Cell Cycle Deregulation in Pre-neoplasia: Case Study of Barrett’s Oesophagus

  • Pierre Lao-Sirieix
  • Rebecca C. Fitzgerald
Part of the Current Cancer Research book series (CUCR)


Most solid tumours develop through a pre-invasive stage referred to as intra-epithelial neoplasia (IEN). The lag time between development of IEN and progression to fully fledged cancer would allow for chemoprevention or therapeutic interventions; however in most cases, IEN remains undetected and the exact mechanisms for progression remain unknown. Barrett’s oesophagus, the premalignant stage of oesophageal adenocarcinoma, is the perfect model to study IEN since the oesophagus is readily accessible by endoscopy and allows for temporal follow-up of patients. Like most IEN, Barrett’s oesophagus and associated dysplasia are characterized by an increase in proliferation and the expansion of the proliferative compartment. These features have been associated with an increased risk of progression to cancer. There is evidence of dysregulation of the G1/S and G2/M checkpoints which may be caused by an accumulation of abnormally expressed growth factors and oncogenes. Furthermore, the abnormally high level of duodeno-gastro-oesophageal acid reflux bathing the distal oesophagus contributes further to increasing proliferation. The real challenge for future research will be to identify causal events and to develop better diagnostic methods and therapeutic options.


Acid Reflux Oesophageal Adenocarcinoma Proliferative Compartment Autocrine Stimulation Luminal Factor 
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. Bani-Hani K, Martin IG, Hardie LJ, Mapstone N, Briggs JA, Forman D et al. (2000) Prospective study of cyclin D1 overexpression in Barrett’s esophagus: association with increased risk of adenocarcinoma. J Natl Cancer Inst 92(16): 1316–1321.CrossRefPubMedGoogle Scholar
  2. Barrett MT, Pritchard D, Palanca-Wessels C, Anderson J, Reid BJ, Rabinovitch PS (2003) Molecular phenotype of spontaneously arising 4 N (G2-tetraploid) intermediates of neoplastic progression in Barrett’s esophagus. Cancer Res 63(14): 4211–4217.PubMedGoogle Scholar
  3. Barrett MT, Sanchez CA, Prevo LJ, Wong DJ, Galipeau PC, Paulson TG et al. (1999) Evolution of neoplastic cell lineages in Barrett oesophagus. Nat Genet 22(1): 106–109.CrossRefPubMedGoogle Scholar
  4. Batlle E, Henderson JT, Beghtel H, van den Born MM, Sancho E, Huls G et al. (2002) Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell 111(2): 251–263.CrossRefPubMedGoogle Scholar
  5. Boynton RF, Huang Y, Blount PL, Reid BJ, Raskind WH, Haggitt RC et al. (1991) Frequent loss of heterozygosity at the retinoblastoma locus in human esophageal cancers. Cancer Res 51(20): 5766–5769.PubMedGoogle Scholar
  6. Brito MJ, Filipe MI, Linehan J, Jankowski J (1995) Association of transforming growth factor alpha (TGFA) and its precursors with malignant change in Barrett’s epithelium: biological and clinical variables. Int J Cancer 60(1): 27–32.CrossRefPubMedGoogle Scholar
