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Published in: Virchows Archiv 6/2009

01-06-2009 | Original Article

Altered expression of CD44 and DKK1 in the progression of Barrett’s esophagus to esophageal adenocarcinoma

Authors: T. Darlavoix, W. Seelentag, P. Yan, A. Bachmann, F. T. Bosman

Published in: Virchows Archiv | Issue 6/2009

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Abstract

Barrett’s esophagus (BE) is an acquired condition in which the normal lining of the esophagus is replaced by intestinal metaplastic epithelium. BE can evolve to esophageal adenocarcinoma (EAC) through low-grade dysplasia (LGD) and high-grade dysplasia (HGD). The only generally accepted marker for increased risk of EAC is the presence of HGD, diagnosed on endoscopic biopsies. More specific markers for the prediction of EAC risk are needed. A tissue microarray was constructed comprising tissue samples from BE, LGD, HGD, and EAC. Marker expression was studied by immunohistochemistry using antibodies against CD44, DKK1, CDX2, COX2, SOX9, OCT1, E-cadherin, and β-catenin. Immunostaining was evaluated semi-quantitatively. CD44 expression decreased in HGD and EAC relative to BE and LGD. DKK1 expression increased in HGD and EAC relative to BE and LDG. CDX2 expression increased in HGD but decreased in EAC. COX2 expression decreased in EAC, and SOX9 expression increased only in the upper crypt epithelial cells in HGD. E-cadherin expression decreased in EAC. Nuclear β-catenin was not significantly different between BE, LGD, and HGD. Loss of CD44 and gain of DKK1 expression characterizes progression from BE and LGD to HGD and EAC, and their altered expression might indicate an increased risk for developing an EAC. This observation warrants inclusion of these immunohistochemically detectable markers in a study with a long patient follow-up.
Literature
1.
go back to reference Flejou JF (2000) Barrett’s oesophagus: from metaplasia to dysplasia and cancer. Gut 54(Suppl 1):i6–i12 Flejou JF (2000) Barrett’s oesophagus: from metaplasia to dysplasia and cancer. Gut 54(Suppl 1):i6–i12
2.
go back to reference Koppert LB, Wijnhoven BP, van Dekken H et al (2005) The molecular biology of esophageal adenocarcinoma. J Surg Oncol 92:169–190PubMedCrossRef Koppert LB, Wijnhoven BP, van Dekken H et al (2005) The molecular biology of esophageal adenocarcinoma. J Surg Oncol 92:169–190PubMedCrossRef
3.
go back to reference Playford RJ (2006) New British society of gastroenterology (BSG) guidelines for the diagnosis and management of Barrett’s oesophagus. Gut 55:442PubMedCrossRef Playford RJ (2006) New British society of gastroenterology (BSG) guidelines for the diagnosis and management of Barrett’s oesophagus. Gut 55:442PubMedCrossRef
4.
go back to reference el-Serag HB, Sonnenberg A (1998) Opposing time trends of peptic ulcer and reflux disease. Gut 43:327–333PubMedCrossRef el-Serag HB, Sonnenberg A (1998) Opposing time trends of peptic ulcer and reflux disease. Gut 43:327–333PubMedCrossRef
5.
go back to reference Blot WJ, McLaughlin JK (1999) The changing epidemiology of esophageal cancer. Semin Oncol 26(5 Suppl 15):2–8PubMed Blot WJ, McLaughlin JK (1999) The changing epidemiology of esophageal cancer. Semin Oncol 26(5 Suppl 15):2–8PubMed
6.
go back to reference Farrow DC, Vaughan TL (1996) Determinants of survival following the diagnosis of esophageal adenocarcinoma (United States). Cancer Causes Control 7:322–327PubMedCrossRef Farrow DC, Vaughan TL (1996) Determinants of survival following the diagnosis of esophageal adenocarcinoma (United States). Cancer Causes Control 7:322–327PubMedCrossRef
7.
