Sugimura. 1974. Studies of intestinal metaplasia in the gastric mucosa by detection of disaccharidases with ‘Tes-Tape.’ J Natl Cancer Inst. 53:19–30.Google Scholar
  82. Kawakami, T., T. Kawcak, Y.J. Li, W. Zhang, Y. Hu, and P.T. Chuang. 2002. Mouse dispatched mutants fail to distribute hedgehog proteins and are defective in hedgehog signaling. Development. 129:5753–65.PubMedGoogle Scholar
  83. Kaye, M.D., P.J. Whorwell, and R. Wright. 1983. Gastric mucosal lymphocyte subpopulations in pernicious anemia and in normal stomach. Clin Immunol Immunopathol. 28:431–40.PubMedGoogle Scholar
  84. Kim, B.M., G. Buchner, I. Miletich, P.T. Sharpe, and R.A. Shivdasani. 2005a. The stomach mes-enchymal transcription factor Barx1 specifies gastric epithelial identity through inhibition of transient Wnt signaling. Dev Cell. 8:611–22.Google Scholar
  85. Kim, J.H., Z. Huang, and R. Mo. 2005b. Gli3 null mice display glandular overgrowth of the developing stomach. Dev Dyn. 234:984–91.Google Scholar
  86. Kim, H.C., J.C. Kim, S.A. Roh, C.S. Yu, J.H. Yook, S.T. Oh, B.S. Kim, K.C. Park, and R. Chang. 2005c. Aberrant CpG island methylation in early-onset sporadic gastric carcinoma. J Cancer Res Clin Oncol. 131:733–40.Google Scholar
  87. Kim, S.K., and D.A. Melton. 1998. Pancreas development is promoted by cyclopamine, a hedgehog signaling inhibitor. Proc Natl Acad Sci USA. 95:13036–41.PubMedGoogle Scholar
  88. Kim, S.S., K. Shetty, V. Katuri, K. Kitisin, H.J. Baek, Y. Tang, B. Marshall, L. Johnson, B. Mishra, and L. Mishra. 2006. TGF-beta signaling pathway inactivation and cell cycle deregulation in the development of gastric cancer: role of the beta-spectrin, ELF. Biochem Biophys Res Commun. 344:1216–23.PubMedGoogle Scholar
  89. Kimura, H., D. Stephen, A. Joyner, and T. Curran. 2005. Gli1 is important for medulloblastoma formation in Ptc1+/- mice. Oncogene. 24:4026–36.PubMedGoogle Scholar
  90. Kinzler, K.W., and B. Vogelstein. 1990. The GLI gene encodes a nuclear protein which binds specific sequences in the human genome. Mol Cell Biol. 10:634–42.PubMedGoogle Scholar
  91. Kishida, O., Y. Miyazaki, Y. Murayama, M. Ogasa, T. Miyazaki, T. Yamamoto, K. Watabe, S. Tsutsui, T. Kiyohara, I. Shimomura, and Y. Shinomura. 2005. Gefitinib (Iressa, ZD1839) inhibits SN38-triggered EGF signals and IL-8 production in gastric cancer cells. Cancer Chemother Pharmacol. 55:584–94.PubMedGoogle Scholar
  92. Klinkenberg-Knol, E.C., F. Nelis, J. Dent, P. Snel, B. Mitchell, P. Prichard, D. Lloyd, N. Havu, M.H. Frame, J. Roman, and A. Walan. 2000. Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa. Gastroenterology. 118:661–9.PubMedGoogle Scholar
  93. Kojima, A., and R.T. Prehn. 1981. Genetic susceptibility to post-thymectomy autoimmune diseases in mice. Immunogenetics. 14:15–27.PubMedGoogle Scholar
  94. Kokkola, A., J. Louhimo, P. Puolakkainen, H. Alfthan, C. Haglund, and H. Rautelin. 2005. Helicobacter pylori infection and low serum pepsinogen I level as risk factors for gastric carcinoma. World J Gastroenterol. 11:1032–6.Google Scholar
  95. Lai, E.C. 2004. Notch signaling: control of cell communication and cell fate. Development. 131:965–73.PubMedGoogle Scholar
  96. Lamberts, R., G. Brunner, and E. Solcia. 2001. Effects of very long (up to 10 years) proton pump blockade on human gastric mucosa. Digestion. 64:205–13.Google Scholar
  97. Lee, J.J., S.C. Ekker, D.P. von Kessler, J.A. Porter, B.I. Sun, and P.A. Beachy. 1994. Autoproteolysis in hedgehog protein biogenesis. Science. 266:1528–37.PubMedGoogle Scholar
