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Increased p53 Expression in the Malignant Transformation of Barrett’s Esophagus is Accompanied by an Upward Shift of the Proliferative Compartment

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Pathology & Oncology Research

Abstract

Neoplastic progression in Barrett’s esophagus (BE) occurs by a multistep process associated with early molecular and morphological changes. This study evaluated cell proliferation and p53 expression and their correlation in the development and progression of esophageal adenocarcinoma. PCNA and p53 expressions were analyzed in biopsy samples by immunohistochemistry including patients with reflux esophagitis, BE, BE with concomitant esophagitis, Barrett’s dysplasia, esophageal adenocarcinoma and a control group without any histological changes. Progressive increase in cell proliferation and p53 expression was found in the sequence of malignant transformation of the esophageal mucosa. While cell proliferation was significantly lower in the control group compared with all other groups, there was no increase in p53 expression of esophageal tissues that were negative for dysplasia. Dysplastic BE tissues revealed significantly higher cell proliferation and p53 expression levels compared to BE, reflux esophagitis or BE with concomitant esophagitis. Both, cell proliferation and p53 expression were significantly higher in adenocarcinoma compared to BE or Barrett’s dysplasia. Interestingly, while just BE with concomitant esophagitis showed significantly higher p53 expression levels than BE, both, BE with concomitant esophagitis and reflux esophagitis revealed significantly higher cell proliferation levels compared to BE. Alterations of cell proliferation and p53 expression showed a strong correlation. Simultaneous activation of cell proliferation and p53 expression strongly suggest their association with esophageal epithelial tumor genesis and particularly, their specific role in the biology of esophageal adenocarcinoma. Quantification of these parameters in BE is thought to be useful to identify patients at higher risk for progression to adenocarcinoma.

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References

  1. Bosetti C, Levi F, Ferlay J et al (2008) Trends in oesophageal cancer incidence and mortality in Europe. Int J Cancer 122(5):1118–1129

    Article  CAS  PubMed  Google Scholar 

  2. Wu X, Chen VW, Andrews PA et al (2007) Incidence of esophageal and gastric cancers among Hispanics, non-Hispanic whites and non-Hispanic blacks in the United States: subsite and histology differences. Cancer Causes Control 18(6):585–593

    Article  PubMed  Google Scholar 

  3. Fléjou JF (2005) Barrett’s oesophagus: from metaplasia to dysplasia and cancer. Gut 54(Suppl 1):i6–i12

    Article  PubMed  Google Scholar 

  4. Spechler SJ, Goyal RK (1986) Barrett’s esophagus. N Engl J Med 315(6):362–371

    CAS  PubMed  Google Scholar 

  5. Westhoff B, Brotze S, Weston A et al (2005) The frequency of Barrett’s esophagus in high-risk patients with chronic GERD. Gastrointest Endosc 61(2):226–231

    Article  PubMed  Google Scholar 

  6. Jankowski JA, Harrison RF, Perry I et al (2000) Barrett’s metaplasia. Lancet 356(9247):2079–2085

    Article  CAS  PubMed  Google Scholar 

  7. Shaheen NJ (2005) Advances in Barrett’s esophagus and esophageal adenocarcinoma. Gastroenterology 128(6):1554–1566

    Article  PubMed  Google Scholar 

  8. Srivastava A, Hornick JL, Li X et al (2007) Extent of low-grade dysplasia is a risk factor for the development of esophageal adenocarcinoma in Barrett’s esophagus. Am J Gastroenterol 102(3):483–493

    Article  PubMed  Google Scholar 

  9. Schlansky B, Dimarino AJ Jr, Loren D et al (2006) A survey of oesophageal cancer: pathology, stage and clinical presentation. Aliment Pharmacol Ther 23(5):587–593

    Article  CAS  PubMed  Google Scholar 

  10. Skacel M, Petras RE, Gramlich TL et al (2000) The diagnosis of low-grade dysplasia in Barrett’s esophagus and its implications for disease progression. Am J Gastroenterol 95(12):3383–3387

    Article  CAS  PubMed  Google Scholar 

  11. McManus DT, Olaru A, Meltzer SJ (2004) Biomarkers of esophageal adenocarcinoma and Barrett’s esophagus. Cancer Res 64(5):1561–1569

    Article  CAS  PubMed  Google Scholar 

  12. Younes M, Ertan A, Lechago LV et al (1997) p53 protein accumulation is a specific marker of malignant potential in Barrett’s metaplasia. Dig Dis Sci 42(4):697–701

    Article  CAS  PubMed  Google Scholar 

  13. Hong MK, Laskin WB, Herman BE et al (1995) Expansion of the Ki-67 proliferative compartment correlates with degree of dysplasia in Barrett’s esophagus. Cancer 75(2):423–429

    Article  CAS  PubMed  Google Scholar 

  14. Prelich G, Tan CK, Kostura M et al (1987) Functional identity of proliferating cell nuclear antigen and a DNA polymerase auxiliary protein. Nature 326(6112):517–520