go back to reference Falk GW, Rice TW, Goldblum JR et al (1999) Jumbo biopsy forceps protocol still misses unsuspected cancer in Barrett’s esophagus with high-grade dysplasia. Gastrointest Endosc 49:170–176PubMedCrossRef Falk GW, Rice TW, Goldblum JR et al (1999) Jumbo biopsy forceps protocol still misses unsuspected cancer in Barrett’s esophagus with high-grade dysplasia. Gastrointest Endosc 49:170–176PubMedCrossRef
8.
go back to reference Heitmiller RF, Redmond M, Hamilton SR (1996) Barrett’s esophagus with high-grade dysplasia. An indication for prophylactic esophagectomy. Ann Surg 224:66–71PubMedCrossRef Heitmiller RF, Redmond M, Hamilton SR (1996) Barrett’s esophagus with high-grade dysplasia. An indication for prophylactic esophagectomy. Ann Surg 224:66–71PubMedCrossRef
9.
go back to reference Shaheen NJ, Crosby MA, Bozymski EM et al (2000) Is there publication bias in the reporting of cancer risk in Barrett’s esophagus? Gastroenterology 119:333–338PubMedCrossRef Shaheen NJ, Crosby MA, Bozymski EM et al (2000) Is there publication bias in the reporting of cancer risk in Barrett’s esophagus? Gastroenterology 119:333–338PubMedCrossRef
10.
go back to reference Flejou JF, Svrcek M (2007) Barrett’s oesophagus—a pathologist’s view. Histopathology 50:3–14PubMedCrossRef Flejou JF, Svrcek M (2007) Barrett’s oesophagus—a pathologist’s view. Histopathology 50:3–14PubMedCrossRef
11.
go back to reference Morales CP, Souza RF, Spechler SJ (2002) Hallmarks of cancer progression in Barrett’s oesophagus. Lancet 360:1587–1589PubMedCrossRef Morales CP, Souza RF, Spechler SJ (2002) Hallmarks of cancer progression in Barrett’s oesophagus. Lancet 360:1587–1589PubMedCrossRef
12.
go back to reference Clement G, Braunschweig R, Pasquier N et al (2006) Alterations of the Wnt signaling pathway during the neoplastic progression of Barrett’s esophagus. Oncogene 25:3084–3092PubMedCrossRef Clement G, Braunschweig R, Pasquier N et al (2006) Alterations of the Wnt signaling pathway during the neoplastic progression of Barrett’s esophagus. Oncogene 25:3084–3092PubMedCrossRef
13.
go back to reference Doucas H, Garcea G, Neal CP et al (2005) Changes in the Wnt signalling pathway in gastrointestinal cancers and their prognostic significance. Eur J Cancer 41:365–379PubMedCrossRef Doucas H, Garcea G, Neal CP et al (2005) Changes in the Wnt signalling pathway in gastrointestinal cancers and their prognostic significance. Eur J Cancer 41:365–379PubMedCrossRef
14.
go back to reference Shi XY, Bhagwandeen B, Leong AS (2008) p16, Cyclin D1, Ki-67, and AMACR as markers for dysplasia in Barrett esophagus. Appl Immunohistochem Mol Morphol 16:447–452PubMedCrossRef Shi XY, Bhagwandeen B, Leong AS (2008) p16, Cyclin D1, Ki-67, and AMACR as markers for dysplasia in Barrett esophagus. Appl Immunohistochem Mol Morphol 16:447–452PubMedCrossRef
15.
go back to reference Shi XY, Bhagwandeen B, Leong AS (2008) CDX2 and villin are useful markers of intestinal metaplasia in the diagnosis of Barrett esophagus. Am J Clin Pathol 129:571–577PubMedCrossRef Shi XY, Bhagwandeen B, Leong AS (2008) CDX2 and villin are useful markers of intestinal metaplasia in the diagnosis of Barrett esophagus. Am J Clin Pathol 129:571–577PubMedCrossRef
16.
go back to reference Nair KS, Naidoo R, Chetty R (2005) Expression of cell adhesion molecules in oesophageal carcinoma and its prognostic value. J Clin Pathol 58:343–351PubMedCrossRef Nair KS, Naidoo R, Chetty R (2005) Expression of cell adhesion molecules in oesophageal carcinoma and its prognostic value. J Clin Pathol 58:343–351PubMedCrossRef
17.
