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Open Access 01-12-2012 | Research

The simultaneous expression of both ephrin B3 receptor and E-cadherin in Barrett`s adenocarcinoma is associated with favorable clinical staging

Authors: Matthias C Schauer, Nikolas H Stoecklein, Joerg Theisen, Feride Kröpil, Stephan Baldus, Arnulf Hoelscher, Markus Feith, Edwin Bölke, Christiane Matuschek, Wilfried Budach, Wolfram Trudo Knoefel

Published in: European Journal of Medical Research | Issue 1/2012

Abstract

Background

In intestinal epithelium, tyrosine kinase receptor Ephrin B3 (Eph B3) maintains the architecture of the crypt-villus axis by repulsive interaction with its ligand ephrin-B1. While loss of Eph B3 is linked to colorectal cancer initiation, overexpression of Eph B3 in cancer cell lines inhibits growth and induces functional changes with decreased mesenchymal and increased epithelial markers. In order to study this tumor suppressor activity of Eph B3 in esophageal adenocarcinoma we analyzed the simultaneous expression of Eph B3 and E-cadherin in both the healthy esophagus and in Barrett’s carcinoma.

Methods

Simultaneous expression of Eph B3 and E-cadherin was investigated in samples from 141 patients with Barrett’s carcinoma and from 20 healthy esophagi using immunhistology and quantitative PCR. Results from healthy squamous epithelium, Barrett’s metaplasia and staging-specific esophageal adenocarcinoma were correlated.

Results

A significantly reduced E-cadherin mRNA expression could be detected in adenocarcinoma compared to dysplasia. The immunhistological activity of E-cadherin and Eph B3 was reduced in adenocarcinoma compared to dysplasia or healthy esophageal mucosa. The intracellular E-cadherin distribution changed significantly from the cytoplasm to the membrane, when the Eph receptor was simultaneously expressed. Simultaneous expression of E-cadherin and Eph B3 showed a significant inverse correlation to tumor stage.

Conclusions

We present novel evidence of the tumor suppressor activity of Eph B3 in esophageal adenocarcinoma possibly due to the impact on redistribution of cellular E-cadherin to the membrane. Our results suggest that this effect might play a role in the dysplasia-adenocarcinoma sequence, the infiltrative growth pattern and the development of lymph node metastases.

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Bonavina L, Via A, Incarbone R, Saino G, Peracchia A: Results of surgical therapy in patients with Barrett`s adenocarcinoma. World J Surg 2003, 27: 1062–1066. 10.1007/s00268-003-7062-0CrossRefPubMed

Fountoulakis A, Zafirellis D, Dolan K, Dexter SP, Martin IG, Sue-Ling HM: Effect of surveillance of Barrett`s oesophagus on the clinical outcome of oesophageal cancer. Br J Surg 2004, 91: 997–1003. 10.1002/bjs.4591CrossRefPubMed

Shaheen N: Advances in Barrett`s esophageal adenocarcinoma. Gastroenterology 2005, 128: 1554–1566. 10.1053/j.gastro.2005.03.032CrossRefPubMed

Feith M, Stein H, Siewert R: Pattern of lymphatic spread of Barrett`s cancer. World J Surg 2003, 27: 1052–1057. 10.1007/s00268-003-7060-2CrossRefPubMed

Siewert J, Stein H, Feith M: Surgical approach to invasive adenocarcinoma of the distal esophagus (Barrett`s cancer). World J Surg 2003, 27: 1058–1061. 10.1007/s00268-003-7061-1CrossRefPubMed

Gale NM, Holland SJ, Valenzuenla DM: Eph receptors and ligands comprise two major specificity subclasses, and are reciprocally compartmentalized during embryogenesis. Neuron 1996, 17: 9–19. 10.1016/S0896-6273(00)80276-7CrossRefPubMed

Mellitzer G, Xu Q, Wilkinson DG: Eph receptors and ephrins restrict cell intermingling and communication. Nature 1999, 400: 77–81. 10.1038/21907CrossRefPubMed