  7. BSG (2005) Guidelines for the diagnosis and management of Barrett’s columnar-lined oesophagus.
  8. Chao DL, Sanchez CA, Galipeau PC, Blount PL, Paulson TG, Cowan DS et al. (2008) Cell Proliferation, Cell Cycle Abnormalities, and Cancer Outcome in Patients with Barrett’s Esophagus: a Long-term Prospective Study. Clin Cancer Res 14(21): 6988–6995.CrossRefPubMedGoogle Scholar
  9. Chen LQ, Hu CY, Gaboury L, Pera M, Ferraro P, Duranceau AC (2001) Proliferative activity in Barrett’s esophagus before and after antireflux surgery. Ann Surg 234(2): 172–180.CrossRefPubMedGoogle Scholar
  10. Clement G, Braunschweig R, Pasquier N, Bosman FT, Benhattar J (2006) Alterations of the Wnt signaling pathway during the neoplastic progression of Barrett’s esophagus. Oncogene 25(21): 3084–3092.CrossRefPubMedGoogle Scholar
  11. Coppola D, Schreiber RH, Mora L, Dalton W, Karl RC (1999) Significance of Fas and retinoblastoma protein expression during the progression of Barrett’s metaplasia to adenocarcinoma. Ann Surg Oncol 6(3): 298–304.CrossRefPubMedGoogle Scholar
  12. DeLancey JO, Thun MJ, Jemal A, Ward EM (2008) Recent trends in Black-White disparities in cancer mortality. Cancer Epidemiol Biomarkers Prev 17(11): 2908–2912.CrossRefPubMedGoogle Scholar
  13. Filipe MI, Jankowski J (1993) Growth factors and oncogenes in Barrett’s oesophagus and gastric metaplasia. Endoscopy 25(9): 637–641.CrossRefPubMedGoogle Scholar
  14. Fitzgerald RC, Omary MB, Triadafilopoulos G (1996) Dynamic effects of acid on Barrett’s esophagus. An ex vivo proliferation and differentiation model. J Clin Invest 98(9): 2120–2128.CrossRefPubMedGoogle Scholar
  15. Fitzgerald RC, Omary MB, Triadafilopoulos G (1998) Altered sodium-hydrogen exchange activity is a mechanism for acid-induced hyperproliferation in Barrett’s esophagus. Am J Physiol 275(1 Pt 1): G47–G55.PubMedGoogle Scholar
  16. Fitzgerald RCOMB, Triadafilopoulos G (1996) Dynamic effects of acid on Barrett’s esophagus: an ex vivo proliferation and differentiation model. J Clin Investig 98(9): 2120–2127.CrossRefPubMedGoogle Scholar
  17. Flejou JF, Paraf F, Muzeau F, Fekete F, Henin D, Jothy S et al. (1994) Expression of c-erbB-2 oncogene product in Barrett’s adenocarcinoma: pathological and prognostic correlations. J Clin Pathol 47(1): 23–26.CrossRefPubMedGoogle Scholar
  18. Forrester K, Almoguera C, Han K, Grizzle WE, Perucho M (1987) Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature 327(6120): 298–303.CrossRefPubMedGoogle Scholar
  19. Freeman A, Morris LS, Mills AD, Stoeber K, Laskey RA, Williams GH et al. (1999) Minichromosome maintenance proteins as biological markers of dysplasia and malignancy. Clin Cancer Res 5(8): 2121–2132.PubMedGoogle Scholar
  20. Galiana C, Lozano JC, Bancel B, Nakazawa H, Yamasaki H (1995) High frequency of Ki-ras amplification and p53 gene mutations in adenocarcinomas of the human esophagus. Mol Carcinog 14(4): 286–293.CrossRefPubMedGoogle Scholar
  21. Galipeau PC, Li X, Blount PL, Maley CC, Sanchez CA, Odze RD et al. (2007) NSAIDs modulate CDKN2A, TP53, and DNA content risk for progression to esophageal adenocarcinoma. PLoS Med 4(2): e67.CrossRefPubMedGoogle Scholar
  22. Geddert H, Heep HJ, Gabbert HE, Sarbia M (2002a) Expression of cyclin B1 in the metaplasia-dysplasia-carcinoma sequence of Barrett esophagus. Cancer 94(1): 212–218.CrossRefPubMedGoogle Scholar
  23. Geddert H, Zeriouh M, Wolter M, Heise JW, Gabbert HE, Sarbia M (2002b) Gene amplification and protein overexpression of c-erb-b2 in Barrett carcinoma and its precursor lesions. Am J Clin Pathol 118(1): 60–66.CrossRefPubMedGoogle Scholar
  24. Gillen P, McDermott M, Grehan D, Hourihane DO, Hennessy TP (1994) Proliferating cell nuclear antigen in the assessment of Barrett’s mucosa. Br J Surg 81(12): 1766–1768.CrossRefPubMedGoogle Scholar