  98. Lee, S.Y., H.S. Han, K.Y. Lee, T.S. Hwang, J.H. Kim, I.K. Sung, H.S. Park, C.J. Jin, and K.W. Choi. 2007. Sonic hedgehog expression in gastric cancer and gastric adenoma. Oncol Rep. 17:1051–5.PubMedGoogle Scholar
  99. Lee, J., K.A. Platt, P. Censullo, and A. Ruiz i Altaba. 1997. Gli1 is a target of Sonic hedgehog that induces ventral neural tube development. Development. 124:2537–52.PubMedGoogle Scholar
  100. Li, Q.L., K. Ito, C. Sakakura, H. Fukamachi, K. Inoue, X.Z. Chi, K.Y. Lee, S. Nomura, C.W. Lee, S.B. Han, H.M. Kim, W.J. Kim, H. Yamamoto, N. Yamashita, T. Yano, T. Ikeda, S. Itohara, J. Inazawa, T. Abe, A. Hagiwara, H. Yamagishi, A. Ooe, A. Kaneda, T. Sugimura, T. Ushijima, S.C. Bae, and Y. Ito. 2002. Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell. 109:113–24.PubMedGoogle Scholar
  101. Li, Q., S.M. Karam, and J.I. Gordon. 1996. Diphtheria toxin-mediated ablation of parietal cells in the stomach of transgenic mice. J Biol Chem. 271:3671–6.PubMedGoogle Scholar
  102. Lin, W., A. Kemper, K.D. McCarthy, P. Pytel, J.P. Wang, I.L. Campbell, M.F. Utset, and B. Popko. 2004. Interferon-gamma induced medulloblastoma in the developing cerebellum. J Neurosci. 24:10074–83.PubMedGoogle Scholar
  103. Litingtung, Y., L. Lei, H. Westphal, and C. Chiang. 1998. Sonic hedgehog is essential to foregut development. Nat Genet. 20:58–61.PubMedGoogle Scholar
  104. Lopez-Diaz, L., K.L. Hinkle, R.N. Jain, Y. Zavros, C.S. Brunkan, T. Keeley, K.A. Eaton, J.L. Merchant, C.S. Chew, and L.C. Samuelson. 2006. Parietal cell hyperstimulation and autoimmune gastritis in cholera toxin transgenic mice. Am J Physiol Gastrointest Liver Physiol. 290:G970–9.PubMedGoogle Scholar
  105. Lundkvist, J., and J. Naslund. 2007. Gamma-secretase: a complex target for Alzheimer's disease. Curr Opin Pharmacol. 7:112–8.PubMedGoogle Scholar
  106. Ma, X., K. Chen, S. Huang, X. Zhang, P.A. Adegboyega, B.M. Evers, H. Zhang, and J. Xie. 2005. Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas. Carcinogenesis. 26:1698–705.PubMedGoogle Scholar
  107. Macarthur, M., G.L. Hold, and E.M. El-Omar. 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:G515–20.PubMedGoogle Scholar
  108. Marigo, V., D.J. Roberts, S.M. Lee, O. Tsukurov, T. Levi, J.M. Gastier, D.J. Epstein, D.J. Gilbert, N.G. Copeland, C.E. Seidman, et al. 1995. Cloning, expression, and chromosomal location of SHH and IHH: two human homologues of the Drosophila segment polarity gene hedgehog. Genomics. 28:44–51.PubMedGoogle Scholar
  109. Matsukura, N., K. Suzuki, T. Kawachi, M. Aoyagi, T. Sugimura, H. Kitaoka, H. Numajiri, A. Shirota, M. Itabashi, and T. Hirota. 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. 65:231–40.PubMedGoogle Scholar
  110. McColl, K.E. 2006. Cancer of the gastric cardia. Best Pract Res Clin Gastroenterol. 20:687–96.PubMedGoogle Scholar
  111. McColl, K.E., E. el-Omar, and D. Gillen. 1998. Interactions between H. pylori infection, gastric acid secretion and anti-secretory therapy. Br Med Bull. 54:121–38.Google Scholar
  112. Merlos-Suarez, A., S. Ruiz-Paz, J. Baselga, and J. Arribas. 2001. Metalloprotease-dependent pro-transforming growth factor-alpha ectodomain shedding in the absence of tumor necrosis factor-alpha-converting enzyme. J Biol Chem. 276:48510–7.PubMedGoogle Scholar
  113. Mesquita, P., A. Raquel, L. Nuno, C.A. Reis, L.F. Silva, J. Serpa, I. Van Seuningen, H. Barros, and L. David. 2006. Metaplasia—a transdifferentiation process that facilitates cancer development: the model of gastric intestinal metaplasia. Crit Rev Oncog. 12:3–26.PubMedGoogle Scholar