Wang HU, Anderson DJ: Eph family transmembrane ligands can mediate repulsive guidance of trunk neural crest migration and motor axon outgrowth. Neuron 1997, 18: 383–396. 10.1016/S0896-6273(00)81240-4CrossRefPubMed

Xu Q, Mellitzer R, Robinson V, Wilkinson DG: In vivo cell sorting in complementary segmental domains mediated by ephrin receptors and ephrins. Nature 1999, 399: 267–271. 10.1038/20452CrossRefPubMed

10.

Katoh Y, Katoh M: Comparative integromics on ephrin family. Oncol Rep 2006, 15: 1391–1395.PubMed

11.

Birchmeier W, Behrens J: Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim Biophys Acta 1994, 1198: 11–26.PubMed

12.

Brantley-Sieders D, Schmidt S, Parker M, Chen J: Eph receptor tyrosine kinases in tumor and tumor microenvironment. Curr Pharm Des 2004, 10: 3431–3442. 10.2174/1381612043383160CrossRefPubMed

13.

Debruyne P, Vermeulen S, Mareel M: The role of E-cadherin/catenin complex in gastrointestinal cancer. Acta Gastroenterol Belg 1999, 62: 393–402.PubMed

14.

Nollet F, Berx G, van Roy F: The role of the E-cadherin/catenin adhesion complex in the development and progression of cancer. Mol Cell Biol Res Commun 1999, 2: 77–85. 10.1006/mcbr.1999.0155CrossRefPubMed

15.

Surawska H, Ma PC, Salgia R: The role of ephrins and Eph receptors in cancer. Cytokine Growth Factor Rev 2004, 15: 419–433. 10.1016/j.cytogfr.2004.09.002CrossRefPubMed

16.

Chiu ST, Chang KJ, Ting CH, Shen HC, Li H, Hsieh FJ: Over-expression of EphB3 enhances cell-cell contacts and suppresses tumor growth in HT-29 human colon cancer cells. Carcinogenesis 2009, 30: 1475–1486. 10.1093/carcin/bgp133CrossRefPubMed

17.

Cortina C, Palomo-Ponce S, Iglesias M, Fernández-Masip JL, Vivancos A, Whissell G, Humà M, Peiró N, Gallego L, Jonkheer S, Davy A, Lloreta J, Sancho E, Batlle E: EphB-ephrin-B interactions suppress colorectal cancer progression by compartmentalizing tumor cells. Nat Genet 2007, 39: 1376–1383. 10.1038/ng.2007.11CrossRefPubMed

18.

Falkenback D, Nilbert M, Oberg S, Johansson J: Prognostic value of cell adhesion in esophageal adenocarcinomas. Dis Esophagus 2008, 21: 97–102. 10.1111/j.1442-2050.2007.00749.xCrossRefPubMed

19.

Feith M, Stein HJ, Mueller J, Siewert JR: Malignant degeneration of Barrett’s esophagus: the role of the Ki-67 proliferation fraction, expression of E-cadherin and p53. Dis Esophagus 2004, 17: 322–327. 10.1111/j.1442-2050.2004.00434.xCrossRefPubMed

20.

Swami S, Kumble G, Striadafilopoulos G: E-cadherin expression in gastroesophageal reflux disease, Barrett’s esophagus, and esophageal adenocarcinoma. An immunhistochemical immunoblot study. Am J Gastroenterol 1995, 90: 1808–1813.

21.

Flejou JF, Svrcek M: Barrett’s esophagus – a pathologist’s view. Histopathology 2007, 50: 3–14. 10.1111/j.1365-2559.2006.02569.xCrossRefPubMed

22.

Gumbiner B, Stevenson B, Grimaldi A: The role of the cell adhesion molecule uvomorulin in the formation and maintenance of the epithelial junctional complex. J Cell Biol 1988, 107: 1575–1587. 10.1083/jcb.107.4.1575CrossRefPubMed

23.

