Journal Mobile Options
Table of Contents
Vol. 79, No. 3, 2012
Issue release date: March 2012
Section title: Original Paper
Pathobiology 2012;79:154–161
(DOI:10.1159/000335694)

Cytokeratin Expression Profiling in Gastric Carcinoma: Clinicopathologic Significance and Comparison with Tumor-Associated Molecules

Takami H. · Sentani K. · Matsuda M. · Oue N. · Sakamoto N. · Yasui W.
Department of Molecular Pathology, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan
email Corresponding Author

Abstract

Objective: The expressions of cytokeratin (CK) 7 and 20 have been studied in various primary and metastatic carcinomas, and their determination may help distinguish the site of origin of metastatic carcinomas. However, little is known about the molecular basis that determines variations in CK patterns in gastric cancers (GCs). The aim of the present study was to analyze the CK expression patterns in a large number of GCs and to investigate how the CK patterns correlate with clinicopathologic parameters, histology, mucin phenotype or several tumor-related molecules. Methods and Results: We immunohistochemically examined the CK7/CK20 patterns, mucin expression profiles (MUC5AC, MUC6, MUC2 and CD10), and the cancer-related molecules (CDX2, p53, EGFR and β-catenin), using a tissue microarray with 870 GCs. The GCs were divided into four patterns; 17% of CK7+/CK20+, 57% of CK7+/CK20–, 9% of CK7–/CK20+ and 17% of CK7–/CK20. GCs with the CK7–/CK20– pattern demonstrated a close relation to undifferentiated adenocarcinoma. CK7 expression was significantly correlated with the expression of MUC5AC and MUC6, while CK20 expression was correlated with MUC2 and CDX2. There were statistically significant associations between CK expression patterns and mucin phenotypes. Conclusion: These results indicate that the CK7/CK20 expression patterns in GCs demonstrated different clinicopathologic features and molecular signatures.

© 2012 S. Karger AG, Basel


  

Key Words

  • Gastric cancer
  • Cytokeratin
  • Mucin phenotype
  • Tumor-associated molecules