  25. Going JJ, Keith WN, Neilson L, Stoeber K, Stuart RC, Williams GH (2002) Aberrant expression of minichromosome maintenance proteins 2 and 5, and Ki-67 in dysplastic squamous oesophageal epithelium and Barrett’s mucosa. Gut 50(3): 373–377.CrossRefPubMedGoogle Scholar
  26. Haigh CR, Attwood SE, Thompson DG, Jankowski JA, Kirton CM, Pritchard DM et al. (2003) Gastrin induces proliferation in Barrett’s metaplasia through activation of the CCK2 receptor. Gastroenterology 124(3): 615–625.CrossRefPubMedGoogle Scholar
  27. Hardwick RH, Shepherd NA, Moorghen M, Newcomb PV, Alderson D (1995) c-erbB-2 overexpression in the dysplasia/carcinoma sequence of Barrett’s oesophagus. J Clin Pathol 48(2): 129–132.CrossRefPubMedGoogle Scholar
  28. Herbst JJ, Berenson MM, McCloskey DW, Wiser WC (1978) Cell proliferation in esophageal columnar epithelium (Barrett’s esophagus). Gastroenterology 75(4): 683–687.PubMedGoogle Scholar
  29. Hong MK, Laskin WB, Herman BE, Johnston MH, Vargo JJ, Steinberg SM et al. (1995) Expansion of the Ki-67 proliferative compartment correlates with degree of dysplasia in Barrett’s esophagus. Cancer 75(2): 423–429.CrossRefPubMedGoogle Scholar
  30. Iftikhar SY, Steele RJ, Watson S, James PD, Dilks K, Hardcastle JD (1992) Assessment of proliferation of squamous, Barrett’s and gastric mucosa in patients with columnar lined Barrett’s oesophagus. Gut 33(6): 733–737.CrossRefPubMedGoogle Scholar
  31. Iihara K, Shiozaki H, Tahara H, Kobayashi K, Inoue M, Tamura S et al. (1993) Prognostic significance of transforming growth factor-alpha in human esophageal carcinoma. Implication for the autocrine proliferation. Cancer 71(10): 2902–2909.CrossRefPubMedGoogle Scholar
  32. Inadomi JM, Somsouk M, Madanick RD, Thomas JP, Shaheen NJ (2009) A cost-utility analysis of ablative therapy for Barrett’s esophagus. Gastroenterology 136: 2101–2114.CrossRefPubMedGoogle Scholar
  33. Jankowski J, Coghill G, Hopwood D, Wormsley KG (1992) Oncogenes and onco-suppressor gene in adenocarcinoma of the oesophagus. Gut 33(8): 1033–1038.CrossRefPubMedGoogle Scholar
  34. Jin Z, Cheng Y, Gu W, Zheng Y, Sato F, Mori Y et al. (2009) A multicenter, double-blinded validation study of methylation biomarkers for progression prediction in Barrett’s esophagus. Cancer Res 69(10): 4112–4115.CrossRefPubMedGoogle Scholar
  35. Kaestner KH, Silberg DG, Traber PG, Schutz G (1997) The mesenchymal winged helix transcription factor Fkh6 is required for the control of gastrointestinal proliferation and differentiation. Genes Dev 11(12): 1583–1595.CrossRefPubMedGoogle Scholar
  36. Kaur B, Omary M, Triadafilopoulos G (2000) Bile salt-induced cell proliferation in an ex vivo model of Barrett’s esophagus is associated with specific PKC isoform modulation. Am J Physiol Gastrointest Liver Physiol 278: G1000–G1009.PubMedGoogle Scholar
  37. Kumble S, Omary MB, Cartwright CA, Triadafilopoulos G (1997) Src activation in malignant and premalignant epithelia of Barrett’s esophagus. Gastroenterology 112(2): 348–356.CrossRefPubMedGoogle Scholar
  38. Lao-Sirieix P, Brais R, Lovat L, Coleman N, Fitzgerald RC (2004) Cell cycle phase abnormalities do not account for disordered proliferation in Barrett’s carcinogenesis. Neoplasia 6(6): 751–760.CrossRefPubMedGoogle Scholar
  39. Lao-Sirieix P, Roy A, Worrall C, Vowler SL, Gardiner S, Fitzgerald RC (2006) Effect of acid suppression on molecular predictors for esophageal cancer. Cancer Epidemiol Biomarkers Prev 15(2): 288–293.CrossRefPubMedGoogle Scholar
  40. Lord RV, O’Grady R, Sheehan C, Field AF, Ward RL (2000) K-ras codon 12 mutations in Barrett’s oesophagus and adenocarcinomas of the oesophagus and oesophagogastric junction. J Gastroenterol Hepatol 15(7): 730–736.CrossRefPubMedGoogle Scholar
  41. Lord RV, Park JM, Wickramasinghe K, DeMeester SR, Oberg S, Salonga D et al. (2003) Vascular endothelial growth factor and basic fibroblast growth factor expression in esophageal adenocarcinoma and Barrett esophagus. J Thorac Cardiovasc Surg 125(2): 246–253.CrossRefPubMedGoogle Scholar