go back to reference Taketo MM (2006) Wnt signaling and gastrointestinal tumorigenesis in mouse models. Oncogene 25:7522–7530PubMedCrossRef Taketo MM (2006) Wnt signaling and gastrointestinal tumorigenesis in mouse models. Oncogene 25:7522–7530PubMedCrossRef
18.
go back to reference Okamoto R, Watanabe M (2004) Molecular and clinical basis for the regeneration of human gastrointestinal epithelia. J Gastroenterol 39:1–6PubMedCrossRef Okamoto R, Watanabe M (2004) Molecular and clinical basis for the regeneration of human gastrointestinal epithelia. J Gastroenterol 39:1–6PubMedCrossRef
19.
20.
go back to reference van Es JH, van Gijn ME, Riccio O et al (2005) Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435:959–963PubMedCrossRef van Es JH, van Gijn ME, Riccio O et al (2005) Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435:959–963PubMedCrossRef
21.
go back to reference Almeida R, Almeida J, Shoshkes M et al (2005) OCT-1 is over-expressed in intestinal metaplasia and intestinal gastric carcinomas and binds to, but does not transactivate, CDX2 in gastric cells. J Pathol 207:396–401PubMedCrossRef Almeida R, Almeida J, Shoshkes M et al (2005) OCT-1 is over-expressed in intestinal metaplasia and intestinal gastric carcinomas and binds to, but does not transactivate, CDX2 in gastric cells. J Pathol 207:396–401PubMedCrossRef
22.
go back to reference Bian YS, Osterheld MC, Fontolliet C et al (2002) p16 inactivation by methylation of the CDKN2A promoter occurs early during neoplastic progression in Barrett’s esophagus. Gastroenterology 122:1113–1121PubMedCrossRef Bian YS, Osterheld MC, Fontolliet C et al (2002) p16 inactivation by methylation of the CDKN2A promoter occurs early during neoplastic progression in Barrett’s esophagus. Gastroenterology 122:1113–1121PubMedCrossRef
23.
go back to reference Brantjes H, Barker N, van Es J et al (2002) TCF: lady justice casting the final verdict on the outcome of Wnt signalling. Biol Chem 383:255–261PubMedCrossRef Brantjes H, Barker N, van Es J et al (2002) TCF: lady justice casting the final verdict on the outcome of Wnt signalling. Biol Chem 383:255–261PubMedCrossRef
24.
go back to reference Yan P, Seelentag W, Bachmann A et al (2007) An agarose matrix facilitates sectioning of tissue microarray blocks. J Histochem Cytochem 55:21–24PubMedCrossRef Yan P, Seelentag W, Bachmann A et al (2007) An agarose matrix facilitates sectioning of tissue microarray blocks. J Histochem Cytochem 55:21–24PubMedCrossRef
25.
go back to reference Villanacci V, Rossi E, Zambelli C et al (2007) COX-2, CDX2, and CDC2 immunohistochemical assessment for dysplasia-carcinoma progression in Barrett’s esophagus. Dig Liver Dis 39:305–311PubMedCrossRef Villanacci V, Rossi E, Zambelli C et al (2007) COX-2, CDX2, and CDC2 immunohistochemical assessment for dysplasia-carcinoma progression in Barrett’s esophagus. Dig Liver Dis 39:305–311PubMedCrossRef
26.
go back to reference Bailey T, Biddlestone L, Shepherd N et al (1998) Altered cadherin and catenin complexes in the Barrett’s esophagus-dysplasia-adenocarcinoma sequence: correlation with disease progression and dedifferentiation. Am J Pathol 152:135–144PubMed Bailey T, Biddlestone L, Shepherd N et al (1998) Altered cadherin and catenin complexes in the Barrett’s esophagus-dysplasia-adenocarcinoma sequence: correlation with disease progression and dedifferentiation. Am J Pathol 152:135–144PubMed
27.
