Gastroenterology
Volume 132, Issue 3 , Pages 1009-1023 , March 2007

Intracellular, Intercellular, and Stromal Invasion of Gastric Mucosa, Preneoplastic Lesions, and Cancer by Helicobacter pylori

  • Vittorio Necchi

      Affiliations

    • Department of Human Pathology, University of Pavia, Pavia, Italy
    • Corresponding Author InformationAddress requests for reprints to: Vittorio Ricci, MD, PhD, Department of Experimental Medicine, Section of Human Physiology, University of Pavia Medical School, Via Forlanini 6, 27100 Pavia, Italy. fax: (39) 0382 987664.
  • ,
  • Maria Elena Candusso

      Affiliations

    • Pathologic Anatomy Service, IRCCS Policlinico S. Matteo, Pavia, Italy
  • ,
  • Francesca Tava

      Affiliations

    • Pathologic Anatomy Service, IRCCS Policlinico S. Matteo, Pavia, Italy
  • ,
  • Ombretta Luinetti

      Affiliations

    • Pathologic Anatomy Service, IRCCS Policlinico S. Matteo, Pavia, Italy
  • ,
  • Ulderico Ventura

      Affiliations

    • Department of Experimental Medicine, University of Pavia, Pavia, Italy
  • ,
  • Roberto Fiocca

      Affiliations

    • Department of Pathology, University of Genova, Genova, Italy
  • ,
  • Vittorio Ricci

      Affiliations

    • Department of Experimental Medicine, University of Pavia, Pavia, Italy
    • V.R. and E.S. share last authorship.
  • ,
  • Enrico Solcia

      Affiliations

    • Pathologic Anatomy Service, IRCCS Policlinico S. Matteo, Pavia, Italy
    • V.R. and E.S. share last authorship.

Received 28 September 2006 ,Accepted 30 November 2006.

