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Increase of Epidermal Growth Factor Receptor Expression in Progression of GERD, Barrett, and Adenocarcinoma of Esophagus

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Abstract

Introduction

Gastroesophageal reflux disease (GERD) is a pathology with a wide range of clinical and endoscopic manifestations. Epidermal growth factor receptor (EGFR), found in the epithelium of the digestive tract, plays an important role in epithelial repair and shows increased expression in different neoplasms, including esophageal tumors.

Objectives

The purpose of this study was to evaluate EGFR expression using immunohistochemistry in esophageal biopsies obtained from patients with GERD, Barrett’s esophagus, and adenocarcinoma of the esophagus.

Methods

EGFR expression was immunohistochemically determined in biopsies from 194 patients with symptoms suggestive of GERD or adenocarcinoma of the esophagus, seen at two Brazilian university hospitals between January 2003 and December 2008. Based on histopathological analysis, patients were divided into three groups: GERD, Barrett’s esophagus and adenocarcinoma of the esophagus. EGFR expression was considered positive when staining was detected in the membrane.

Results

Mean age was 55.25 years (range 30–90). Patients with GERD (n = 127) accounted for 65.5 % of the sample, compared with 12.4 % (n = 24) of patients with Barrett’s esophagus and 22.2 % (n = 43) of patients with esophageal adenocarcinoma. Immunohistochemical analysis was positive for EGFR in 19.1 % of the patients (37/194), divided as follows: 8.7 % (11/127) in the GERD group, 25 % (6/24) in the Barrett’s esophagus group, and 46.5 % (20/43) in the esophageal adenocarcinoma group. Statistical analysis revealed significant differences between the three groups (p = 0.0001).

Conclusions

GERD patients showed lower levels of EGFR expression than patients with Barrett’s esophagus or patients with adenocarcinoma of the esophagus, suggesting a direct relationship between EGFR expression and disease progression.

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References

  1. Moraes-Filho JP, Navarro-Rodriguez T, Barbuti R, Eisig J, Chinzon D, Bernardo W. Guidelines for the diagnosis and management of gastroesophageal reflux disease: an evidence-based consensus. Arq Gastroenterol. 2010;47:99–115.

    Article  PubMed  Google Scholar 

  2. Locke GR 3rd, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ 3rd. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology. 1997;112:1448–1456.

    Article  PubMed  Google Scholar 

  3. Jones RH, Lydeard SE, Hobbs FD, et al. Dyspepsia in England and Scotland. Gut. 1990;31:401–405.

    Article  PubMed  CAS  Google Scholar 

  4. Moraes-Filho JP, Chinzon D, Eisig JN, Hashimoto CL, Zaterka S. Prevalence of heartburn and gastroesophageal reflux disease in the urban Brazilian population. Arq Gastroenterol. 2005;42:122–127.

    Article  PubMed  Google Scholar 

  5. Gurski RR, da Rosa AR, do Valle E, de Borba MA, Valiati AA. Extraesophageal manifestations of gastroesophageal reflux disease. J Bras Pneumol. 2006;32:150–160.

    PubMed  Google Scholar 

  6. Kahrilas PJ, Shaheen NJ, Vaezi MF. American Gastroenterological Association Institute technical review on the management of gastroesophageal reflux disease. Gastroenterology. 2008;135:1392–1413.

    Article  PubMed  Google Scholar 

  7. Kahrilas PJ. Clinical practice. Gastroesophageal reflux disease. N Engl J Med. 2008;359:1700–1707.

    Article  PubMed  CAS  Google Scholar 

  8. Kongara K, Varilek G, Soffer EE. Salivary growth factors and cytokines are not deficient in patients with gastroesophageal reflux disease or Barrett’s esophagus. Dig Dis Sci. 2001;46:606–609.

    Article  PubMed  CAS  Google Scholar 

  9. Campos GM, Peters JH, DeMeester TR, Oberg S, Crookes PF, Mason RJ. The pattern of esophageal acid exposure in gastroesophageal reflux disease influences the severity of the disease. Arch Surg. 1999;134:882–887.

    Article  PubMed  CAS  Google Scholar 

  10. Demeester TR, Johnson LF, Joseph GJ, Toscano MS, Hall AW, Skinner DB. Patterns of gastroesophageal reflux in health and disease. Ann Surg. 1976;184:459–470.

