Epithelial-cadherin and beta-catenin expression changes in pancreatic intraepithelial neoplasia.

Abstract

Cadherins and associated catenins are important mediators of epithelial cell-cell adhesion, as well as the Wnt-signaling pathway. Significant changes in their expression or structure have been implicated in malignancy. This study aimed to investigate the epithelial-cadherin (E-cadherin) and beta-catenin expression changes during multistage, pancreatic ductal carcinogenesis. Ninety-four Whipple resection specimens were retrieved from the surgical pathology files of the University Health Network (Toronto, Canada), from which tissue microarray blocks containing 36 pancreatic ductal adenocarcinomas, 34 PanIN-1A lesions, 28 PanIN-1B lesions, 27 PanIN-2 lesions, 16 PanIN-3 lesions, and 32 normal ducts were constructed. The E-cadherin, beta-catenin, and the phosphorylated glycogen synthase kinase-3beta of the Wnt/beta-catenin pathway were immunohistochemically evaluated in these duct/PanIN lesions. There was marked increase in the cytoplasmic E-cadherin expression in PanIN lesions (P < 0.0001) and adenocarcinoma (P = 0.005) compared with normal pancreatic ducts. In contrast, reduced/loss of E-cadherin membranous expression was also significant in ductal adenocarcinoma compared with both the PanIN lesions (P < 0.0001) and normal ducts (P = 0.05). The beta-catenin expression showed significantly more frequent aberrant nuclear localization in high-grade PanIN lesions, particularly PanIN2 and in adenocarcinoma compared with normal ducts or low grade PanIN lesions (P < 0.0001). However, there was a lack of correlation between phospho(Ser9)-glycogen synthase kinase-3beta cytoplasmic expression and beta-catenin aberrant nuclear expression (P = 0.07). Aberration in the expression of E-cadherin and its associated beta-catenin is evident in pre-invasive (PanIN) neoplastic pancreatic duct cells, suggesting involvement of pathways leading to beta-catenin stabilization during pancreatic duct cell carcinogenesis.