References

  1. Carneiro F, Sobrinho-Simoes M: Metastatic pattern of gastric carcinoma. Hum Pathol 1996;27:213–214.
  2. Yasui W, Oue N, Kitadai Y, Nakayama H: Recent advances in molecular pathobiology of gastric carcinoma; in Kaminishi M, Takubo K, Mafune K (eds): The Diversity of Gastric Carcinoma: Pathogenesis, Diagnosis and Therapy. Tokyo, Springer, 2005, pp 51–71.
  3. Tatematsu M, Tsukamoto T, Inada K: Stem cells and gastric cancer: role of gastric and intestinal mixed intestinal metaplasia. Cancer Sci 2003;94:135–141.
  4. Yasui W, Sentani K, Motoshita J, Nakayama H: Molecular pathobiology of gastric cancer. Scand J Surg 2006;95:225–231.
  5. Chu PG, Weiss LM: Keratin expression in human tissues and neoplasms. Histopathology 2002;40:403–439.
  6. Chu P, Wu E, Weiss LM: Cytokeratin 7 and cytokeratin 20 expression in epithelial neoplasms: a survey of 435 cases. Mod Pathol 2000;13:962–972.
  7. Moll R: Cytokeratins in the histological diagnosis of malignant tumors. Int J Biol Markers 1994;9:63–69.
  8. Moll R, Lowe A, Laufer J, Franke WW: Cytokeratin 20 in human carcinomas. A new histodiagnostic marker detected by monoclonal antibodies. Am J Pathol 1992;140:427–447.
  9. Schwerer MJ, Baczako K: Expression of cytokeratins typical for ductal and squamous differentiation in the human stomach: an immunohistochemical study of normal foveolar epithelium, Helicobacter pylori gastritis and intestinal metaplasia. Histopathology 1996;29:131–137.
  10. Ramaekers F, van Niekerk C, Poels L, Schaafsma E, Huijsmans A, Robben H, Schaart G, Vooijs P: Use of monoclonal antibodies to keratin 7 in the differential diagnosis of adenocarcinomas. Am J Pathol 1990;136:641–655.
  11. Tot T: Cytokeratins 20 and 7 as biomarkers: usefulness in discriminating primary from metastatic adenocarcinoma. Eur J Cancer 2002;38:758–763.
  12. Park SY, Kim HS, Hong EK, Kim WH: Expression of cytokeratins 7 and 20 in primary carcinomas of the stomach and colorectum and their value in the differential diagnosis of metastatic carcinomas to the ovary. Hum Pathol 2002;33:1078–1085.
  13. Moll R: Cytokeratins as markers of differentiation in the diagnosis of epithelial tumors. Subcell Biochem 1998;31:205–262.
  14. Wauters CC, Smedts F, Gerrits LG, Bosman FT, Ramaekers FC: Keratins 7 and 20 as diagnostic markers of carcinomas metastatic to the ovary. Hum Pathol 1995;26:852–855.
  15. Kirchner T, Muller S, Hattori T, Mukaisyo K, Papadopoulos T, Brabletz T, Jung A: Metaplasia, intraepithelial neoplasia and early cancer of the stomach are related to dedifferentiated epithelial cells defined by cytokeratin-7 expression in gastritis. Virchows Arch 2001;439:512–522.
  16. Ormsby AH, Goldblum JR, Rice TW, Richter JE, Gramlich TL: The utility of cytokeratin subsets in distinguishing Barrett’s-related oesophageal adenocarcinoma from gastric adenocarcinoma. Histopathology 2001;38:307–311.
  17. Kim MA, Lee HS, Yang HK, Kim WH: Cytokeratin expression profile in gastric carcinomas. Hum Pathol 2004;35:576–581.
  18. Shen B, Ormsby AH, Shen C, Dumot JA, Shao YW, Bevins CL, Gramlich TL: Cytokeratin expression patterns in noncardia, intestinal metaplasia-associated gastric adenocarcinoma: implication for the evaluation of intestinal metaplasia and tumors at the esophagogastric junction. Cancer 2002;94:820–831.
  19. Gurbuz Y, Kose N: Cytokeratin expression patterns of gastric carcinomas according to Lauren and Goseki classification. Appl Immunohistochem Mol Morphol 2006;14:303–308.
  20. Lee MJ, Lee HS, Kim WH, Choi Y, Yang M: Expression of mucins and cytokeratins in primary carcinomas of the digestive system. Mod Pathol 2003;16:403–410.
  21. Xue L, Zhang X, Li Y, Yang H, Li X, Mi J, Wang H, Wang J, Yan X: Differences of immunophenotypic markers and signaling molecules between adenocarcinomas of gastric cardia and distal stomach. Hum Pathol 2011;42:594–601.
  22. Sobin LH, Wittekind CH (eds): TNM Classification Of Malignant Tumors, ed 6. New York, Wiley, 2002, pp 65–68.
  23. Japanese Gastric Cancer Association: Japanese classification of gastric carcinoma, 3rd English edition. Gastric Cancer 2011;14:101–112.
  24. Mizoshita T, Tsukamoto T, Nakanishi H, Inada K, Ogasawara N, Joh T, Itoh M, Yamamura Y, Tatematsu M: Expression of Cdx2 and the phenotype of advanced gastric cancers: relationship with prognosis. J Cancer Res Clin Oncol 2003;129:727–734.
  25. Sauter G, Mirlacher M: Tissue microarrays for predictive molecular pathology. J Clin Pathol 2002;55:575–576.
  26. Sentani K, Oue N, Tashiro T, Sakamoto N, Nishisaka T, Fukuhara T, Taniyama K, Matsuura H, Arihiro K, Ochiai A, Yasui W: Immunohistochemical staining of reg IV and claudin-18 is useful in the diagnosis of gastrointestinal signet ring cell carcinoma. Am J Surg Pathol 2008;32:1182–1189.
  27. Hoos A, Urist MJ, Stojadinovic A, Mastorides S, Dudas ME, Leung DH, Kuo D, Brennan MF, Lewis JJ, Cordon-Cardo C: Validation of tissue microarrays for immunohistochemical profiling of cancer specimens using the example of human fibroblastic tumors. Am J Pathol 2001;158:1245–1151.
  28. Lee HS, Cho SB, Lee HE, Kim MA, Kim JH, Park do J, Kim JH, Yang HK, Lee BL, Kim WH: Protein expression profiling and molecular classification of gastric cancer by the tissue array method. Clin Cancer Res 2007;13:4154–4163.
  29. Gulmann C, Counihan I, Grace A, Patchett S, Leen E, Leader M, Kay E: Cytokeratin 7/20 and mucin expression patterns in oesophageal, cardia and distal gastric adenocarcinomas. Histopathology 2003;43:453–461.
  30. Pinto-de-Sousa J, David L, Reis CA, Gomes R, Silva L, Pimenta A: Mucins MUC1, MUC2, MUC5AC and MUC6 expression in the evaluation of differentiation and clinico-biological behaviour of gastric carcinoma. Virchows Arch 2002;440:304–310.
  31. Pinto-de-Sousa J, Reis CA, David L, Pimenta A, Cardoso-de-Oliveira M: MUC5B expression in gastric carcinoma: relationship with clinico-pathological parameters and with expression of mucins MUC1, MUC2, MUC5AC and MUC6. Virchows Arch 2004;444:224–230.
  32. Chan CW, Wong NA, Liu Y, Bicknell D, Turley H, Hollins L, Miller CJ, Wilding JL, Bodmer WF: Gastrointestinal differentiation marker cytokeratin 20 is regulated by homeobox gene CDX1. Proc Natl Acad Sci USA 2009;106:1936–1941.