References 

  1. Rauws EAJ, Langenberg W, Houthoff HJ, Zanen HC, Tytgat GNJ. Campylobacter pyloridis-associated chronic antral gastritis. Gastroenterology. 1988;94:33–40
  2. Fiocca R, Villani L, Luinetti O, Gianatti A, Perego M, Alvisi C, et al. Helicobacter colonization and histopathological profile of chronic gastritis in patients with or without dyspepsia, mucosal erosion and peptic ulcer: a morphological approach to the study of ulcerogenesis in man. Virchows Arch. 1992;420:489–498
  3. Fiocca R, Luinetti O, Villani L, Chiaravalli AM, Capella C, Solcia E. Epithelial cytotoxicity, immune responses, and inflammatory components of Helicobacter pylori gastritis. Scand J Gastroenterol. 1994;29(Suppl 205):11–21
  4. Crabtree JE, Wyatt JI, Trejdosiewicz LK, Peichl P, Nichols PH, Ramsay N, et al. Interleukin-8 expression in Helicobacter pylori infected, normal, and neoplastic gastroduodenal mucosa. J Clin Pathol. 1994;47:61–66
  5. Barrera C, Ye G, Espejo R, Gunasena S, Almanza R, Leary J, et al. Expression of cathepsins B, L, S, and D by gastric epithelial cells implicates them as antigen presenting cells in local immune responses. Hum Immunol. 2001;62:1081–1091
  6. Lindholm C, Quiding-Jarbrink M, Lonroth H, Hamlet A, Svennerholm AM. Local cytokine response in Helicobacter pylori-infected subjects. Infect Immun. 1998;66:5964–5971
  7. Engstrand L, Scheynius A, Pahlson C, Grimelius L, Schwan A, Gustavsson S. Association of Campylobacter pylori with induced expression of class II transplantation antigens on gastric epithelial cells. Infect Immun. 1989;57:827–832
  8. Ye G, Barrera C, Fan X, Gourley WK, Crowe SE, Ernst PB, et al. 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. 1997;99:1628–1636
  9. Owen RL, Pierce NF, Apple RT, Cray WC. M cell transport of Vibrio cholerae from the intestinal lumen into Peyer’s patches: a mechanism for antigen sampling and for microbial transepithelial migration. J Infect Dis. 1986;153:1108–1118
  10. Neutra MR, Phillips TL, Mayer EL, Fishkind DJ. Transport of membrane-bound macromolecules by M cells in follicle-associated epithelium of rabbit Peyer’s patch. Cell Tissue Res. 1987;247:537–546
  11. Finzi G, Cornaggia M, Capella C, Fiocca R, Bosi F, Solcia E, et al. Cathepsin E in follicle associated epithelium of intestine and tonsils: localization to M cells and possible role in antigen processing. Histochemistry. 1993;99:201–211
  12. Galgani M, Busiello I, Censini S, Zappacosta S, Racioppi L, Zarrilli R. Helicobacter pylori induces apoptosis of human monocytes but not monocyte-derived dendritic cells: role of the cag pathogenicity island. Infect Immun. 2004;72:4480–4485
  13. Hafsi N, Voland P, Schwendy S, Rad R, Reindl W, Gerhard M, et al. Human dendritic cells respond to Helicobacter pylori, promoting NK cell and Th1-effector responses in vitro. J Immunol. 2004;173:1249–1257
  14. Gebert B, Fischer W, Haas R. The Helicobacter pylori vacuolating cytotoxin: from cellular vacuolation to immunosuppressive activities. Rev Physiol Biochem Pharmacol. 2004;152:205–220
  15. Petersen AM, Krogfelt KA. Helicobacter pylori: an invading microorganism? (A review). FEMS Immunol Med Microbiol. 2003;36:117–126
  16. Chen XG, Correa P, Offerhaus J. Ultrastructure of the gastric mucosa harboring Campylobacter-like organisms. Am J Clin Pathol. 1986;86:575–582
  17. Hazell SL, Lee A, Brady L, Hennessy W. Campylobacter pyloridis and gastritis: association with intercellular spaces and adaptation to an environment of mucus as important factors in colonization of the gastric epithelium. J Infect Dis. 1986;153:658–663
  18. Tricottet V, Bruneval P, Vire O, Camilleri JP, Bloch F, Bonte N, et al. Campylobacter-like organisms and surface epithelium abnormalities in active, chronic gastritis in humans: an ultrastructural study. Ultrastruct Pathol. 1986;10:113–122
  19. Bode G, Malfertheiner P, Ditschuneit H. Pathogenetic implications of ultrastructural findings in Campylobacter pylori-related gastroduodenal disease. Scand J Gastroenterol. 1988;23(Suppl 142):25–39
  20. Andersen LP, Holck S. Possible evidence of invasiveness of Helicobacter (Campylobacter) pylori. Eur J Clin Microbiol Infect Dis. 1990;9:135–138
  21. Chan WY, Hui PK, Leung KM, Thomas TM. Modes of Helicobacter colonization and gastric epithelial damage. Histopathology. 1992;21:521–528
  22. Noach LA, Rolf TM, Tytgat GN. Electron microscopic study of association between Helicobacter pylori and gastric and duodenal mucosa. J Clin Pathol. 1994;47:699–704