    Article  CAS  PubMed  Google Scholar 

  15. Reid BJ, Sanchez CA, Blount PL et al (1993) Barrett’s esophagus: cell cycle abnormalities in advancing stages of neoplastic progression. Gastroenterology 105(1):119–129

    CAS  PubMed  Google Scholar 

  16. el-Deiry WS, Harper JW, O’Connor PM et al (1994) WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res 54(5):1169–1174

    CAS  PubMed  Google Scholar 

  17. Ramel S, Reid BJ, Sanchez CA et al (1992) Evaluation of p53 protein expression in Barrett’s esophagus by two-parameter flow cytometry. Gastroenterology 102(4 Pt 1):1220–1228

    CAS  PubMed  Google Scholar 

  18. Wang DY, Xiang YY, Tanaka M et al (1994) High prevalence of p53 protein overexpression in patients with esophageal cancer in Linxian, China and its relationship to progression and prognosis. Cancer 74(12):3089–3096

    Article  CAS  PubMed  Google Scholar 

  19. Slade N, Moll UM (2003) Mutational analysis of p53 in human tumors: immunocytochemistry. Methods Mol Biol 234:231–243

    CAS  PubMed  Google Scholar 

  20. Bian YS, Osterheld MC, Bosman FT et al (2001) p53 gene mutation and protein accumulation during neoplastic progression in Barrett’s esophagus. Mod Pathol 14(5):397–403

    Article  CAS  PubMed  Google Scholar 

  21. Geboes K, Van Eyken P et al (2000) The diagnosis of dysplasia and malignancy in Barrett’s oesophagus. Histopathology 37(2):99–107

    Article  CAS  PubMed  Google Scholar 

  22. Polkowski W, van Lanschot JJ, ten Kate FJ et al (1995) The value of p53 and Ki67 as markers for tumour progression in the Barrett’s dysplasia–carcinoma sequence. Surg Oncol 4(3):163–171

    Article  CAS  PubMed  Google Scholar 

  23. Herszenyi L, Hritz I, Pregun I et al (2007) Alterations of glutathione S-transferase and matrix metalloproteinase-9 expressions are early events in esophageal carcinogenesis. World J Gastroenterol 13(5):676–682

    CAS  PubMed  Google Scholar 

  24. Hritz I, Kuester D, Vieth M et al (2006) Secretory leukocyte protease inhibitor expression in various types of gastritis: a specific role of Helicobacter pylori infection. Eur J Gastroenterol Hepatol 18(3):277–282

    Article  CAS  PubMed  Google Scholar 

  25. Hritz I, Herszenyi L, Molnar B et al (2005) Proton pump inhibitor co-therapy normalizes the increased cell turnover of the gastric mucosa both in NSAID and selective COX-2 users. Int J Immunpathol Pharmacol 18(1):75–84

    CAS  Google Scholar 

  26. Hritz I, Herszenyi L, Molnar B et al (2005) Long-term omeprazole and esomeprazole treatment does not significantly increase gastric epithelial cell proliferation and epithelial growth factor receptor expression and has no effect on apoptosis and p53 expression. World J Gastroenterol 11(30):4721–4726

    CAS  PubMed  Google Scholar 

  27. Fitzgerald RC et al (2006) Molecular basis of Barrett’s oesophagus and oesophageal adenocarcinoma. Gut 55(12):1810–1820

    Article  CAS  PubMed  Google Scholar 

  28. Reid BJ, Weinstein WM, Lewin KJ et al (1988) Endoscopic biopsy can detect high-grade dysplasia or early adenocarcinoma in Barrett’s esophagus without grossly recognizable neoplastic lesions. Gastroenterology 94(1):81–90

    CAS  PubMed  Google Scholar 

  29. Theisen J, Nigro JJ, DeMeester TR et al (2004) Chronology of the Barrett’s metaplasia–dysplasia–carcinoma sequence. Dis Esophagus 17(1):67–70

    Article  CAS  PubMed  Google Scholar 

  30. Kleeff J, Friess H, Liao Q et al (2002) Immunohistochemical presentation in non-malignant and malignant Barrett’s epithelium. Dis Esophagus 15(1):10–15

    Article  CAS  PubMed  Google Scholar 

  31. Biasco G et al (2004) Cell proliferation and differentiation in familial adenomatous polyposis (FAP). Hum Pathol 35(12):1573

    Article  PubMed  Google Scholar 

  32. Scalmati A, Roncucci L, Ghidini G et al (1990) Epithelial cell kinetics in the remaining colorectal mucosa after surgery for cancer of the large bowel. Cancer Res 50(24):7937–7941

    CAS  PubMed  Google Scholar 

  33. Bechi P, Balzi M, Becciolini A et al (1996) Helicobacter pylori and cell proliferation of the gastric mucosa: possible implications for gastric carcinogenesis. Am J Gastroenterol 91(2):271–276