  114. Mishra, L., K. Shetty, Y. Tang, A. Stuart, and S.W. Byers. 2005. The role of TGF-beta and Wnt signaling in gastrointestinal stem cells and cancer. Oncogene. 24:5775–89.PubMedGoogle Scholar
  115. Motoyama, J., J. Liu, R. Mo, Q. Ding, M. Post, and C.C. Hui. 1998. Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus. Nat Genet. 20:54–7.PubMedGoogle Scholar
  116. Mutoh, H., S. Sakurai, K. Satoh, H. Osawa, Y. Hakamata, T. Takeuchi, and K. Sugano. 2004a. Cdx1 induced intestinal metaplasia in the transgenic mouse stomach: comparative study with Cdx2 transgenic mice. Gut. 53:1416–23.Google Scholar
  117. Mutoh, H., S. Sakurai, K. Satoh, K. Tamada, H. Kita, H. Osawa, T. Tomiyama, Y. Sato, H. Yamamoto, N. Isoda, T. Yoshida, K. Ido, and K. Sugano. 2004b. Development of gastric carcinoma from intestinal metaplasia in Cdx2-transgenic mice. Cancer Res. 64:7740–7.Google Scholar
  118. Nielsen, C.M., J. Williams, G.R. van den Brink, G.Y. Lauwers, and D.J. Roberts. 2004. Hh pathway expression in human gut tissues and in inflammatory gut diseases. Lab Invest. 84:1631–42.PubMedGoogle Scholar
  119. Nishizawa, T., H. Suzuki, T. Masaoka, Y. Minegishi, E. Iwasahi, and T. Hibi. 2007. Helicobacter pylori eradication restored sonic hedgehog expression in the stomach. Hepatogastroenterology. 54:697–700.PubMedGoogle Scholar
  120. Nojima, M., H. Suzuki, M. Toyota, Y. Watanabe, R. Maruyama, S. Sasaki, Y. Sasaki, H. Mita, N. Nishikawa, K. Yamaguchi, K. Hirata, F. Itoh, T. Tokino, M. Mori, K. Imai, and Y. Shinomura. 2007. Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer. Oncogene. 26:4699–713.PubMedGoogle Scholar
  121. Nompleggi, D.J., M. Beinborn, A. Roy, and M.M. Wolfe. 1994. The effect of recombinant cytokines on [14C]-aminopyrine accumulation by isolated canine parietal cells. J Pharmacol Exp Ther. 270:440–5.PubMedGoogle Scholar
  122. Nomura, S., T. Baxter, H. Yamaguchi, C. Leys, A.B. Vartapetian, J.G. Fox, J.R. Lee, T.C. Wang, and J.R. Goldenring. 2004. Spasmolytic polypeptide expressing metaplasia to preneoplasia in H. felis-infected mice. Gastroenterology. 127:582–94.PubMedGoogle Scholar
  123. Nomura, A.M., L.N. Kolonel, K. Miki, G.N. Stemmermann, L.R. Wilkens, M.T. Goodman, G.I. Perez-Perez, and M.J. Blaser. 2005a. Helicobacter pylori, pepsinogen, and gastric adenocarci-noma in Hawaii. J Infect Dis. 191:2075–81.Google Scholar
  124. Nomura, S., S.H. Settle, C.M. Leys, A.L. Means, R.M. Peek, Jr., S.D. Leach, C.V. Wright, R.J. Coffey, and J.R. Goldenring. 2005b. Evidence for repatterning of the gastric fundic epithelium associated with Menetrier's disease and TGFalpha overexpression. Gastroenterology. 128:1292–305.Google Scholar
  125. Nusslein-Volhard, C., and E. Wieschaus. 1980. Mutations affecting segment number and polarity in Drosophila. Nature. 287:795–801.PubMedGoogle Scholar
  126. Ogasawara, N., T. Tsukamoto, T. Mizoshita, K. Inada, X. Cao, Y. Takenaka, T. Joh, and M. Tatematsu. 2006. Mutations and nuclear accumulation of beta-catenin correlate with intestinal phenotypic expression in human gastric cancer. Histopathology. 49:612–21.PubMedGoogle Scholar
  127. Oshima, H., A. Matsunaga, T. Fujimura, T. Tsukamoto, M.M. Taketo, and M. Oshima. 2006. Carcinogenesis in mouse stomach by simultaneous activation of the Wnt signaling and pros-taglandin E2 pathway. Gastroenterology. 131:1086–95.PubMedGoogle Scholar
  128. Oshima, H., M. Oshima, K. Inaba, and M.M. Taketo. 2004. Hyperplastic gastric tumors induced by activated macrophages in COX-2/mPGES-1 transgenic mice. EMBO J. 23:1669–78.PubMedGoogle Scholar