  23. El-Shoura SM. Helicobacter pylori: I (Ultrastructural sequences of adherence, attachment, and penetration into the gastric mucosa). Ultrastruct Pathol. 1995;19:323–333
  24. Engstrand L, Graham D, Scheynius A, Genta RM, El-Zaatari F. Is the sanctuary where Helicobacter pylori avoids antibacterial treatment intracellular?. Am J Clin Pathol. 1997;108:504–509
  25. Jhala NC, Siegal GP, Klemm K, Atkinson BF, Jhala DN. Infiltration of Helicobacter pylori in the gastric mucosa. Am J Clin Pathol. 2003;119:101–107
  26. Jhala D, Jhala N, Lechago J, Haber M. Helicobacter heilmannii gastritis: association with acid peptic diseases and comparison with Helicobacter pylori gastritis. Mod Pathol. 1999;12:534–538
  27. Lu H, Yamaoka Y, Graham DY. Helicobacter pylori virulence factors: facts and fantasies. Curr Opin Gastroenterol. 2005;21:653–659
  28. Amieva MR, Vogelmann R, Covacci A, Tompkins LS, Nelson WJ, Falkow S. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science. 2003;300:1430–1434
  29. Suzuki K, Kokai Y, Sawada N, Takakuwa R, Kuwahara K, Isogai E, et al. SS1 Helicobacter pylori disrupts the paracellular barrier of the gastric mucosa and leads to neutrophilic gastritis in mice. Virchows Arch. 2002;440:318–324
  30. Evans DG, Evans DJ, Graham DY. Adherence and internalization of Helicobacter pylori by HEp-2 cells. Gastroenterology. 1992;102:1557–1567
  31. Bjorkholm B, Zhukhovitsky V, Lofman C, Hulten K, Enroth H, Block M, et al. Helicobacter pylori entry into human gastric epithelial cells: a potential determinant of virulence, persistence, and treatment failures. Helicobacter. 2000;5:148–154
  32. Ko GH, Kang SM, Kim YK, Lee JH, Park CK, Youn HS, et al. Invasiveness of Helicobacter pylori into human gastric mucosa. Helicobacter. 1999;4:77–81
  33. Semino-Mora C, Doi SQ, Marty A, Simko V, Carlstedt I, Dubois A. Intracellular and interstitial expression of Helicobacter pylori virulence genes in gastric precancerous intestinal metaplasia and adenocarcinoma. J Infect Dis. 2003;187:1165–1177
  34. Andersen LP, Holck S, Povlsen CO. Campylobacter pylori detected by indirect immunohistochemical technique. APMIS. 1988;96:559–564
  35. Sommi P, Ricci V, Fiocca R, Necchi V, Romano M, Telford JL, et al. Persistence of Helicobacter pylori VacA toxin and vacuolating potential in cultured gastric epithelial cells. Am J Physiol. 1998;275:G681–G688
  36. Fiocca R, Necchi V, Sommi P, Ricci V, Telford J, Cover TL, et al. Release of Helicobacter pylori vacuolating cytotoxin by both a specific secretion pathway and budding of outer membrane vesicles (Uptake of released toxin and vesicles by gastric epithelium). J Pathol. 1999;188:220–226
  37. Ricci V, Sommi P, Fiocca R, Romano M, Solcia E, Ventura U. Helicobacter pylori vacuolating toxin accumulates within the endosomal-vacuolar compartment of cultured gastric cells and potentiates the vacuolating activity of ammonia. J Pathol. 1997;183:453–459
  38. Cover TL, Tummuru MKR, Cao P, Thompson SA, Blaser MJ. Divergence of genetic sequences for the vacuolating cytotoxin among Helicobacter pylori strains. J Biol Chem. 1994;269:10566–10573
  39. Tummuru MKR, Cover TL, Blaser MJ. Mutation of the cytotoxin-associated cagA gene does not affect the vacuolating cytotoxin activity of Helicobacter pylori. Infect Immun. 1994;62:2609–2613
  40. Fiocca R, Cornaggia M, Villani L, Capella C, Solcia E, Samloff IM. Expression of pepsinogen II in gastric cancer (Its relationship to local invasion and lymph node metastases). Cancer. 1988;61:956–962
  41. Fiocca R, Villani L, Tenti P, Cornaggia M, Finzi G, Capella C, et al. Widespread expression of intestinal markers in gastric carcinoma: a light and electron microscopic study using BD-5 monoclonal antibody. J Clin Pathol. 1988;41:178–187
  42. Fiocca R, Villani L, Tenti P, Cornaggia M, Finzi G, Riva C, et al. The foveolar cell component of gastric cancer. Hum Pathol. 1990;21:260–270
  43. Rugge M, Correa P, Dixon MF, Hattori T, Leandro G, Lewin K, et al. Gastric dysplasia: the Padova international classification. Am J Surg Pathol. 2000;24:167–176
  44. Solcia E, Luinetti O, Tava F, Klersy C, Grillo F, Pandolfo N, et al. Identification of a lower grade muconodular subtype of gastric mucinous cancer. Virchows Arch. 2004;445:572–579
  45. Kaye GI, Fenoglio CM, Pascal RR, Lane N. Comparative electron microscopic features of normal, hyperplastic, and adenomatous human colonic epithelium (Variations in cellular structure relative to the process of epithelial differentiation). Gastroenterology. 1973;64:926–945
