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Altered expression of adhesion molecules and epithelial-mesenchymal transition in silica-induced rat lung carcinogenesis.
Lab Invest. 2004 Aug; 84(8):999-1012.LI

Abstract

Loss of the epithelial phenotype and disruption of adhesion molecules is a hallmark in the epithelial-mesenchymal transition (EMT) reported in several types of cancer. Most of the studies about the relevance of adhesion and junction molecules in lung cancer have been performed using established tumors or in vitro models. The sequential molecular events leading to EMT during lung cancer progression are still not well understood. We have used a rat model for multistep lung carcinogenesis to study the status of adherens and tight junction proteins and mesenchymal markers during EMT. After silica-induced chronic inflammation, rats sequentially develop epithelial hyperplasia, preneoplastic lesions, and tumors such as adenocarcinomas and squamous cell carcinomas. In comparison with normal and hyperplastic bronchiolar epithelium and with hyperplastic alveolar type II cells, the expression levels of E-cadherin, alpha-catenin and beta-catenin were significantly reduced in adenomatoid preneoplastic lesions and in late tumors. The loss of E-cadherin in tumors was associated with its promoter hypermethylation. alpha- and beta-catenin dysregulation lead to cytoplasmic accumulation in some carcinomas. No nuclear beta-catenin localization was found at any stage of any preneoplastic or neoplastic lesion. Zonula occludens protein-1 was markedly decreased in 66% of adenocarcinomas and in 100% squamous cell carcinomas. The mesenchymal-associated proteins N-cadherin and vimentin were analyzed as markers for EMT. N-cadherin was de novo expressed in 32% of adenocarcinomas and 33% of squamous cell carcinomas. Vimentin-positive tumor cells were found in 35% of adenocarcinomas and 88% of squamous cell carcinomas. Mesenchymal markers were absent in precursor lesions, both hyperplastic and adenomatoid. The present results show that silica-induced rat lung carcinogenesis is a good model to study EMT in vivo, and also provide in vivo evidence suggesting that the changes in cell-cell adhesion molecules are an early event in lung carcinogenesis, while EMT occurs at a later stage.

Authors+Show Affiliations

Department of Histology and Pathology and Division of Oncology (Center for Applied Biomedical Research, CIMA), University of Navarra, Pamplona, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15195114

Citation

Blanco, David, et al. "Altered Expression of Adhesion Molecules and Epithelial-mesenchymal Transition in Silica-induced Rat Lung Carcinogenesis." Laboratory Investigation; a Journal of Technical Methods and Pathology, vol. 84, no. 8, 2004, pp. 999-1012.
Blanco D, Vicent S, Elizegi E, et al. Altered expression of adhesion molecules and epithelial-mesenchymal transition in silica-induced rat lung carcinogenesis. Lab Invest. 2004;84(8):999-1012.
Blanco, D., Vicent, S., Elizegi, E., Pino, I., Fraga, M. F., Esteller, M., Saffiotti, U., Lecanda, F., & Montuenga, L. M. (2004). Altered expression of adhesion molecules and epithelial-mesenchymal transition in silica-induced rat lung carcinogenesis. Laboratory Investigation; a Journal of Technical Methods and Pathology, 84(8), 999-1012.
Blanco D, et al. Altered Expression of Adhesion Molecules and Epithelial-mesenchymal Transition in Silica-induced Rat Lung Carcinogenesis. Lab Invest. 2004;84(8):999-1012. PubMed PMID: 15195114.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Altered expression of adhesion molecules and epithelial-mesenchymal transition in silica-induced rat lung carcinogenesis. AU - Blanco,David, AU - Vicent,Silvestre, AU - Elizegi,Eider, AU - Pino,Irene, AU - Fraga,Mario F, AU - Esteller,Manel, AU - Saffiotti,Umberto, AU - Lecanda,Fernando, AU - Montuenga,Luis M, PY - 2004/6/15/pubmed PY - 2004/9/3/medline PY - 2004/6/15/entrez SP - 999 EP - 1012 JF - Laboratory investigation; a journal of technical methods and pathology JO - Lab Invest VL - 84 IS - 8 N2 - Loss of the epithelial phenotype and disruption of adhesion molecules is a hallmark in the epithelial-mesenchymal transition (EMT) reported in several types of cancer. Most of the studies about the relevance of adhesion and junction molecules in lung cancer have been performed using established tumors or in vitro models. The sequential molecular events leading to EMT during lung cancer progression are still not well understood. We have used a rat model for multistep lung carcinogenesis to study the status of adherens and tight junction proteins and mesenchymal markers during EMT. After silica-induced chronic inflammation, rats sequentially develop epithelial hyperplasia, preneoplastic lesions, and tumors such as adenocarcinomas and squamous cell carcinomas. In comparison with normal and hyperplastic bronchiolar epithelium and with hyperplastic alveolar type II cells, the expression levels of E-cadherin, alpha-catenin and beta-catenin were significantly reduced in adenomatoid preneoplastic lesions and in late tumors. The loss of E-cadherin in tumors was associated with its promoter hypermethylation. alpha- and beta-catenin dysregulation lead to cytoplasmic accumulation in some carcinomas. No nuclear beta-catenin localization was found at any stage of any preneoplastic or neoplastic lesion. Zonula occludens protein-1 was markedly decreased in 66% of adenocarcinomas and in 100% squamous cell carcinomas. The mesenchymal-associated proteins N-cadherin and vimentin were analyzed as markers for EMT. N-cadherin was de novo expressed in 32% of adenocarcinomas and 33% of squamous cell carcinomas. Vimentin-positive tumor cells were found in 35% of adenocarcinomas and 88% of squamous cell carcinomas. Mesenchymal markers were absent in precursor lesions, both hyperplastic and adenomatoid. The present results show that silica-induced rat lung carcinogenesis is a good model to study EMT in vivo, and also provide in vivo evidence suggesting that the changes in cell-cell adhesion molecules are an early event in lung carcinogenesis, while EMT occurs at a later stage. SN - 0023-6837 UR - https://www.unboundmedicine.com/medline/citation/15195114/Altered_expression_of_adhesion_molecules_and_epithelial_mesenchymal_transition_in_silica_induced_rat_lung_carcinogenesis_ L2 - https://doi.org/10.1038/labinvest.3700129 DB - PRIME DP - Unbound Medicine ER -