  129. Pai, R., B. Soreghan, I.L. Szabo, M. Pavelka, D. Baatar, and A.S. Tarnawski. 2002. Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nat Med. 8:289–93.PubMedGoogle Scholar
  130. Pan, Y., C.B. Bai, A.L. Joyner, and B. Wang. 2006. Sonic hedgehog signaling regulates Gli2 tran-scriptional activity by suppressing its processing and degradation. Mol Cell Biol. 26:3365–77.PubMedGoogle Scholar
  131. Peek, R.M., Jr., and J.E. Crabtree. 2006. Helicobacter infection and gastric neoplasia. J Pathol. 208:233–48.PubMedGoogle Scholar
  132. Piedimonte, L.R., I.K. Wailes, and H.L. Weiner. 2005. Medulloblastoma: mouse models and novel targeted therapies based on the Sonic hedgehog pathway. Neurosurg Focus. 19:E8.PubMedGoogle Scholar
  133. Pin, C.L., A.C. Bonvissuto, and S.F. Konieczny. 2000. Mist1 expression is a common link among serous exocrine cells exhibiting regulated exocytosis. Anat Rec. 259:157–67.PubMedGoogle Scholar
  134. Pissarnitski, D. 2007. Advances in gamma-secretase modulation. Curr Opin Drug Discov Dev. 10:392–402.Google Scholar
  135. Porter, J.A., S.C. Ekker, W.J. Park, D.P. von Kessler, K.E. Young, C.H. Chen, Y. Ma, A.S. Woods, R.J. Cotter, E.V. Koonin, and P.A. Beachy. 1996a. Hedgehog patterning activity: role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain. Cell. 86:21–34.Google Scholar
  136. Porter, J.A., D.P. von Kessler, S.C. Ekker, K.E. Young, J.J. Lee, K. Moses, and P.A. Beachy. 1995. The product of hedgehog autoproteolytic cleavage active in local and long-range signalling. Nature. 374:363–6.PubMedGoogle Scholar
  137. Porter, J.A., K.E. Young, and P.A. Beachy. 1996b. Cholesterol modification of hedgehog signaling proteins in animal development. Science. 274:255–9.Google Scholar
  138. Powell, D.W., R.C. Mifflin, J.D. Valentich, S.E. Crowe, J.I. Saada, and A.B. West. 1999a. Myofibroblasts. I. Paracrine cells important in health and disease. Am J Physiol. 277:C1–9.Google Scholar
  139. Powell, D.W., R.C. Mifflin, J.D. Valentich, S.E. Crowe, J.I. Saada, and A.B. West. 1999b. Myofibroblasts. II. Intestinal subepithelial myofibroblasts. Am J Physiol. 277:C183–201.Google Scholar
  140. Prenzel, N., E. Zwick, H. Daub, M. Leserer, R. Abraham, C. Wallasch, and A. Ullrich. 1999. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature. 402:884–8.PubMedGoogle Scholar
  141. Ramalho-Santos, M., D.A. Melton, and A.P. McMahon. 2000. Hedgehog signals regulate multiple aspects of gastrointestinal development. Development. 127:2763–72.PubMedGoogle Scholar
  142. Ramsey, V.G., J.M. Doherty, C.C. Chen, T.S. Stappenbeck, S.F. Konieczny, and J.C. Mills. 2007. The maturation of mucus-secreting gastric epithelial progenitors into digestive-enzyme secreting zymogenic cells requires Mist1. Development. 134:211–22.PubMedGoogle Scholar
  143. Rindi, G., R. Fiocca, A. Morocutti, A. Jacobs, N. Miller, and B. Thjodleifsson. 2005. Effects of 5 years of treatment with rabeprazole or omeprazole on the gastric mucosa. Eur J Gastroenterol Hepatol. 17:559–66.PubMedGoogle Scholar
  144. Riobo, N.A., and D.R. Manning. 2007. Pathways of signal transduction employed by vertebrate hedgehogs. Biochem J. 403:369–79.PubMedGoogle Scholar
  145. Rocco, A., R. Caruso, S. Toracchio, L. Rigoli, F. Verginelli, T. Catalano, M. Neri, M.C. Curia, L. Ottini, V. Agnese, V. Bazan, A. Russo, G. Pantuso, G. Colucci, R. Mariani-Costantini, and G. Nardone. 2006. Gastric adenomas: relationship between clinicopathological findings, Helicobacter pylori infection, APC mutations and COX-2 expression. Ann Oncol. 17(Suppl 7): vii103–8.PubMedGoogle Scholar