  42. Maley CC, Galipeau PC, Finley JC, Wongsurawat VJ, Li X, Sanchez CA et al. (2006) Genetic clonal diversity predicts progression to esophageal adenocarcinoma. Nat Genet 38(4): 468–473.CrossRefPubMedGoogle Scholar
  43. Meltzer SJ, Zhou D, Weinstein WM (1989) Tissue-specific expression of c-Ha-ras in premalignant gastrointestinal mucosae. Exp Mol Pathol 51(3): 264–274.CrossRefPubMedGoogle Scholar
  44. Morgan C, Alazawi W, Sirieix P, Freeman N, Coleman N, Fitzgerald RC (2003) Immediate and early gene response to in vitro acid exposure in a Barrett’s adenocarcinoma cell line. Gut 52(Suppl 1): A44.Google Scholar
  45. Naef AP, Savary M, Ozzello L (1975) Columnar-lined lower esophagus: an acquired lesion with malignant predisposition. Report on 140 cases of Barrett’s esophagus with 12 adenocarcinomas. J Thorac Cardiovasc Surg 70(5): 826–835.PubMedGoogle Scholar
  46. Nakamura T, Nekarda H, Hoelscher AH, Bollschweiler E, Harbeck N, Becker K et al. (1994) Prognostic value of DNA ploidy and c-erbB-2 oncoprotein overexpression in adenocarcinoma of Barrett’s esophagus. Cancer 73(7): 1785–1794.CrossRefPubMedGoogle Scholar
  47. Neshat K, Sanchez CA, Galipeau PC, Blount PL, Levine DS, Joslyn G et al. (1994) p53 mutations in Barrett’s adenocarcinoma and high-grade dysplasia. Gastroenterology 106(6): 1589–1595.PubMedGoogle Scholar
  48. Onwuegbusi BA, Aitchison A, Chin SF, Kranjac T, Mills I, Huang Y et al. (2006) Impaired transforming growth factor beta signalling in Barrett’s carcinogenesis due to frequent SMAD4 inactivation. Gut 55(6): 764–774.CrossRefPubMedGoogle Scholar
  49. Onwuegbusi BA, Rees JR, Lao-Sirieix P, Fitzgerald RC (2007) Selective loss of TGFbeta Smad-dependent signalling prevents cell cycle arrest and promotes invasion in oesophageal adenocarcinoma cell lines. PLoS One 2: e177.CrossRefPubMedGoogle Scholar
  50. O’Shaughnessy JA, Kelloff GJ, Gordon GB, Dannenberg AJ, Hong WK, Fabian CJ et al. (2002) Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development. Clin Cancer Res 8(2): 314–346.PubMedGoogle Scholar
  51. Ouatu-Lascar R, Fitzgerald RC, Triadafilopoulos G (1999) Differentiation and proliferation in Barrett’s esophagus and the effects of acid suppression. Gastroenterology 117(2): 327–335.CrossRefPubMedGoogle Scholar
  52. Pabst O, Zweigerdt R, Arnold HH (1999) Targeted disruption of the homeobox transcription factor Nkx2-3 in mice results in postnatal lethality and abnormal development of small intestine and spleen. Development 126(10): 2215–2225.PubMedGoogle Scholar
  53. Parrilla P, Martinez de Haro LF, Ortiz A, Munitiz V, Molina J, Bermejo J et al. (2003) Long-term results of a randomized prospective study comparing medical and surgical treatment of Barrett’s esophagus. Ann Surg 237(3): 291–298.CrossRefPubMedGoogle Scholar
  54. Paulson TG, Galipeau PC, Xu L, Kissel HD, Li X, Blount PL et al. (2008) p16 mutation spectrum in the premalignant condition Barrett’s esophagus. PLoS One 3(11): e3809.CrossRefPubMedGoogle Scholar
  55. Pellish LJ (1980) HJAaeGL. Cell proliferation in three types of Barrett’s epithelium. Gut 21: 26–31.CrossRefPubMedGoogle Scholar
  56. Persons DL, Croughan WS, Borelli KA, Cherian R (1998) Interphase cytogenetics of esophageal adenocarcinoma and precursor lesions. Cancer Genet Cytogenet 106(1): 11–17.CrossRefPubMedGoogle Scholar
  57. Peters FTM, Ganesh S, Kuipers EJ, Sluiter WJ, Klinkenberg-Knol EC, Lamers CBHW et al. (1999) Endoscopic regression of Barrett’s oesophagus during omeprazole treatment; a randomised double blind study. Gut 45(4): 489–494.CrossRefPubMedGoogle Scholar
  58. Rabinovitch PS, Longton G, Blount PL, Levine DS, Reid BJ (2001) Predictors of progression in Barrett’s esophagus III: baseline flow cytometric variables. Am J Gastroenterol 96(11): 3071–3083.CrossRefPubMedGoogle Scholar