    Article  PubMed  CAS  Google Scholar 

  11. DeMeester TR, Johnson LF. The evaluation of objective measurements of gastroesophageal reflux and their contribution to patient management. Surg Clin North Am. 1976;56:39–53.

    PubMed  CAS  Google Scholar 

  12. Wang C, Hunt RH. Precise role of acid in non-erosive reflux disease. Digestion. 2008;78:31–41.

    Article  PubMed  Google Scholar 

  13. Orlando RC. Esophageal epithelial defense against acid injury. J Clin Gastroenterol. 1991;13:S1–S5.

    Article  PubMed  Google Scholar 

  14. Marcinkiewicz M, Han K, Zbroch T, et al. The potential role of the esophageal pre-epithelial barrier components in the maintenance of integrity of the esophageal mucosa in patients with endoscopically negative gastroesophageal reflux disease. Am J Gastroenterol. 2000;95:1652–1660.

    Article  PubMed  CAS  Google Scholar 

  15. Barlow WJ, Orlando RC. The pathogenesis of heartburn in nonerosive reflux disease: a unifying hypothesis. Gastroenterology. 2005;128:771–778.

    Article  PubMed  Google Scholar 

  16. Okuyama M, Fujiwara Y, Tanigawa T, et al. Roles of ZO-1 and epidermal growth factor in esophageal epithelial defense against acid. Digestion. 2007;75:135–141.

    PubMed  CAS  Google Scholar 

  17. Jankowski J, Murphy S, Coghill G, et al. Epidermal growth factor receptors in the oesophagus. Gut. 1992;33:439–443.

    Article  PubMed  CAS  Google Scholar 

  18. Jankowski J, Coghill G, Tregaskis B, Hopwood D, Wormsley KG. Epidermal growth factor in the oesophagus. Gut. 1992;33:1448–1453.

    Article  PubMed  CAS  Google Scholar 

  19. Reindel JF, Gough AW, Pilcher GD, Bobrowski WF, Sobocinski GP, de la Iglesia FA. Systemic proliferative changes and clinical signs in cynomolgus monkeys administered a recombinant derivative of human epidermal growth factor. Toxicol Pathol. 2001;29:159–173.

    Article  PubMed  CAS  Google Scholar 

  20. Playford RJ, Hanby AM, Gschmeissner S, Peiffer LP, Wright NA, McGarrity T. The epidermal growth factor receptor (EGF-R) is present on the basolateral, but not the apical, surface of enterocytes in the human gastrointestinal tract. Gut. 1996;39:262–266.

    Article  PubMed  CAS  Google Scholar 

  21. Alroy I, Yarden Y. The ErbB signaling network in embryogenesis and oncogenesis: signal diversification through combinatorial ligand-receptor interactions. FEBS Lett. 1997;410:83–86.

    Article  PubMed  CAS  Google Scholar 

  22. Koppert LB, Wijnhoven BP, van Dekken H, Tilanus HW, Dinjens WN. The molecular biology of esophageal adenocarcinoma. J Surg Oncol. 2005;92:169–190.

    Article  PubMed  CAS  Google Scholar 

  23. Morgan S, Grandis JR. ErbB receptors in the biology and pathology of the aerodigestive tract. Exp Cell Res. 2009;315:572–582.

    Article  PubMed  CAS  Google Scholar 

  24. Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008;358:1160–1174.

    Article  PubMed  CAS  Google Scholar 

  25. Wilkinson NW, Black JD, Roukhadze E, et al. Epidermal growth factor receptor expression correlates with histologic grade in resected esophageal adenocarcinoma. J Gastrointest Surg. 2004;8:448–453.

    Article  PubMed  Google Scholar 

  26. Jankowski J, Hopwood D, Pringle R, Wormsley KG. Increased expression of epidermal growth factor receptors in Barrett’s esophagus associated with alkaline reflux: a putative model for carcinogenesis. Am J Gastroenterol. 1993;88:402–408.

    PubMed  CAS  Google Scholar 

  27. Li Y, Wo JM, Ray MB, et al. Cyclooxygenase-2 and epithelial growth factor receptor up-regulation during progression of Barrett’s esophagus to adenocarcinoma. World J Gastroenterol. 2006;12:928–934.