    CAS  PubMed  Google Scholar 

  34. Peters FT, Ganesh S, Kuipers EJ et al (1998) Epithelial cell proliferative activity of Barrett’s esophagus: methodology and correlation with traditional cancer risk markers. Dig Dis Sci 43(7):1501–1506

    Article  CAS  PubMed  Google Scholar 

  35. Rioux-Leclercq N, Turlin B, Sutherland F et al (1999) Analysis of Ki-67, p53 and Bcl-2 expression in the dysplasia–carcinoma sequence of Barrett’s esophagus. Oncol Rep 6(4):877–882

    CAS  PubMed  Google Scholar 

  36. Kim R, Clarke MR, Melhem MF et al (1997) Expression of p53, PCNA, and CerbB-2 in Barrett’s metaplasia and adenocarcinoma. Dig Dis Sci 42(12):2453–2462

    Article  CAS  PubMed  Google Scholar 

  37. Kataoka H, Joh T, Kasugai K et al (1997) Mitogenic properties of human gastric juice. Dig Dis Sci 42(8):1747–1754

    Article  CAS  PubMed  Google Scholar 

  38. Lagergren J, Bergstrom R, Lindgren A et al (1999) Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 340(11):825–831

    Article  CAS  PubMed  Google Scholar 

  39. Shaheen N, Ransohoff DF et al (2002) Gastroesophageal reflux, Barrett esophagus, and esophageal cancer: scientific review. JAMA 287(15):1972–1981

    Article  PubMed  Google Scholar 

  40. Peters FT, Ganesh S, Kuipers EJ et al (2000) Effect of elimination of acid reflux on epithelial cell proliferative activity of Barrett esophagus. Scand J Gastroenterol 35(12):1238–1244

    Article  CAS  PubMed  Google Scholar 

  41. Ireland AP, Clark GW, DeMeester TR (1997) Barrett’s esophagus. The significance of p53 in clinical practice. Ann Surg 225(1):17–30

    Article  CAS  PubMed  Google Scholar 

  42. Flejou JF, Potet F, Muzeau F et al (1993) Overexpression of p53 protein in Barrett’s syndrome with malignant transformation. J Clin Pathol 46(4):330–333

    Article  CAS  PubMed  Google Scholar 

  43. Schneider PM, Casson AG, Levin B et al (1996) Mutations of p53 in Barrett’s esophagus and Barrett’s cancer: a prospective study of 98 cases. J Thorac Cardiovasc Surg 111(2):323–331

    Article  CAS  PubMed  Google Scholar 

  44. Hornick JL, Mino-Kenudson M, Lauwers GY et al (2008) Buried Barrett’s epithelium following photodynamic therapy shows reduced crypt proliferation and absence of DNA content abnormalities. Am J Gastroenterol 103(1):38–47

    PubMed  Google Scholar 

  45. Younes M, Lebovitz RM, Lechago LV et al (1993) p53 protein accumulation in Barrett’s metaplasia, dysplasia, and carcinoma: a follow-up study. Gastroenterology 105(6):1637–1642

    CAS  PubMed  Google Scholar 

  46. Sun WH, Sun YL, Fang RN et al (2005) Expression of cyclooxygenase-2 and matrix metalloproteinase-9 in gastric carcinoma and its correlation with angiogenesis. Jpn J Clin Oncol 35(12):707–713

    Article  PubMed  Google Scholar 

  47. Takeuchi T, Hisanaga M, Nagao M et al (2004) The membrane-anchored matrix metalloproteinase (MMP) regulator RECK in combination with MMP-9 serves as an informative prognostic indicator for colorectal cancer. Clin Cancer Res 10(16):5572–5579

    Article  CAS  PubMed  Google Scholar 

  48. Samantaray S, Sharma R, Chattopadhyaya TK et al (2004) Increased expression of MMP-2 and MMP-9 in esophageal squamous cell carcinoma. J Cancer Res Clin Oncol 130(1):37–44

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. 2nd Dept Medicine, Semmelweis University, 1088, Budapest, Szentkirályi u. 46, Hungary

    Istvan Hritz, Hajnalka Gyorffy, Bela Molnar, Gabor Lakatos, Ferenc Sipos, Istvan Pregun, Mark Juhasz, Laszlo Pronai, Zsuzsa Schaff, Zsolt Tulassay & Laszlo Herszenyi

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  1. Istvan Hritz
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  2. Hajnalka Gyorffy
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Correspondence to Istvan Hritz.

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Hritz, I., Gyorffy, H., Molnar, B. et al. Increased p53 Expression in the Malignant Transformation of Barrett’s Esophagus is Accompanied by an Upward Shift of the Proliferative Compartment. Pathol. Oncol. Res. 15, 183–192 (2009). https://doi.org/10.1007/s12253-008-9095-z

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  • DOI: https://doi.org/10.1007/s12253-008-9095-z

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