  146. Roelink, H., J.A. Porter, C. Chiang, Y. Tanabe, D.T. Chang, P.A. Beachy, and T.M. Jessell. 1995. Floor plate and motor neuron induction by different concentrations of the amino-terminal cleavage product of sonic hedgehog autoproteolysis. Cell. 81:445–55.PubMedGoogle Scholar
  147. Rohatgi, R., L. Milenkovic, and M.P. Scott. 2007. Patched1 regulates hedgehog signaling at the primary cilium. Science. 317:372–6.PubMedGoogle Scholar
  148. Rugge, M., F. Di Mario, M. Cassaro, R. Baffa, F. Farinati, J. Rubio, Jr., and V. Ninfo. 1993. Pathology of the gastric antrum and body associated with Helicobacter pylori infection in non-ulcerous patients: is the bacterium a promoter of intestinal metaplasia? Histopathology. 22:9–15.Google Scholar
  149. Ruiz i Altaba, A., P. Sanchez, and N. Dahmane. 2002. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer. 2:361–72.PubMedGoogle Scholar
  150. Sahin, U., and C.P. Blobel. 2007. Ectodomain shedding of the EGF-receptor ligand epigen is mediated by ADAM17. FEBS Lett. 581:41–4.PubMedGoogle Scholar
  151. Sanderson, M.P., P.J. Dempsey, and A.J. Dunbar. 2006. Control of ErbB signaling through met-alloprotease mediated ectodomain shedding of EGF-like factors. Growth Factors. 24:121–36.PubMedGoogle Scholar
  152. Sanderson, M.P., S.N. Erickson, P.J. Gough, K.J. Garton, P.T. Wille, E.W. Raines, A.J. Dunbar, and P.J. Dempsey. 2005. ADAM10 mediates ectodomain shedding of the betacellulin precursor activated by p-aminophenylmercuric acetate and extracellular calcium influx. J Biol Chem. 280:1826–37.PubMedGoogle Scholar
  153. Scarff, K.L., L.M. Judd, B.H. Toh, P.A. Gleeson, and I.R. Van Driel. 1999. Gastric H(+),K(+)-adenosine triphosphatase beta subunit is required for normal function, development, and membrane structure of mouse parietal cells. Gastroenterology. 117:605–18.PubMedGoogle Scholar
  154. Schmidt, P.H., J.R. Lee, V. Joshi, R.J. Playford, R. Poulsom, N.A. Wright, and J.R. Goldenring. 1999. Identification of a metaplastic cell lineage associated with human gastric adenocarci-noma. Lab Invest. 79:639–46.PubMedGoogle Scholar
  155. Schultheis, P.J., L.L. Clarke, P. Meneton, M. Harline, G.P. Boivin, G. Stemmermann, J.J. Duffy, T. Doetschman, M.L. Miller, and G.E. Shull. 1998. Targeted disruption of the murine Na+/H+ exchanger isoform 2 gene causes reduced viability of gastric parietal cells and loss of net acid secretion. J Clin Invest. 101:1243–53.PubMedGoogle Scholar
  156. Sekine, A., Y. Akiyama, K. Yanagihara, and Y. Yuasa. 2006. Hath1 up-regulates gastric mucin gene expression in gastric cells. Biochem Biophys Res Commun. 344:1166–71.PubMedGoogle Scholar
  157. Shannon, J.M., and B.A. Hyatt. 2004. Epithelial-mesenchymal interactions in the developing lung. Annu Rev Physiol. 66:625–45.PubMedGoogle Scholar
  158. Shao, J.S., W. Schepp, and D.H. Alpers. 1998. Expression of intrinsic factor and pepsinogen in the rat stomach identifies a subset of parietal cells. Am J Physiol. 274:G62–70.PubMedGoogle Scholar
  159. Sheehan, K.M., C. Gulmann, G.S. Eichler, J.N. Weinstein, H.L. Barrett, E.W. Kay, R.M. Conroy, L.A. Liotta, and E.F. Petricoin, 3rd. 2007. Signal pathway profiling of epithelial and stromal compartments of colonic carcinoma reveals epithelial-mesenchymal transition. Oncogene. 27(3):323–31.PubMedGoogle Scholar
