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. 1998 Jul;43(Suppl 1):S27–S32. doi: 10.1136/gut.43.2008.s27

Importance of changes in epithelial cell turnover during Helicobacter pylori infection in gastric carcinogenesis

M Anti, A Armuzzi, A Gasbarrini, G Gasbarrini
PMCID: PMC1766608  PMID: 9764036

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Figure 1 .

Figure 1

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Bi-directional migration of gastric epithelial cells during the proliferation/differentiation process. 


Figure 2 .

Figure 2

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Relation between antral epithelial cell proliferation and mucosal inflammatory cell infiltrate. Computer aided image analysis was used to evaluate acute (polymorphonuclear cells) and chronic (mononuclear cells) inflammation in gastric antral lamina propria from biopsy specimens. Thirty seven subjects, 20 H pylori positive and 17 H pylori negative, were included in the analysis. Consecutive sections (stained with haematoxylin and eosin) from those examined for cell proliferation were evaluated in each case. Mononuclear cells were automatically evaluated using microdensitometric software (Microscience Phoenix Inc.), whereas polymorphonuclear cells were evaluated using software for linear morphometry (Microscience Phoenix Inc.). The number of inflammatory cells counted was expressed as density (cells/mm2). A significant relation was found between total labelling index and both polymorphonuclear and mononuclear cell densities. (Spearman rank test R=0.42; p<0.05). 


Figure 3 .

Figure 3

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Apoptotic indexes in 20 H pylori positive and 17 H pylori negative dyspeptic patients. Epithelial apoptosis was assessed using the TUNEL method on antral glands from endoscopic biopsy specimens. The apoptotic index was expressed as the percentage of labelled cells to total cells in each case. Median values are shown by horizontal bars. No significant differences were found between the two groups (Mann-Whitney U test; p=0.07). 


Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anti M., Armelao F., Marra G., Percesepe A., Bartoli G. M., Palozza P., Parrella P., Canetta C., Gentiloni N., De Vitis I. Effects of different doses of fish oil on rectal cell proliferation in patients with sporadic colonic adenomas. Gastroenterology. 1994 Dec;107(6):1709–1718. doi: 10.1016/0016-5085(94)90811-7. [DOI] [PubMed] [Google Scholar]
  2. Anti M., Marra G., Armelao F., Bartoli G. M., Ficarelli R., Percesepe A., De Vitis I., Maria G., Sofo L., Rapaccini G. L. Effect of omega-3 fatty acids on rectal mucosal cell proliferation in subjects at risk for colon cancer. Gastroenterology. 1992 Sep;103(3):883–891. doi: 10.1016/0016-5085(92)90021-p. [DOI] [PubMed] [Google Scholar]
  3. Biasco G., Paganelli G. M., Santucci R., Miglioli M., Barbara L. Cell proliferation kinetics as a marker of gastric cancer risk. Ital J Gastroenterol. 1991 Jan;23(1):24–28. [PubMed] [Google Scholar]
  4. Blaser M. J., Chyou P. H., Nomura A. Age at establishment of Helicobacter pylori infection and gastric carcinoma, gastric ulcer, and duodenal ulcer risk. Cancer Res. 1995 Feb 1;55(3):562–565. [PubMed] [Google Scholar]
  5. Boise L. H., González-García M., Postema C. E., Ding L., Lindsten T., Turka L. A., Mao X., Nuñez G., Thompson C. B. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell. 1993 Aug 27;74(4):597–608. doi: 10.1016/0092-8674(93)90508-n. [DOI] [PubMed] [Google Scholar]
  6. Brenes F., Ruiz B., Correa P., Hunter F., Rhamakrishnan T., Fontham E., Shi T. Y. Helicobacter pylori causes hyperproliferation of the gastric epithelium: pre- and post-eradication indices of proliferating cell nuclear antigen. Am J Gastroenterol. 1993 Nov;88(11):1870–1875. [PubMed] [Google Scholar]
  7. Brito M. J., Williams G. T., Thompson H., Filipe M. I. Expression of p53 in early (T1) gastric carcinoma and precancerous adjacent mucosa. Gut. 1994 Dec;35(12):1697–1700. doi: 10.1136/gut.35.12.1697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bukin Y. V., Zaridze D. G., Draudin-Krylenko V. A., Orlov E. N., Sigacheva N. A., Dawei F., Kurtzman MYa, Schlenskaya I. N., Gorbacheva O. N., Nechipai A. M. Effect of beta-carotene supplementation on the activity of ornithine decarboxylase (ODC) in stomach mucosa of patients with chronic atrophic gastritis. Eur J Cancer Prev. 1993 Jan;2(1):61–68. doi: 10.1097/00008469-199301000-00010. [DOI] [PubMed] [Google Scholar]
  9. Cahill R. J., Kilgallen C., Beattie S., Hamilton H., O'Morain C. Gastric epithelial cell kinetics in the progression from normal mucosa to gastric carcinoma. Gut. 1996 Feb;38(2):177–181. doi: 10.1136/gut.38.2.177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cahill R. J., Xia H., Kilgallen C., Beattie S., Hamilton H., O'Morain C. Effect of eradication of Helicobacter pylori infection on gastric epithelial cell proliferation. Dig Dis Sci. 1995 Aug;40(8):1627–1631. doi: 10.1007/BF02212681. [DOI] [PubMed] [Google Scholar]
  11. Clarke A. R., Gledhill S., Hooper M. L., Bird C. C., Wyllie A. H. p53 dependence of early apoptotic and proliferative responses within the mouse intestinal epithelium following gamma-irradiation. Oncogene. 1994 Jun;9(6):1767–1773. [PubMed] [Google Scholar]
  12. Clarke A. R., Purdie C. A., Harrison D. J., Morris R. G., Bird C. C., Hooper M. L., Wyllie A. H. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature. 1993 Apr 29;362(6423):849–852. doi: 10.1038/362849a0. [DOI] [PubMed] [Google Scholar]
  13. Collins J. S., Hamilton P. W., Watt P. C., Sloan J. M., Love A. H. Quantitative histological study of mucosal inflammatory cell densities in endoscopic duodenal biopsy specimens from dyspeptic patients using computer linked image analysis. Gut. 1990 Aug;31(8):858–861. doi: 10.1136/gut.31.8.858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Collins J. S., Hamilton P. W., Watt P. C., Sloan J. M., Love A. H. Superficial gastritis and Campylobacter pylori in dyspeptic patients--a quantitative study using computer-linked image analysis. J Pathol. 1989 Aug;158(4):303–310. doi: 10.1002/path.1711580407. [DOI] [PubMed] [Google Scholar]