  

Author Contacts

Wataru Yasui, MD, PhD
Department of Molecular Pathology
Hiroshima University Graduate School of Biomedical Sciences
1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551 (Japan)
Tel. +81 82 257 5145, E-Mail wyasui@hiroshima-u.ac.jp

  

Article Information

Received: November 7, 2011
Accepted after revision: December 12, 2011
Published online: January 28, 2012
Number of Print Pages : 8
Number of Figures : 4, Number of Tables : 2, Number of References : 32

  

Publication Details

Pathobiology (Exploring the basis of disease)

Vol. 79, No. 3, Year 2012 (Cover Date: March 2012)

Journal Editor: Borisch B. (Geneva), Yasui W. (Hiroshima)
ISSN: 1015-2008 (Print), eISSN: 1423-0291 (Online)

For additional information: http://www.karger.com/PAT


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Carneiro F, Sobrinho-Simoes M: Metastatic pattern of gastric carcinoma. Hum Pathol 1996;27:213–214.
  2. Yasui W, Oue N, Kitadai Y, Nakayama H: Recent advances in molecular pathobiology of gastric carcinoma; in Kaminishi M, Takubo K, Mafune K (eds): The Diversity of Gastric Carcinoma: Pathogenesis, Diagnosis and Therapy. Tokyo, Springer, 2005, pp 51–71.
  3. Tatematsu M, Tsukamoto T, Inada K: Stem cells and gastric cancer: role of gastric and intestinal mixed intestinal metaplasia. Cancer Sci 2003;94:135–141.
  4. Yasui W, Sentani K, Motoshita J, Nakayama H: Molecular pathobiology of gastric cancer. Scand J Surg 2006;95:225–231.
  5. Chu PG, Weiss LM: Keratin expression in human tissues and neoplasms. Histopathology 2002;40:403–439.
  6. Chu P, Wu E, Weiss LM: Cytokeratin 7 and cytokeratin 20 expression in epithelial neoplasms: a survey of 435 cases. Mod Pathol 2000;13:962–972.
  7. Moll R: Cytokeratins in the histological diagnosis of malignant tumors. Int J Biol Markers 1994;9:63–69.
  8. Moll R, Lowe A, Laufer J, Franke WW: Cytokeratin 20 in human carcinomas. A new histodiagnostic marker detected by monoclonal antibodies. Am J Pathol 1992;140:427–447.
  9. Schwerer MJ, Baczako K: Expression of cytokeratins typical for ductal and squamous differentiation in the human stomach: an immunohistochemical study of normal foveolar epithelium, Helicobacter pylori gastritis and intestinal metaplasia. Histopathology 1996;29:131–137.
  10. Ramaekers F, van Niekerk C, Poels L, Schaafsma E, Huijsmans A, Robben H, Schaart G, Vooijs P: Use of monoclonal antibodies to keratin 7 in the differential diagnosis of adenocarcinomas. Am J Pathol 1990;136:641–655.
  11. Tot T: Cytokeratins 20 and 7 as biomarkers: usefulness in discriminating primary from metastatic adenocarcinoma. Eur J Cancer 2002;38:758–763.
  12. Park SY, Kim HS, Hong EK, Kim WH: Expression of cytokeratins 7 and 20 in primary carcinomas of the stomach and colorectum and their value in the differential diagnosis of metastatic carcinomas to the ovary. Hum Pathol 2002;33:1078–1085.
  13. Moll R: Cytokeratins as markers of differentiation in the diagnosis of epithelial tumors. Subcell Biochem 1998;31:205–262.
  14. Wauters CC, Smedts F, Gerrits LG, Bosman FT, Ramaekers FC: Keratins 7 and 20 as diagnostic markers of carcinomas metastatic to the ovary. Hum Pathol 1995;26:852–855.
  15. Kirchner T, Muller S, Hattori T, Mukaisyo K, Papadopoulos T, Brabletz T, Jung A: Metaplasia, intraepithelial neoplasia and early cancer of the stomach are related to dedifferentiated epithelial cells defined by cytokeratin-7 expression in gastritis. Virchows Arch 2001;439:512–522.