  160. Shiotani, A., H. Iishi, S. Ishiguro, M. Tatsuta, Y. Nakae, and J.L. Merchant. 2005a. Epithelial cell turnover in relation to ongoing damage of the gastric mucosa in patients with early gastric cancer: increase of cell proliferation in paramalignant lesions. J Gastroenterol. 40:337–44.Google Scholar
  161. Shiotani, A., H. Iishi, N. Uedo, S. Ishiguro, M. Tatsuta, Y. Nakae, M. Kumamoto, and J.L. Merchant. 2005b. Evidence that loss of sonic hedgehog is an indicator of Helicobater pylori-induced atrophic gastritis progressing to gastric cancer. Am J Gastroenterol. 100:581–7.Google Scholar
  162. Shiotani, A., H. Iishi, N. Uedo, M. Kumamoto, Y. Nakae, S. Ishiguro, M. Tatsuta, and D.Y. Graham. 2005c. Histologic and serum risk markers for noncardia early gastric cancer. Int J Cancer. 115:463–9.Google Scholar
  163. Shiotani, A., N. Uedo, H. Iishi, M. Tatsuta, S. Ishiguro, Y. Nakae, T. Kamada, K. Haruma, and J.L. Merchant. 2007. Re-expression of sonic hedgehog and reduction of CDX2 after Helicobacter pylori eradication prior to incomplete intestinal metaplasia. Int J Cancer. 121(6):1182–9.PubMedGoogle Scholar
  164. Sierra, R., C. Une, V. Ramirez, M.I. Gonzalez, J.A. Ramirez, A. de Mascarel, R. Barahona, R. Salas-Aguilar, R. Paez, G. Avendano, A. Avalos, N. Broutet, and F. Megraud. 2006. Association of serum pepsinogen with atrophic body gastritis in Costa Rica. Clin Exp Med. 6:72–8.PubMedGoogle Scholar
  165. Silberg, D.G., J. Sullivan, E. Kang, G.P. Swain, J. Moffett, N.J. Sund, S.D. Sackett, and K.H. Kaestner. 2002. Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice. Gastroenterology. 122:689–96.PubMedGoogle Scholar
  166. Sipponen, P., P. Ranta, T. Helske, I. Kaariainen, T. Maki, A. Linnala, O. Suovaniemi, A. Alanko, and M. Harkonen. 2002. Serum levels of amidated gastrin-17 and pepsinogen I in atrophic gastritis: an observational case-control study. Scand J Gastroenterol. 37:785–91.PubMedGoogle Scholar
  167. Smith, H., Y.H. Lou, P. Lacy, and K.S. Tung. 1992. Tolerance mechanism in experimental ovarian and gastric autoimmune diseases. J Immunol. 149:2212–8.PubMedGoogle Scholar
  168. Sobral, L.M., P.F. Montan, H. Martelli-Junior, E. Graner, and R.D. Coletta. 2007. Opposite effects of TGF-beta1 and IFN-gamma on transdifferentiation of myofibroblast in human gingival cell cultures. J Clin Periodontol. 34:397–406.PubMedGoogle Scholar
  169. Spicer, Z., M.L. Miller, A. Andringa, T.M. Riddle, J.J. Duffy, T. Doetschman, and G.E. Shull. 2000. Stomachs of mice lacking the gastric H,K-ATPase alpha -subunit have achlorhydria, abnormal parietal cells, and ciliated metaplasia. J Biol Chem. 275:21555–65.PubMedGoogle Scholar
  170. Stepan, V., N. Pausawasdi, S. Ramamoorthy, and A. Todisco. 2004. The Akt and MAPK signal-transduction pathways regulate growth factor actions in isolated gastric parietal cells. Gastroenterology. 127:1150–61.PubMedGoogle Scholar
  171. Stepan, V., S. Ramamoorthy, H. Nitsche, Y. Zavros, J.L. Merchant, and A. Todisco. 2005. Regulation and function of the sonic hedgehog signal transduction pathway in isolated gastric parietal cells. J Biol Chem. 280:15700–8.PubMedGoogle Scholar
  172. Stockbruegger, R.W., P.B. Cotton, G.G. Menon, J.O. Beilby, B.A. Bartholomew, M.J. Hill, and C.L. Walters. 1984. Pernicious anaemia, intragastric bacterial overgrowth, and possible consequences. Scand J Gastroenterol. 19:355–64.PubMedGoogle Scholar
  173. Suzuki, K., H. Fukui, T. Kayahara, M. Sawada, H. Seno, H. Hiai, R. Kageyama, H. Okano, and T. Chiba. 2005a. Hes1-deficient mice show precocious differentiation of Paneth cells in the small intestine. Biochem Biophys Res Commun. 328:348–52.Google Scholar