  15. Correa P., Fox J., Fontham E., Ruiz B., Lin Y. P., Zavala D., Taylor N., Mackinley D., de Lima E., Portilla H. Helicobacter pylori and gastric carcinoma. Serum antibody prevalence in populations with contrasting cancer risks. Cancer. 1990 Dec 15;66(12):2569–2574. doi: 10.1002/1097-0142(19901215)66:12<2569::aid-cncr2820661220>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
  16. Correa P., Haenszel W., Cuello C., Zavala D., Fontham E., Zarama G., Tannenbaum S., Collazos T., Ruiz B. Gastric precancerous process in a high risk population: cohort follow-up. Cancer Res. 1990 Aug 1;50(15):4737–4740. [PubMed] [Google Scholar]
  17. Correa P. Human gastric carcinogenesis: a multistep and multifactorial process--First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res. 1992 Dec 15;52(24):6735–6740. [PubMed] [Google Scholar]
  18. Correa P. The gastric microenvironment determines Helicobacter pylori colonization. Am J Gastroenterol. 1995 Sep;90(9):1379–1381. [PubMed] [Google Scholar]
  19. Cover T. L., Dooley C. P., Blaser M. J. Characterization of and human serologic response to proteins in Helicobacter pylori broth culture supernatants with vacuolizing cytotoxin activity. Infect Immun. 1990 Mar;58(3):603–610. doi: 10.1128/iai.58.3.603-610.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Crabtree J. E., Taylor J. D., Wyatt J. I., Heatley R. V., Shallcross T. M., Tompkins D. S., Rathbone B. J. Mucosal IgA recognition of Helicobacter pylori 120 kDa protein, peptic ulceration, and gastric pathology. Lancet. 1991 Aug 10;338(8763):332–335. doi: 10.1016/0140-6736(91)90477-7. [DOI] [PubMed] [Google Scholar]
  21. Davies G. R., Simmonds N. J., Stevens T. R., Sheaff M. T., Banatvala N., Laurenson I. F., Blake D. R., Rampton D. S. Helicobacter pylori stimulates antral mucosal reactive oxygen metabolite production in vivo. Gut. 1994 Feb;35(2):179–185. doi: 10.1136/gut.35.2.179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ellis R. E., Yuan J. Y., Horvitz H. R. Mechanisms and functions of cell death. Annu Rev Cell Biol. 1991;7:663–698. doi: 10.1146/annurev.cb.07.110191.003311. [DOI] [PubMed] [Google Scholar]
  23. Farrow S. N., Brown R. New members of the Bcl-2 family and their protein partners. Curr Opin Genet Dev. 1996 Feb;6(1):45–49. doi: 10.1016/s0959-437x(96)90009-x. [DOI] [PubMed] [Google Scholar]
  24. Forman D., Newell D. G., Fullerton F., Yarnell J. W., Stacey A. R., Wald N., Sitas F. Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation. BMJ. 1991 Jun 1;302(6788):1302–1305. doi: 10.1136/bmj.302.6788.1302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Goldstone A. R., Quirke P., Dixon M. F. Helicobacter pylori infection and gastric cancer. J Pathol. 1996 Jun;179(2):129–137. doi: 10.1002/(SICI)1096-9896(199606)179:2<129::AID-PATH504>3.0.CO;2-C. [DOI] [PubMed] [Google Scholar]
  26. Guarner J., Mohar A., Parsonnet J., Halperin D. The association of Helicobacter pylori with gastric cancer and preneoplastic gastric lesions in Chiapas, Mexico. Cancer. 1993 Jan 15;71(2):297–301. doi: 10.1002/1097-0142(19930115)71:2<297::aid-cncr2820710205>3.0.co;2-9. [DOI] [PubMed] [Google Scholar]
  27. Hall P. A., Coates P. J., Ansari B., Hopwood D. Regulation of cell number in the mammalian gastrointestinal tract: the importance of apoptosis. J Cell Sci. 1994 Dec;107(Pt 12):3569–3577. doi: 10.1242/jcs.107.12.3569. [DOI] [PubMed] [Google Scholar]
  28. Hengartner M. O., Ellis R. E., Horvitz H. R. Caenorhabditis elegans gene ced-9 protects cells from programmed cell death. Nature. 1992 Apr 9;356(6369):494–499. doi: 10.1038/356494a0. [DOI] [PubMed] [Google Scholar]
  29. Hengartner M. O. Programmed cell death in invertebrates. Curr Opin Genet Dev. 1996 Feb;6(1):34–38. doi: 10.1016/s0959-437x(96)90007-6. [DOI] [PubMed] [Google Scholar]
  30. Ierardi E., Francavilla A., Balzano T., Traversa A., Principi M., Monno R. A., Amoruso A., Ingrosso M., Pisani A., Panella C. Effect of Helicobacter pylori eradication on gastric epithelial proliferation. Relationship with ras oncogene p21 expression. Ital J Gastroenterol Hepatol. 1997 Jun;29(3):214–219. [PubMed] [Google Scholar]
  31. Imatani A., Sasano H., Yabuki N., Kato K., Ohara S., Asaki S., Toyota T., Nagura H. In situ analysis of tissue dynamics and p53 expression in human gastric mucosa. J Pathol. 1996 May;179(1):39–42. doi: 10.1002/(SICI)1096-9896(199605)179:1<39::AID-PATH543>3.0.CO;2-E. [DOI] [PubMed] [Google Scholar]