    PubMed  CAS  Google Scholar 

  28. Wang KL, Wu TT, Choi IS, et al. Expression of epidermal growth factor receptor in esophageal and esophagogastric junction adenocarcinomas: association with poor outcome. Cancer. 2007;109:658–667.

    Article  PubMed  CAS  Google Scholar 

  29. Levine DS, Haggitt RC, Blount PL, Rabinovitch PS, Rusch VW, Reid BJ. An endoscopic biopsy protocol can differentiate high-grade dysplasia from early adenocarcinoma in Barrett’s esophagus. Gastroenterology. 1993;105:40–50.

    PubMed  CAS  Google Scholar 

  30. Flora-Filho R, Camara-Lopes LH. Histological criteria of esophagitis in the gastroesophageal reflux disease. Reevaluation of the sensitivity of the esophageal 24-hours pHmetry. Arq Gastroenterol. 2000;37:197–202.

    Article  PubMed  CAS  Google Scholar 

  31. Lundell LR, Dent J, Bennett JR, et al. Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut. 1999;45:172–180.

    Article  PubMed  CAS  Google Scholar 

  32. Riddell RH. The biopsy diagnosis of gastroesophageal reflux disease, “carditis,” and Barrett’s esophagus, and sequelae of therapy. Am J Surg Pathol. 1996;20:S31–S50.

    Article  PubMed  Google Scholar 

  33. Pera M, Cameron AJ, Trastek VF, Carpenter HA, Zinsmeister AR. Increasing incidence of adenocarcinoma of the esophagus and esophagogastric junction. Gastroenterology. 1993;104:510–513.

    PubMed  CAS  Google Scholar 

  34. Altorki NK, Oliveria S, Schrump DS. Epidemiology and molecular biology of Barrett’s adenocarcinoma. Semin Surg Oncol. 1997;13:270–280.

    Article  PubMed  CAS  Google Scholar 

  35. Sakai Y, Nelson KG, Snedeker S, et al. Expression of epidermal growth factor in suprabasal cells of stratified squamous epithelia: implications for a role in differentiation. Cell Growth Differ. 1994;5:527–535.

    PubMed  CAS  Google Scholar 

  36. Qureshi FG, Tchorzewski MT, Duncan MD, Harmon JW. EGF and IGF-I synergistically stimulate proliferation of human esophageal epithelial cells. J Surg Res. 1997;69:354–358.

    Article  PubMed  CAS  Google Scholar 

  37. Breider MA, Bleavins MR, Reindel JF, Gough AW, de la Iglesia FA. Cellular hyperplasia in rats following continuous intravenous infusion of recombinant human epidermal growth factor. Vet Pathol. 1996;33:184–194.

    Article  PubMed  CAS  Google Scholar 

  38. Juhl CO, Vinter-Jensen L, Poulsen SS, Orntoft TF, Dajani EZ. Chronic treatment with epidermal growth factor causes esophageal epithelial hyperplasia in pigs and rats. Dig Dis Sci. 1995;40:2717–2723.

    Article  PubMed  CAS  Google Scholar 

  39. Zhao J, Yang J, Vinter-Jensen L, Zhuang F, Gregersen H. Biomechanical properties of esophagus during systemic treatment with epidermal growth factor in rats. Ann Biomed Eng. 2003;31:700–709.

    Article  PubMed  Google Scholar 

  40. Jimenez P, Lanas A, Piazuelo E, Esteva F. Effect of growth factors and prostaglandin E2 on restitution and proliferation of rabbit esophageal epithelial cells. Dig Dis Sci. 1998;43:2309–2316.

    Article  PubMed  CAS  Google Scholar 

  41. Fujiwara Y, Higuchi K, Takashima T, et al. Roles of epidermal growth factor and Na +/H + exchanger-1 in esophageal epithelial defense against acid-induced injury. Am J Physiol Gastrointest Liver Physiol. 2006;290:G665–G673.

    Article  PubMed  CAS  Google Scholar 

  42. Fujiwara Y, Higuchi K, Hamaguchi M, et al. Increased expression of transforming growth factor-alpha and epidermal growth factor receptors in rat chronic reflux esophagitis. J Gastroenterol Hepatol. 2004;19:521–527.