  16. Ormsby AH, Goldblum JR, Rice TW, Richter JE, Gramlich TL: The utility of cytokeratin subsets in distinguishing Barrett’s-related oesophageal adenocarcinoma from gastric adenocarcinoma. Histopathology 2001;38:307–311.
  17. Kim MA, Lee HS, Yang HK, Kim WH: Cytokeratin expression profile in gastric carcinomas. Hum Pathol 2004;35:576–581.
  18. Shen B, Ormsby AH, Shen C, Dumot JA, Shao YW, Bevins CL, Gramlich TL: Cytokeratin expression patterns in noncardia, intestinal metaplasia-associated gastric adenocarcinoma: implication for the evaluation of intestinal metaplasia and tumors at the esophagogastric junction. Cancer 2002;94:820–831.
  19. Gurbuz Y, Kose N: Cytokeratin expression patterns of gastric carcinomas according to Lauren and Goseki classification. Appl Immunohistochem Mol Morphol 2006;14:303–308.
  20. Lee MJ, Lee HS, Kim WH, Choi Y, Yang M: Expression of mucins and cytokeratins in primary carcinomas of the digestive system. Mod Pathol 2003;16:403–410.
  21. Xue L, Zhang X, Li Y, Yang H, Li X, Mi J, Wang H, Wang J, Yan X: Differences of immunophenotypic markers and signaling molecules between adenocarcinomas of gastric cardia and distal stomach. Hum Pathol 2011;42:594–601.
  22. Sobin LH, Wittekind CH (eds): TNM Classification Of Malignant Tumors, ed 6. New York, Wiley, 2002, pp 65–68.
  23. Japanese Gastric Cancer Association: Japanese classification of gastric carcinoma, 3rd English edition. Gastric Cancer 2011;14:101–112.
  24. Mizoshita T, Tsukamoto T, Nakanishi H, Inada K, Ogasawara N, Joh T, Itoh M, Yamamura Y, Tatematsu M: Expression of Cdx2 and the phenotype of advanced gastric cancers: relationship with prognosis. J Cancer Res Clin Oncol 2003;129:727–734.
  25. Sauter G, Mirlacher M: Tissue microarrays for predictive molecular pathology. J Clin Pathol 2002;55:575–576.
  26. Sentani K, Oue N, Tashiro T, Sakamoto N, Nishisaka T, Fukuhara T, Taniyama K, Matsuura H, Arihiro K, Ochiai A, Yasui W: Immunohistochemical staining of reg IV and claudin-18 is useful in the diagnosis of gastrointestinal signet ring cell carcinoma. Am J Surg Pathol 2008;32:1182–1189.
  27. Hoos A, Urist MJ, Stojadinovic A, Mastorides S, Dudas ME, Leung DH, Kuo D, Brennan MF, Lewis JJ, Cordon-Cardo C: Validation of tissue microarrays for immunohistochemical profiling of cancer specimens using the example of human fibroblastic tumors. Am J Pathol 2001;158:1245–1151.
  28. Lee HS, Cho SB, Lee HE, Kim MA, Kim JH, Park do J, Kim JH, Yang HK, Lee BL, Kim WH: Protein expression profiling and molecular classification of gastric cancer by the tissue array method. Clin Cancer Res 2007;13:4154–4163.
  29. Gulmann C, Counihan I, Grace A, Patchett S, Leen E, Leader M, Kay E: Cytokeratin 7/20 and mucin expression patterns in oesophageal, cardia and distal gastric adenocarcinomas. Histopathology 2003;43:453–461.
  30. Pinto-de-Sousa J, David L, Reis CA, Gomes R, Silva L, Pimenta A: Mucins MUC1, MUC2, MUC5AC and MUC6 expression in the evaluation of differentiation and clinico-biological behaviour of gastric carcinoma. Virchows Arch 2002;440:304–310.
  31. Pinto-de-Sousa J, Reis CA, David L, Pimenta A, Cardoso-de-Oliveira M: MUC5B expression in gastric carcinoma: relationship with clinico-pathological parameters and with expression of mucins MUC1, MUC2, MUC5AC and MUC6. Virchows Arch 2004;444:224–230.
  32. Chan CW, Wong NA, Liu Y, Bicknell D, Turley H, Hollins L, Miller CJ, Wilding JL, Bodmer WF: Gastrointestinal differentiation marker cytokeratin 20 is regulated by homeobox gene CDX1. Proc Natl Acad Sci USA 2009;106:1936–1941.