Gastroenterology

Gastroenterology

Volume 123, Issue 4, October 2002, Pages 1052-1060
Gastroenterology

Clinical–Liver, Pancreas, and Biliary Tract
Aberrant expression of MUC5AC and MUC6 gastric mucins and sialyl Tn antigen in intraepithelial neoplasms of the pancreas,☆☆

https://doi.org/10.1053/gast.2002.36018Get rights and content

Abstract

Background & Aims: It has recently been suggested that infiltrating adenocarcinoma of the pancreas arises from histologically well-defined precursor ductal lesions called pancreatic intraepithelial neoplasia (PanIN-1A, -1B, -2, and -3). This study examined alterations in the pattern and the level of expression of several mucin genes (MUC1, MUC2, MUC5AC, and MUC6) and mucin-associated tumor antigens (Nd2 and sialyl Tn) in these precursor lesions. Methods: We examined 139 PanINs and 68 infiltrating ductal adenocarcinomas of the pancreas by using immunohistochemistry and in situ hybridization methods. Results: Overexpression of MUC1, a pan-epithelial mucin, and MUC6, a pyloric-gland mucin, and de novo expression of MUC5AC, a gastric foveolar mucin, was observed in all stages of PanINs and invasive ductal adenocarcinoma. In contrast, the expression of mucin-associated carbohydrate antigen, sialyl Tn, was markedly increased only in PanlN-3 and invasive ductal adenocarcinoma. In addition, a decrease in the expression of these mucin-associated peptide and carbohydrate antigens was correlated with the degree of differentiation of the tumor. Conclusions: Expression of both gastric-foveolar and pyloric-gland mucin in PanINs is an early event, whereas sialyl Tn expression is a late event in the recently defined progression model of pancreatic carcinogenesis. This altered mucin gene expression provides new insight into the role of cell lineage–associated metaplasia in pancreatic carcinogenesis.

GASTROENTEROLOGY 2002;123:1052-1060

Section snippets

Specimen selection and identification of pancreatic intraepithelial neoplasias

Representative paraffin-embedded tissue blocks from 20 selected cases of infiltrating adenocarcinoma were obtained from the Department of Pathology at the University of Chicago and from 48 cases from the Department of Anatomic Pathology at the University of California, San Francisco. H&E-stained sections from each case were screened by light microscopy for PanINs and infiltrating carcinomas. PanIN lesions were identified and graded by 2 pathologists. Criteria established at a National Cancer

Normal pancreas

By using immunohistochemical methods, only weak focal expression of all mucin proteins was observed in the intercalating ducts. MUC1 protein was expressed in 18% and 23% of normal intralobular and interlobular ducts, respectively, whereas MUC6 protein was expressed in 12% and 27% of normal intralobular and interlobular ducts, respectively. MUC2 was not expressed in normal ducts. Both MUC5AC protein and Nd2-defined antigen were expressed at very low frequency, 4% and 2%, respectively. MUC1

Discussion

Recent advances in physicochemical, immunochemical, and molecular biologic methods have increased our understanding of the structures of both carbohydrate and peptide moieties of mucin glycoproteins.1, 2, 9 To date, at least 14 mucin genes have been identified and characterized and these mucin glycoproteins are broadly classified into secreted or membrane-associated forms. In normal tissues, mucin genes are expressed in a cell- and tissue-type–specific fashion.1, 2, 4, 5, 6, 7, 41, 43, 44 For

Acknowledgements

The authors thank David Geller for his editorial assistance.

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    Address requests for reprints to: Young S. Kim, M.D., VA Medical Center, GI Research Laboratory (151M2), 4150 Clement Street, San Francisco, California 94121. e-mail: [email protected]; fax: (415) 750-6972.

    ☆☆

    Supported by United States Public Health Service grant CA24321 from the National Cancer Institute, an Oberkotter Foundation grant, and by the Veterans Affairs Medical Research Service.

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