    Article  PubMed  CAS  Google Scholar 

  43. Jankowski J, Hopwood D, Wormsley KG. Expression of epidermal growth factor, transforming growth factor alpha and their receptor in gastro-oesophageal diseases. Dig Dis. 1993;11:1–11.

    Article  PubMed  CAS  Google Scholar 

  44. Poller DN, Steele RJ, Morrell K. Epidermal growth factor receptor expression in Barrett’s esophagus. Arch Pathol Lab Med. 1992;116:1226–1227.

    PubMed  CAS  Google Scholar 

  45. Mukaida H, Yamamoto T, Hirai T, et al. Expression of human epidermal growth factor and its receptor in esophageal cancer. Jpn J Surg. 1990;20:275–282.

    Article  PubMed  CAS  Google Scholar 

  46. Scagliotti GV, Selvaggi G, Novello S, Hirsch FR. The biology of epidermal growth factor receptor in lung cancer. Clin Cancer Res. 2004;10:4227s–4232s.

    Article  PubMed  CAS  Google Scholar 

  47. Mansour EG, Ravdin PM, Dressler L. Prognostic factors in early breast carcinoma. Cancer. 1994;74:381–400.

    Article  PubMed  CAS  Google Scholar 

  48. Vet JA, Debruyne FM, Schalken JA. Molecular prognostic factors in bladder cancer. World J Urol. 1994;12:84–88.

    Article  PubMed  CAS  Google Scholar 

  49. O’Dwyer PJ, Benson AB III. Epidermal growth factor receptor-targeted therapy in colorectal cancer. Semin Oncol. 2002;29:10–17.

    PubMed  Google Scholar 

  50. Yacoub L, Goldman H, Odze RD. Transforming growth factor-alpha, epidermal growth factor receptor, and MiB-1 expression in Barrett’s-associated neoplasia: correlation with prognosis. Mod Pathol. 1997;10:105–112.

    PubMed  CAS  Google Scholar 

  51. Lazebnik Y. What are the hallmarks of cancer? Nat Rev Cancer. 2010;10:232–233.

    Article  PubMed  CAS  Google Scholar 

  52. Yarden Y. The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities. Eur J Cancer Engl. 2001;37:S3–S8.

    Article  CAS  Google Scholar 

  53. Voldborg BR, Damstrup L, Spang-Thomsen M, Poulsen HS. Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. Ann Oncol. 1997;8:1197–1206.

    Article  PubMed  CAS  Google Scholar 

  54. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.

    Article  PubMed  CAS  Google Scholar 

  55. Okawa T, Michaylira CZ, Kalabis J, et al. The functional interplay between EGFR overexpression, hTERT activation, and p53 mutation in esophageal epithelial cells with activation of stromal fibroblasts induces tumor development, invasion, and differentiation. Genes Dev. 2007;21:2788–2803.

    Article  PubMed  CAS  Google Scholar 

  56. Logan A. Intracrine regulation at the nucleus–a further mechanism of growth factor activity? J Endocrinol. 1990;125:339–343.

    Article  PubMed  CAS  Google Scholar 

  57. Aaronson SA. Growth factors and cancer. Science. 1991;254:1146–1153.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, Post Graduation Program in Digestive Surgery, Hospital de Clínicas de Porto Alegre, Rua Santa Cecília 1373/316 Bairro Santana, CEP 90420-041, Porto Alegre, RS, Brazil

    Guilherme Pretto, Richard Ricachenevsky Gurski, Daniel Navarini & Wolfgan William Schmidt Aguiar

  2. Department of Surgery, Post Graduation Program in Digestive Surgery, Federal University of Santa Maria, Santa Maria, RS, Brazil

    Marcelo Binato

  3. Department of Pathology, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

    Luise Meurer

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  1. Guilherme Pretto
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  2. Richard Ricachenevsky Gurski
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Correspondence to Guilherme Pretto.

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Pretto, G., Gurski, R.R., Binato, M. et al. Increase of Epidermal Growth Factor Receptor Expression in Progression of GERD, Barrett, and Adenocarcinoma of Esophagus. Dig Dis Sci 58, 115–122 (2013). https://doi.org/10.1007/s10620-012-2316-z

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  • DOI: https://doi.org/10.1007/s10620-012-2316-z

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