  32. Ishida M., Gomyo Y., Tatebe S., Ohfuji S., Ito H. Apoptosis in human gastric mucosa, chronic gastritis, dysplasia and carcinoma: analysis by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling. Virchows Arch. 1996 Jul;428(4-5):229–235. doi: 10.1007/BF00196695. [DOI] [PubMed] [Google Scholar]
  33. Joypaul B. V., Newman E. L., Hopwood D., Grant A., Qureshi S., Lane D. P., Cuschieri A. Expression of p53 protein in normal, dysplastic, and malignant gastric mucosa: an immunohistochemical study. J Pathol. 1993 Jul;170(3):279–283. doi: 10.1002/path.1711700310. [DOI] [PubMed] [Google Scholar]
  34. Kuipers E. J., Pérez-Pérez G. I., Meuwissen S. G., Blaser M. J. Helicobacter pylori and atrophic gastritis: importance of the cagA status. J Natl Cancer Inst. 1995 Dec 6;87(23):1777–1780. doi: 10.1093/jnci/87.23.1777. [DOI] [PubMed] [Google Scholar]
  35. Kuipers E. J., Uyterlinde A. M., Peña A. S., Roosendaal R., Pals G., Nelis G. F., Festen H. P., Meuwissen S. G. Long-term sequelae of Helicobacter pylori gastritis. Lancet. 1995 Jun 17;345(8964):1525–1528. doi: 10.1016/s0140-6736(95)91084-0. [DOI] [PubMed] [Google Scholar]
  36. Lauwers G. Y., Scott G. V., Hendricks J. Immunohistochemical evidence of aberrant bcl-2 protein expression in gastric epithelial dysplasia. Cancer. 1994 Jun 15;73(12):2900–2904. doi: 10.1002/1097-0142(19940615)73:12<2900::aid-cncr2820731205>3.0.co;2-0. [DOI] [PubMed] [Google Scholar]
  37. Levine A. J. p53, the cellular gatekeeper for growth and division. Cell. 1997 Feb 7;88(3):323–331. doi: 10.1016/s0092-8674(00)81871-1. [DOI] [PubMed] [Google Scholar]
  38. Lipkin M., Correa P., Mikol Y. B., Higgins P. J., Cuello C., Zarama G., Fontham E., Zavala D. Proliferative and antigenic modifications in human epithelial cells in chronic atrophic gastritis. J Natl Cancer Inst. 1985 Oct;75(4):613–619. [PubMed] [Google Scholar]
  39. Lowe S. W., Schmitt E. M., Smith S. W., Osborne B. A., Jacks T. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature. 1993 Apr 29;362(6423):847–849. doi: 10.1038/362847a0. [DOI] [PubMed] [Google Scholar]
  40. Lynch D. A., Axon A. T. Helicobacter pylori, gastric cancer and gastric epithelial kinetics: a review. Eur J Gastroenterol Hepatol. 1995 Aug;7 (Suppl 1):S17–S23. [PubMed] [Google Scholar]
  41. Lynch D. A., Mapstone N. P., Clarke A. M., Sobala G. M., Jackson P., Morrison L., Dixon M. F., Quirke P., Axon A. T. Cell proliferation in Helicobacter pylori associated gastritis and the effect of eradication therapy. Gut. 1995 Mar;36(3):346–350. doi: 10.1136/gut.36.3.346. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Mannick E. E., Bravo L. E., Zarama G., Realpe J. L., Zhang X. J., Ruiz B., Fontham E. T., Mera R., Miller M. J., Correa P. Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: effect of antibiotics and antioxidants. Cancer Res. 1996 Jul 15;56(14):3238–3243. [PubMed] [Google Scholar]
  43. Merritt A. J., Potten C. S., Kemp C. J., Hickman J. A., Balmain A., Lane D. P., Hall P. A. The role of p53 in spontaneous and radiation-induced apoptosis in the gastrointestinal tract of normal and p53-deficient mice. Cancer Res. 1994 Feb 1;54(3):614–617. [PubMed] [Google Scholar]
  44. Moss S. F., Calam J., Agarwal B., Wang S., Holt P. R. Induction of gastric epithelial apoptosis by Helicobacter pylori. Gut. 1996 Apr;38(4):498–501. doi: 10.1136/gut.38.4.498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Nomura A., Stemmermann G. N., Chyou P. H., Kato I., Perez-Perez G. I., Blaser M. J. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med. 1991 Oct 17;325(16):1132–1136. doi: 10.1056/NEJM199110173251604. [DOI] [PubMed] [Google Scholar]
  46. Nuñez G., Clarke M. F. The Bcl-2 family of proteins: regulators of cell death and survival. Trends Cell Biol. 1994 Nov;4(11):399–403. doi: 10.1016/0962-8924(94)90053-1. [DOI] [PubMed] [Google Scholar]
  47. Panella C., Ierardi E., Polimeno L., Balzano T., Ingrosso M., Amoruso A., Traversa A., Francavilla A. Proliferative activity of gastric epithelium in progressive stages of Helicobacter pylori infection. Dig Dis Sci. 1996 Jun;41(6):1132–1138. doi: 10.1007/BF02088228. [DOI] [PubMed] [Google Scholar]