  46. Terres AM, Pajares JM, Hopkins AM, Murphy A, Moran A, Baird AW, et al. Helicobacter pylori disrupts epithelial barrier function in a process inhibited by protein kinase C activators. Infect Immun. 1998;66:2943–2950
  47. Papini E, Satin B, Norais N, de Bernard M, Telford JL, Rappuoli R, et al. Selective increase of the permeability of polarized epithelial cell monolayers by Helicobacter pylori vacuolating toxin. J Clin Invest. 1998;102:813–820
  48. Ekstrom AM, Held M, Hansson LE, Engstrand L, Nyren O. Helicobacter pylori in gastric cancer established by CagA immunoblot as a marker of past infection. Gastroenterology. 2001;121:784–791
  49. Danesh J, Youngman L, Clark S, Parish S, Peto R, Collins R. Helicobacter pylori infection and early onset myocardial infarction: case-control and sibling pairs study. BMJ. 1999;319:1157–1162
  50. Salardi S, Cacciari E, Menegatti M, Landi F, Mazzanti L, Stella FA, et al. Helicobacter pylori and type 1 diabetes mellitus in children. J Pediatr Gastroenterol Nutr. 1999;28:307–309
  51. Larizza D, Calcaterra V, Martinetti M, Negrini R, De Silvestri A, Cisternino M, et al. Helicobacter pylori infection and autoimmune thyroid disease in young patients: the disadvantage of carrying the human leukocyte antigen-DRB1*0301 allele. J Clin Endocrinol Metab. 2006;91:176–179
  52. Ndawula EM, Owen RJ, Mihr G, Borman P, Hurtado A. Helicobacter pylori bacteraemia. Eur J Clin Microbiol Infect Dis. 1994;13:621
  53. Rescigno M, Urbano M, Valzasina B, Francolini M, Rotta G, Bonasio R, et al. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol. 2001;2:361–367
  54. Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP, et al. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat Immunol. 2004;5:1166–1174
  55. Neri M, Susi D, Bovani I, Laterza F, Porreca E, Cuccurullo F. Gastric mucosal infiltration by Helicobacter pylori favours bacterial survival after treatment. Aliment Pharmacol Ther. 1996;10:181–185
  56. Marzio L, Angelucci D, Grossi L, Diodoro MG, Di Campli E, Cellini L. Anti-Helicobacter pylori specific antibody immunohistochemistry improves the diagnostic accuracy of Helicobacter pylori in biopsy specimen from patients treated with triple therapy. Am J Gastroenterol. 1998;93:223–226
  57. Genta RM, Gurer IE, Graham DY, Krishnan B, Segura AM, Gutierrez O, et al. Adherence of Helicobacter pylori to areas of incomplete intestinal metaplasia in the gastric mucosa. Gastroenterology. 1996;111:1206–1211
  58. Bravo JC, Correa P. Sulphomucins favour adhesion of Helicobacter pylori to metaplastic gastric mucosa. J Clin Pathol. 1999;52:137–140
  59. Oh JD, Karam SM, Gordon JI. Intracellular Helicobacter pylori in gastric epithelial progenitors. Proc Natl Acad Sci U S A. 2005;102:5186–5191
  60. Segal ED, Cha J, Lo J, Falkow S, Tompkins LS. Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori. Proc Natl Acad Sci U S A. 1999;96:14559–14564
  61. Hatakeyama M. Oncogenic mechanisms of the Helicobacter pylori CagA protein. Nat Rev Cancer. 2004;4:688–694
  62. Maeda S, Yoshida H, Ogura K, Mitsuno Y, Hirata Y, Yamaji Y, et al. H pylori activates NF-κB through a signaling pathway involving IκB kinases, NF-κB-inducing kinase, TRAF2, and TRAF6 in gastric cancer cells. Gastroenterology. 2000;119:97–108
  63. Kim JJ, Tao H, Carloni E, Leung WK, Graham DY, Sepulveda AR. Helicobacter pylori impairs DNA mismatch repair in gastric epithelial cells. Gastroenterology. 2002;123:542–553
  64. Mera R, Fontham ET, Bravo LE, Bravo JC, Piazuelo MB, Camargo MC, et al. Long term follow up of patients treated for Helicobacter pylori infection. Gut. 2005;54:1536–1540
  65. Tava F, Luinetti O, Ghigna MR, Alvisi C, Perego M, Trespi E, et al. Type or extension of intestinal metaplasia and immature/atypical “indefinite for dysplasia” lesions as predictors of gastric neoplasia. Hum Pathol. 2006;37:1489–1497
  66. Uemura N, Mukai T, Okamoto S, Yamaguchi S, Mashiba H, Taniyama K, et al. Effect of Helicobacter pylori eradication on subsequent development of cancer after endoscopic resection of early gastric cancer. Cancer Epidemiol Biomarkers Prev. 1997;6:639–642

 Supported in part by grants from the Italian Ministry of Health to IRCCS Policlinico S. Matteo, from the University of Pavia (Fondo d’Ateneo per la Ricerca; to E.S. and U.V.), and from the Italian Ministry for University and Research (to V.R. and U.V.) (Progetti di Ricerca di Interesse Nazionale 2004065448_002 and 2004064334_003, respectively).

PII: S0016-5085(07)00188-6

doi: 10.1053/j.gastro.2007.01.049

Gastroenterology
Volume 132, Issue 3 , Pages 1009-1023 , March 2007