Butz S, Larue L: Expression of catenins during mouse embryonic development and in adult tissues. Cell Adhes Commun 1995, 3: 337–352. 10.3109/15419069509081018CrossRefPubMed

24.

Hay ED: The mesenchymal cell, its role in the embryo, and the remarkable signalling mechanisms that create it. Dev Dyn 2005, 233: 706–720. 10.1002/dvdy.20345CrossRefPubMed

25.

Gavert N, Ben-Ze’ev A: Epithelial-mesenchymal transition and the invasive potential of tumors. Trends Mol Med 2008, 14: 199–209. 10.1016/j.molmed.2008.03.004CrossRefPubMed

26.

Lee JM, Dedhar S, Kalluri R, Thompson EW: The epithelial-mesenchymal transition: new insights in signalling, development, and disease. J Cell Biol 2006, 27: 973–981.CrossRef

27.

Guarino M, Rubino B, Ballabio G: The role of epithelial-mesenchymal transition in cancer pathology. Pathology 2007, 39: 305–318. 10.1080/00313020701329914CrossRefPubMed

28.

Helm J, Enkemann S, Coppola D, Barthel JS, Kelley ST, Yeatman TJ: Dedifferentiation precedes invasion in the progression from Barrett`s metaplasia to esophageal adenocarcinoma. Clin Cancer Res 2005, 11: 2478–2485. 10.1158/1078-0432.CCR-04-1280CrossRefPubMed

29.

Darlavoix T, Seelentag W, Yan P, Bachmann A, Bosman FT: Altered expression of CD44 and DKK1 in the progression of Barrett’s esophagus to esophageal adenocarcinoma. Virchows Arch 2009, 454: 629–637. 10.1007/s00428-009-0769-zCrossRefPubMed

30.

Reid BJ, Levine DS, Longton G, Blount PL, Rabinovitch PS: Predictors of progression to cancer in Barrett’s esophagus: baseline histology and flow cytometry identify low- and high-risk patient subsets. Am J Gastroenterol 2000, 95: 1669–1676.PubMedCentralPubMed

31.

Batlle E, Henderson J, Beghtel H, Born M, Sancho E, Huls G, Meeldijk J, Robertson J, Wetering M, Pawson T, Clevers H: β-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/EphrinB. Cell 2002, 111: 251–263. 10.1016/S0092-8674(02)01015-2CrossRefPubMed

32.

Holmberg J, Genander M, Halford MM, Anneren C, Sondell M, Chumley MJ, Silvany RE, Henkemeyer M, Frisen J: EphB receptors coordinate migration and proliferation in the intestinal stem cell niche. Cell 2006, 125: 1151–1163. 10.1016/j.cell.2006.04.030CrossRefPubMed

33.

Batlle E, Bacani J, Begthel H, Jonkheer S, Gregorieff A, van de Born M, Malats M, Sancho E, Boon E, Pawson T, Gallinger S, Pals S, Clevers H: EphB receptor activity suppresses colorectal cancer progression. Nature 2005, 435: 1126–1130. Additional Query: May 3, 2012 10.1038/nature03626CrossRefPubMed

Title: The simultaneous expression of both ephrin B3 receptor and E-cadherin in Barrett`s adenocarcinoma is associated with favorable clinical staging
Authors: Matthias C Schauer
Nikolas H Stoecklein
Joerg Theisen
Feride Kröpil
Stephan Baldus
Arnulf Hoelscher
Markus Feith
Edwin Bölke
Christiane Matuschek
Wilfried Budach
Wolfram Trudo Knoefel
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: European Journal of Medical Research / Issue 1/2012
Electronic ISSN: 2047-783X
DOI: https://doi.org/10.1186/2047-783X-17-10

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The simultaneous expression of both ephrin B3 receptor and E-cadherin in Barrett`s adenocarcinoma is associated with favorable clinical staging

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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