  59. Reid BJ, Blount PL, Rubin CE, Levine DS, Haggitt RC, Rabinovitch PS (1992) Flow-cytometric and histological progression to malignancy in Barrett’s esophagus: prospective endoscopic surveillance of a cohort. Gastroenterology 102(4 Pt 1): 1212–1219.PubMedGoogle Scholar
  60. Reid BJ, Sanchez CA, Blount PL, Levine DS (1993) Barrett’s esophagus: cell cycle abnormalities in advancing stages of neoplastic progression. Gastroenterology 105(1): 119–129.PubMedGoogle Scholar
  61. Sancho E, Batlle E, Clevers H (2003) Live and let die in the intestinal epithelium. Curr Opin Cell Biol 15(6): 763–770.CrossRefPubMedGoogle Scholar
  62. Sarbia M, Arjumand J, Wolter M, Reifenberger G, Heep H, Gabbert HE (2001a) Frequent c-myc amplification in high-grade dysplasia and adenocarcinoma in Barrett esophagus. Am J Clin Pathol 115(6): 835–840.CrossRefPubMedGoogle Scholar
  63. Sarbia M, Bektas N, Muller W, Heep H, Borchard F, Gabbert HE (1999) Expression of cyclin E in dysplasia, carcinoma, and nonmalignant lesions of Barrett esophagus. Cancer 86(12): 2597–2601.CrossRefPubMedGoogle Scholar
  64. Sarbia M, Tekin U, Zeriouh M, Donner A, Gabbert HE (2001b) Expression of the RB protein, allelic imbalance of the RB gene and amplification of the CDK4 gene in metaplasias, dysplasias and carcinomas in Barrett’s oesophagus. Anticancer Res 21(1A): 387–392.PubMedGoogle Scholar
  65. Schulmann K, Sterian A, Berki A, Yin J, Sato F, Xu Y et al. (2005) Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett’s-associated neoplastic progression and predicts progression risk. Oncogene 24(25): 4138–4148.PubMedGoogle Scholar
  66. Sciallero S, Giaretti W, Bonelli L, Geido E, Rapallo A, Conio M et al. (1993) DNA content analysis of Barrett’s esophagus by flow cytometry. Endoscopy 25(9): 648–651.CrossRefPubMedGoogle Scholar
  67. Sirieix PS, O’Donovan M, Brown J, Save V, Coleman N, Fitzgerald RC (2003) Surface expression of minichromosome maintenance proteins provides a novel method for detecting patients at risk for developing adenocarcinoma in Barrett’s esophagus. Clin Cancer Res 9(7): 2560–2566.PubMedGoogle Scholar
  68. Souza RF, Morales CP, Spechler SJ (2001) Review article: a conceptual approach to understanding the molecular mechanisms of cancer development in Barrett’s oesophagus. Aliment Pharmacol Ther 15(8): 1087–1100.CrossRefPubMedGoogle Scholar
  69. Souza RF, Shewmake K, Terada LS, Spechler SJ (2002) Acid exposure activates the mitogen-activated protein kinase pathways in Barrett’s esophagus. Gastroenterology 122(2): 299–307.CrossRefPubMedGoogle Scholar
  70. Trautmann B, Wittekind C, Strobel D, Meixner H, Keymling J, Gossner L et al. (1996) K-ras point mutations are rare events in premalignant forms of Barrett’s oesophagus. Eur J Gastroenterol Hepatol 8(8): 799–804.PubMedGoogle Scholar
  71. Tselepis C, Morris CD, Wakelin D, Hardy R, Perry I, Luong QT et al. (2003) Upregulation of the oncogene c-myc in Barrett’s adenocarcinoma: induction of c-myc by acidified bile acid in vitro. Gut 52(2): 174–180.CrossRefPubMedGoogle Scholar
  72. Walch A, Bink K, Gais P, Stangl S, Hutzler P, Aubele M et al. (2000) Evaluation of c-erbB-2 overexpression and Her-2/neu gene copy number heterogeneity in Barrett’s adenocarcinoma. Anal Cell Pathol 20(1): 25–32.PubMedGoogle Scholar
  73. Walch A, Specht K, Bink K, Zitzelsberger H, Braselmann H, Bauer M et al. (2001) Her-2/neu gene amplification, elevated mRNA expression, and protein overexpression in the metaplasia-dysplasia-adenocarcinoma sequence of Barrett’s esophagus. Lab Invest 81(6): 791–801.PubMedGoogle Scholar
  74. Wang KK, Sampliner RE (2008) Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett’s esophagus. Am J Gastroenterol 103: 788–797.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Cancer Cell UnitHutchison-MRC Research CentreCambridgeUK

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