28.
go back to reference Clevers H, Batlle E (2006) EphB/EphrinB receptors and Wnt signaling in colorectal cancer. Cancer Res 66:2–5PubMedCrossRef Clevers H, Batlle E (2006) EphB/EphrinB receptors and Wnt signaling in colorectal cancer. Cancer Res 66:2–5PubMedCrossRef
29.
go back to reference Gregorieff A, Pinto D, Begthel H et al (2005) Expression pattern of Wnt signaling components in the adult intestine. Gastroenterology 129:626–638PubMed Gregorieff A, Pinto D, Begthel H et al (2005) Expression pattern of Wnt signaling components in the adult intestine. Gastroenterology 129:626–638PubMed
30.
go back to reference Mutoh H, Sakamoto H, Hayakawa H et al (2006) The intestine-specific homeobox gene Cdx2 induces expression of the basic helix-loop-helix transcription factor Math1. Differentiation 74:313–321PubMedCrossRef Mutoh H, Sakamoto H, Hayakawa H et al (2006) The intestine-specific homeobox gene Cdx2 induces expression of the basic helix-loop-helix transcription factor Math1. Differentiation 74:313–321PubMedCrossRef
31.
go back to reference Liu T, Zhang X, So CK et al (2007) Regulation of Cdx2 expression by promoter methylation, and effects of Cdx2 transfection on morphology and gene expression of human esophageal epithelial cells. Carcinogenesis 28:488–496PubMedCrossRef Liu T, Zhang X, So CK et al (2007) Regulation of Cdx2 expression by promoter methylation, and effects of Cdx2 transfection on morphology and gene expression of human esophageal epithelial cells. Carcinogenesis 28:488–496PubMedCrossRef
32.
go back to reference Greenawalt DM, Duong C, Smyth GK et al (2007) Gene expression profiling of esophageal cancer: comparative analysis of Barrett’s esophagus, adenocarcinoma, and squamous cell carcinoma. Int J Cancer 120:1914–1921PubMedCrossRef Greenawalt DM, Duong C, Smyth GK et al (2007) Gene expression profiling of esophageal cancer: comparative analysis of Barrett’s esophagus, adenocarcinoma, and squamous cell carcinoma. Int J Cancer 120:1914–1921PubMedCrossRef
33.
go back to reference Ngan CY, Yamamoto H, Seshimo I et al (1996) Expression of CD44H and CD44v3 in normal oesophagus, Barrett mucosa and oesophageal carcinoma. J Clin Pathol 49:489–492CrossRef Ngan CY, Yamamoto H, Seshimo I et al (1996) Expression of CD44H and CD44v3 in normal oesophagus, Barrett mucosa and oesophageal carcinoma. J Clin Pathol 49:489–492CrossRef
34.
go back to reference Lagorce-Pages C, Paraf F et al (1998) Expression of CD44 in premalignant and malignant Barrett’s oesophagus. Histopathology 32:7–14PubMedCrossRef Lagorce-Pages C, Paraf F et al (1998) Expression of CD44 in premalignant and malignant Barrett’s oesophagus. Histopathology 32:7–14PubMedCrossRef
35.
go back to reference Menges M, Goebel R, Pueschel W et al (2002) Expression of CD44v5 and -v6 in Barrett’s carcinoma is not increased compared to that in nondysplastic Barrett’s mucosa. Exp Mol Pathol 72:207–212PubMedCrossRef Menges M, Goebel R, Pueschel W et al (2002) Expression of CD44v5 and -v6 in Barrett’s carcinoma is not increased compared to that in nondysplastic Barrett’s mucosa. Exp Mol Pathol 72:207–212PubMedCrossRef
36.
go back to reference Niehrs C (2006) Function and biological roles of the Dickkopf family of Wnt modulators. Oncogene 25:7469–7481PubMedCrossRef Niehrs C (2006) Function and biological roles of the Dickkopf family of Wnt modulators. Oncogene 25:7469–7481PubMedCrossRef
37.
go back to reference Sato H, Suzuki H, Toyota M et al (2007) Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors. Carcinogenesis 28:2459–2466PubMedCrossRef Sato H, Suzuki H, Toyota M et al (2007) Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors. Carcinogenesis 28:2459–2466PubMedCrossRef
38.
go back to reference Aguilera O, Fraga MF, Ballestar E et al (2006) Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer. Oncogene 25:4116–4121PubMedCrossRef Aguilera O, Fraga MF, Ballestar E et al (2006) Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer. Oncogene 25:4116–4121PubMedCrossRef
39.