  48. Parsonnet J., Friedman G. D., Vandersteen D. P., Chang Y., Vogelman J. H., Orentreich N., Sibley R. K. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med. 1991 Oct 17;325(16):1127–1131. doi: 10.1056/NEJM199110173251603. [DOI] [PubMed] [Google Scholar]
  49. Parsonnet J., Vandersteen D., Goates J., Sibley R. K., Pritikin J., Chang Y. Helicobacter pylori infection in intestinal- and diffuse-type gastric adenocarcinomas. J Natl Cancer Inst. 1991 May 1;83(9):640–643. doi: 10.1093/jnci/83.9.640. [DOI] [PubMed] [Google Scholar]
  50. Peek R. M., Jr, Moss S. F., Tham K. T., Pérez-Pérez G. I., Wang S., Miller G. G., Atherton J. C., Holt P. R., Blaser M. J. Helicobacter pylori cagA+ strains and dissociation of gastric epithelial cell proliferation from apoptosis. J Natl Cancer Inst. 1997 Jun 18;89(12):863–868. doi: 10.1093/jnci/89.12.863. [DOI] [PubMed] [Google Scholar]
  51. Polyak K., Waldman T., He T. C., Kinzler K. W., Vogelstein B. Genetic determinants of p53-induced apoptosis and growth arrest. Genes Dev. 1996 Aug 1;10(15):1945–1952. doi: 10.1101/gad.10.15.1945. [DOI] [PubMed] [Google Scholar]
  52. Potten C. S. What is an apoptotic index measuring? A commentary. Br J Cancer. 1996 Dec;74(11):1743–1748. doi: 10.1038/bjc.1996.624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Que F. G., Gores G. J. Cell death by apoptosis: basic concepts and disease relevance for the gastroenterologist. Gastroenterology. 1996 Apr;110(4):1238–1243. doi: 10.1053/gast.1996.v110.pm8613014. [DOI] [PubMed] [Google Scholar]
  54. Ranzani G. N., Luinetti O., Padovan L. S., Calistri D., Renault B., Burrel M., Amadori D., Fiocca R., Solcia E. p53 gene mutations and protein nuclear accumulation are early events in intestinal type gastric cancer but late events in diffuse type. Cancer Epidemiol Biomarkers Prev. 1995 Apr-May;4(3):223–231. [PubMed] [Google Scholar]
  55. Ricci V., Ciacci C., Zarrilli R., Sommi P., Tummuru M. K., Del Vecchio Blanco C., Bruni C. B., Cover T. L., Blaser M. J., Romano M. Effect of Helicobacter pylori on gastric epithelial cell migration and proliferation in vitro: role of VacA and CagA. Infect Immun. 1996 Jul;64(7):2829–2833. doi: 10.1128/iai.64.7.2829-2833.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Saegusa M., Takano Y., Okayasu I. Bcl-2 expression and its association with cell kinetics in human gastric carcinomas and intestinal metaplasia. J Cancer Res Clin Oncol. 1995;121(6):357–363. doi: 10.1007/BF01225688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Shiao Y. H., Rugge M., Correa P., Lehmann H. P., Scheer W. D. p53 alteration in gastric precancerous lesions. Am J Pathol. 1994 Mar;144(3):511–517. [PMC free article] [PubMed] [Google Scholar]
  58. Sobala G. M., Schorah C. J., Shires S., Lynch D. A., Gallacher B., Dixon M. F., Axon A. T. Effect of eradication of Helicobacter pylori on gastric juice ascorbic acid concentrations. Gut. 1993 Aug;34(8):1038–1041. doi: 10.1136/gut.34.8.1038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Thompson C. B. Apoptosis in the pathogenesis and treatment of disease. Science. 1995 Mar 10;267(5203):1456–1462. doi: 10.1126/science.7878464. [DOI] [PubMed] [Google Scholar]
  60. Tsujii M., Kawano S., Tsuji S., Ito T., Nagano K., Sasaki Y., Hayashi N., Fusamoto H., Kamada T. Cell kinetics of mucosal atrophy in rat stomach induced by long-term administration of ammonia. Gastroenterology. 1993 Mar;104(3):796–801. doi: 10.1016/0016-5085(93)91015-a. [DOI] [PubMed] [Google Scholar]
  61. Tsujii M., Kawano S., Tsuji S., Takei Y., Tamura K., Fusamoto H., Kamada T. Mechanism for ammonia-induced promotion of gastric carcinogenesis in rats. Carcinogenesis. 1995 Mar;16(3):563–566. doi: 10.1093/carcin/16.3.563. [DOI] [PubMed] [Google Scholar]
  62. White E. Life, death, and the pursuit of apoptosis. Genes Dev. 1996 Jan 1;10(1):1–15. doi: 10.1101/gad.10.1.1. [DOI] [PubMed] [Google Scholar]
  63. Wyllie A. H. Apoptosis and carcinogenesis. Eur J Cell Biol. 1997 Jul;73(3):189–197. [PubMed] [Google Scholar]
  64. Wyllie A. H., Kerr J. F., Currie A. R. Cell death: the significance of apoptosis. Int Rev Cytol. 1980;68:251–306. doi: 10.1016/s0074-7696(08)62312-8. [DOI] [PubMed] [Google Scholar]

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