Cadherins, catenins and APC in pleural malignant mesothelioma

Abstract

Malignant mesothelioma is an aggressive disease of the pleura, and less commonly the peritoneum, with a very poor prognosis. The present study has examined the expression of cell adhesion molecules including cadherins, catenins, and APC in order to determine whether abnormal expression of components of the Wnt signalling pathway contribute to the variable phenotype of malignant mesothelioma. Sixty-three malignant mesotheliomas and nine cases of reactive mesothelial hyperplasia were analysed by immunohistochemistry for E-cadherin, N-cadherin, alpha-catenin, beta-catenin, and the C- and N-terminals of APC. In addition, DNA was extracted from formalin-fixed, paraffin wax blocks, and a 226 bp fragment of exon 3 of the beta-catenin gene was amplified, sequenced, and screened for activating mutations in the glycogen synthase kinase 3beta (GSK-3beta) phosphorylation targets. E-cadherin expression was detected in 48% of the epithelioid mesotheliomas but was observed in only 7% of sarcomatoid mesotheliomas. N-cadherin, alpha-catenin, beta-catenin, and the C- and N-terminals of APC did not show differential expression between the mesothelioma phenotypes. Abnormal nuclear localization of beta-catenin was demonstrated in 19% of mesotheliomas. Mutations of beta-catenin phosphorylation sites were not detected in any of the 62 mesotheliomas examined. Positive staining for the N-terminal of APC was seen in all of the cases of reactive mesothelial hyperplasia, as well as in all the mesotheliomas. Staining for the C-terminal of APC was negative in 23% mesotheliomas, despite being present in all the cases of reactive hyperplasia. The present study provides the first evidence that beta-catenin accumulates in the nucleus in malignant mesotheliomas. In addition, APC expression was altered in some mesotheliomas, suggesting that a truncated APC gene product may contribute to abnormal Wnt signalling and dysregulation of cell proliferation in malignant mesothelioma.