go back to reference Ali I, Rafiee P, Hogan WJ et al (2006) Dickkopf homologs in squamous mucosa of esophagitis patients are overexpressed compared with Barrett’s patients and healthy controls. Am J Gastroenterol 101:1437–1448PubMedCrossRef Ali I, Rafiee P, Hogan WJ et al (2006) Dickkopf homologs in squamous mucosa of esophagitis patients are overexpressed compared with Barrett’s patients and healthy controls. Am J Gastroenterol 101:1437–1448PubMedCrossRef
40.
go back to reference Van Baal JW, Bozikas A, Pronk R et al (2008) Cytokeratin and CDX-2 expression in Barrett’s esophagus. Scand J Gastroenterol 43:132–140PubMedCrossRef Van Baal JW, Bozikas A, Pronk R et al (2008) Cytokeratin and CDX-2 expression in Barrett’s esophagus. Scand J Gastroenterol 43:132–140PubMedCrossRef
41.
go back to reference Wegner M (1999) From head to toes: the multiple facets of Sox proteins. Nucleic Acids Res 27:1409–1420PubMedCrossRef Wegner M (1999) From head to toes: the multiple facets of Sox proteins. Nucleic Acids Res 27:1409–1420PubMedCrossRef
42.
go back to reference Blache P, van de Wetering M, Duluc I et al (2004) SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes. J Cell Biol 166:37–47PubMedCrossRef Blache P, van de Wetering M, Duluc I et al (2004) SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes. J Cell Biol 166:37–47PubMedCrossRef
43.
go back to reference Ferguson HR, Wild CP, Anderson LA et al (2008) Cyclooxygenase-2 and inducible nitric oxide synthase gene polymorphisms and risk of reflux esophagitis, Barrett’s esophagus, and esophageal adenocarcinoma. Cancer Epidemiol Biomarkers Prev 17:727–731PubMedCrossRef Ferguson HR, Wild CP, Anderson LA et al (2008) Cyclooxygenase-2 and inducible nitric oxide synthase gene polymorphisms and risk of reflux esophagitis, Barrett’s esophagus, and esophageal adenocarcinoma. Cancer Epidemiol Biomarkers Prev 17:727–731PubMedCrossRef
44.
go back to reference Feith M, Stein HJ, Mueller J et al (2004) Malignant degeneration of Barrett’s esophagus: the role of the Ki-67 proliferation fraction, expression of E-cadherin and p53. Dis Esophagus 17:322–327PubMedCrossRef Feith M, Stein HJ, Mueller J et al (2004) Malignant degeneration of Barrett’s esophagus: the role of the Ki-67 proliferation fraction, expression of E-cadherin and p53. Dis Esophagus 17:322–327PubMedCrossRef
45.
go back to reference Wijnhoven BP, Nollet F, De Both NJ et al (2000) Genetic alterations involving exon 3 of the beta-catenin gene do not play a role in adenocarcinomas of the esophagus. Int J Cancer 86:533–537PubMedCrossRef Wijnhoven BP, Nollet F, De Both NJ et al (2000) Genetic alterations involving exon 3 of the beta-catenin gene do not play a role in adenocarcinomas of the esophagus. Int J Cancer 86:533–537PubMedCrossRef
46.
go back to reference Williams LJ, Guernsey DL, Casson AG (2006) Biomarkers in the molecular pathogenesis of esophageal (Barrett) adenocarcinoma. Curr Oncol 13:33–43PubMed Williams LJ, Guernsey DL, Casson AG (2006) Biomarkers in the molecular pathogenesis of esophageal (Barrett) adenocarcinoma. Curr Oncol 13:33–43PubMed
Metadata
Title
Altered expression of CD44 and DKK1 in the progression of Barrett’s esophagus to esophageal adenocarcinoma
Authors
T. Darlavoix
W. Seelentag
P. Yan
A. Bachmann
F. T. Bosman
Publication date
01-06-2009
Publisher
Springer-Verlag
Published in
Virchows Archiv / Issue 6/2009
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI
https://doi.org/10.1007/s00428-009-0769-z

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