  174. Suzuki, H., Y. Minegishi, Y. Nomoto, T. Ota, T. Masaoka, G.R. van den Brink, and T. Hibi. 2005b. Down-regulation of a morphogen (sonic hedgehog) gradient in the gastric epithelium of Helicobacter pylori-infected Mongolian gerbils. J Pathol. 206:186–97.Google Scholar
  175. Taipale, J., J.K. Chen, M.K. Cooper, B. Wang, R.K. Mann, L. Milenkovic, M.P. Scott, and P.A. Beachy. 2000. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature. 406:1005–9.PubMedGoogle Scholar
  176. Takaishi, S., and T.C. Wang. 2007. Gene expression profiling in a mouse model of Helicobacter-induced gastric cancer. Cancer Sci. 98:284–93.PubMedGoogle Scholar
  177. Tian, H., J. Jeong, B.D. Harfe, C.J. Tabin, and A.P. McMahon. 2005. Mouse Disp1 is required in sonic hedgehog-expressing cells for paracrine activity of the cholesterol-modified ligand. Development. 132:133–42.PubMedGoogle Scholar
  178. Toh, B.H., I.R. van Driel, and P.A. Gleeson. 1997. Pernicious anemia. N Engl J Med. 337:1441–8.PubMedGoogle Scholar
  179. Tsukamoto, T., T. Mizoshita, and M. Tatematsu. 2006. Gastric-and-intestinal mixed-type intestinal metaplasia: aberrant expression of transcription factors and stem cell intestinalization. Gastric Cancer. 9:156–66.PubMedGoogle Scholar
  180. Uhal, B.D., J.K. Kim, X. Li, and M. Molina-Molina. 2007. Angiotensin-TGF-beta 1 crosstalk in human idiopathic pulmonary fibrosis: autocrine mechanisms in myofibroblasts and macro-phages. Curr Pharm Des. 13:1247–56.PubMedGoogle Scholar
  181. van den Brink, G.R., J.C. Hardwick, C. Nielsen, C. Xu, F.J. ten Kate, J. Glickman, S.J. van Deventer, D.J. Roberts, and M.P. Peppelenbosch. 2002. Sonic hedgehog expression correlates with fundic gland differentiation in the adult gastrointestinal tract. Gut. 51:628–33.PubMedGoogle Scholar
  182. Van Den Brink, G.R., J.C. Hardwick, G.N. Tytgat, M.A. Brink, F.J. Ten Kate, S.J. Van Deventer, and M.P. Peppelenbosch. 2001. Sonic hedgehog regulates gastric gland morphogenesis in man and mouse. Gastroenterology. 121:317–28.PubMedGoogle Scholar
  183. van Den Brink, G.R., F.J. ten Kate, C.Y. Ponsioen, M.M. Rive, G.N. Tytgat, S.J. van Deventer, and M.P. Peppelenbosch. 2000. Expression and activation of NF-kappa B in the antrum of the human stomach. J Immunol. 164:3353–9.Google Scholar
  184. Wang, T.C., M.W. Babyatsky, P.S. Oates, Z. Zhang, L. Tillotson, M. Chulak, S.J. Brand, and E.V. Schmidt. 1995. A rat gastrin-human gastrin chimeric transgene directs antral G cell-specific expression in transgenic mice. Am. J. Physiol. 268:G1025–36.PubMedGoogle Scholar
  185. Wang, T.C., C.A. Dangler, D. Chen, J.R. Goldenring, T. Koh, R. Raychowdhury, R.J. Coffey, S. Ito, A. Varro, G.J. Dockray, and J.G. Fox. 2000. Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer. Gastroenterology. 118:36–47.PubMedGoogle Scholar
  186. Wang, T.C., J.R. Goldenring, C. Dangler, S. Ito, A. Mueller, W.K. Jeon, T.J. Koh, and J.G. Fox. 1998. Mice lacking secretory phospholipase A2 show altered apoptosis and differentiation with Helicobacter felis infection. Gastroenterology. 114:675–689.PubMedGoogle Scholar
  187. Wang, J., W. Lin, B. Popko, and I.L. Campbell. 2004. Inducible production of interferon-gamma in the developing brain causes cerebellar dysplasia with activation of the Sonic hedgehog pathway. Mol Cell Neurosci. 27:489–96.PubMedGoogle Scholar
  188. Wang, J., N. Pham-Mitchell, C. Schindler, and I.L. Campbell. 2003. Dysregulated Sonic hedgehog signaling and medulloblastoma consequent to IFN-alpha-stimulated STAT2-independent production of IFN-gamma in the brain. J Clin Invest. 112:535–43.PubMedGoogle Scholar
