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CANCER

Endothelin-1 Is Required During Epithelial to Mesenchymal Transition in Ovarian Cancer Progression

Laura Rosanò^*, Francesca Spinella^*, Valeriana Di Castro^*, Samantha Decandia^*, Maria Rita Nicotra, Pier Giorgio Natali^* and Anna Bagnato^*,1

^* Laboratory of Molecular Pathology and Ultrastructure, Regina Elena Cancer Institute, 00158 Rome, Italy; and Molecular Biology and Pathology Institute, National Research Council, 00137 Rome, Italy

To whom requests for reprints should be addressed at ¹ Laboratory of Molecular Pathology and Ultrastructure, Regina Elena Cancer Institute, Via delle Messi D’Oro 156, 00158 Rome, Italy. E-mail: bagnato{at}ifo.it

Abstract

In a range of human cancers, tumorigenesis is promoted by activation of the endothelin A receptor (ET_AR)/endothelin-1 (ET-1) axis. ET-1 and ET_AR are overexpressed in primary and metastatic ovarian carcinomas, and high levels of ET-1 are detectable in patient ascites, suggesting that ET-1 may promote tumor dissemination. Moreover, in these tumors, engagement of ET_A receptor by ET-1 triggers tumor growth, survival, angiogenesis, and invasiveness. Thus, ET-1 enhances the secretion of matrix metalloproteinases, disrupts intercellular communications, and stimulates cell migration and invasion. Therefore, we investigated the role of the ET-1/ET_AR autocrine axis in promoting epithelial to mesenchymal transition (EMT) in ovarian tumor cells, a key event in cancer metastasis, in which epithelial cells depolarize, disassemble cell-cell contacts, and adopt an invasive phenotype. Here, we examine the potential role of ET-1 in regulating cell morphology and behavior and epithelial and mesenchymal proteins employing an in vitro 3-D culture system. We found that in 3-D serum-free collagen I gel cultures, HEY and OVCA 433 ovarian carcinoma cells undergo fibroblast-like morphologic changes between 3 and 5 days of ET-1 treatment. In these cells, ET-1 induces loss of adherens and tight-junction protein expression, E-cadherin, ß-catenin, and zonula occludens-1, and gain of N-cadherin and vimentin expression. These results confirm the ability of ET-1 to promote EMT, a metastable process involving sustained loss of epithelial markers and gain of mesenchymal markers. Collectively, these findings provide evidence of a critical role for the ET-1/ET_AR axis during distinct steps of ovarian carcinoma progression, thus underlining this axis as a potential target in the treatment of ovarian cancer.

Key Words: EMT • ovarian cancer • ET-1 • ET_A receptor • invasion

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