  189. Watanabe, T., M. Tada, H. Nagai, S. Sasaki, and M. Nakao. 1998. Helicobacter pylori infection induces gastric cancer in mongolian gerbils. Gastroenterology. 115:642–8.PubMedGoogle Scholar
  190. Wendler, F., X. Franch-Marro, and J.P. Vincent. 2006. How does cholesterol affect the way hedgehog works? Development. 133:3055–61.Google Scholar
  191. Whittingham, S., and I.R. Mackay. 2005. Autoimmune gastritis: historical antecedents, outstanding discoveries, and unresolved problems. Int Rev Immunol. 24:1–29.PubMedGoogle Scholar
  192. Williams, C., and K.E. McColl. 2006. Review article: proton pump inhibitors and bacterial overgrowth. Aliment Pharmacol Ther. 23:3–10.PubMedGoogle Scholar
  193. Wright, N.A. 1996. Migration of the ductular elements of gut-associated glands gives clues to the histogenesis of structures associated with responses to acid hypersecretory state: the origins of “gastric metaplasia” in the duodenum of the specialized mucosa of Barrett'sesophagus and of pseudopyloric metaplasia. Yale J Biol Med. 69:147–53.PubMedGoogle Scholar
  194. Yanai, K., S. Nagai, J. Wada, N. Yamanaka, M. Nakamura, N. Torata, H. Noshiro, M. Tsuneyoshi, M. Tanaka, and M. Katano. 2007. Hedgehog signaling pathway is a possible therapeutic target for gastric cancer. J Surg Oncol. 95:55–62.PubMedGoogle Scholar
  195. Yang, Q., N.A. Bermingham, M.J. Finegold, and H.Y. Zoghbi. 2001. Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science. 294:2155–8.PubMedGoogle Scholar
  196. Zavros, Y., K.A. Eaton, W. Kang, S. Rathinavelu, V. Katukuri, J.Y. Kao, L.C. Samuelson, and J.L. Merchant. 2005. Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma. Oncogene. 24:2354–66.PubMedGoogle Scholar
  197. Zavros, Y., S. Rathinavelu, J.Y. Kao, A. Todisco, J. DelValle, J.V. Weinstock, M.J. Low, and J. L. Merchant. 2003. Treatment of Helicobacter gastritis with interleukin-4 requires somatosta-tin. Proc Natl Acad Sci. 100:12944–9.PubMedGoogle Scholar
  198. Zavros, Y., G. Rieder, A. Ferguson, and J.L. Merchant. 2002a. Gastritis and hypergastrinemia due to Acinetobacter lwoffii in mice. Infect Immun. 70:2630–9.Google Scholar
  199. Zavros, Y., G. Rieder, A. Ferguson, L.C. Samuelson, and J.L. Merchant. 2002b. Genetic or chemical hypochlorhydria is associated with inflammation that modulates parietal and G-cell populations in mice. Gastroenterology. 122:119–33.Google Scholar
  200. Zavros, Y., M. Waghray, A. Tessier, L. Bai, A. Todisco, D.L. Gumucio, L.C. Samuelson, A. Dlugosz, and J.L. Merchant. 2007. Reduced pepsin a processing of sonic hedgehog in parietal cells precedes gastric atrophy and transformation. J Biol Chem. 282(46):33265–74.PubMedGoogle Scholar
  201. Zeng, X., J.A. Goetz, L.M. Suber, W.J. Scott, Jr., C.M. Schreiner, and D.J. Robbins. 2001. A freely diffusible form of Sonic hedgehog mediates long-range signalling. Nature. 411:716–20.PubMedGoogle Scholar
  202. Zhao, C.H., X.M. Bu, and N. Zhang. 2007. Hypermethylation and aberrant expression of Wnt antagonist secreted frizzled-related protein 1 in gastric cancer. World J Gastroenterol. 13:2214–7.PubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2009

Authors and Affiliations

  • Juanita L. Merchant
    • 1
  • Yana Zavros
    • 2
  1. 1.Department of Internal MedicineUniversity of MichiganAnn ArborUSA
  2. 2.Department of Molecular and Cellular PhysiologyUniversity of CincinnatiCincinnatiUSA

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