HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Free Full Text (PDF) Free Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rosanò, L. Articles by Bagnato, A. Search for Related Content PubMed PubMed Citation Articles by Rosanò, L. Articles by Bagnato, A.

---

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

This article has been cited by other articles:

				O. Rayhman, E. Klipper, L. Muller, B. Davidson, R. Reich, and R. Meidan Small Interfering RNA Molecules Targeting Endothelin-Converting Enzyme-1 Inhibit Endothelin-1 Synthesis and the Invasive Phenotype of Ovarian Carcinoma Cells Cancer Res., November 15, 2008; 68(22): 9265 - 9273. [Abstract] [Full Text] [PDF]

				S. He, G. Prasanna, and T. Yorio Endothelin-1-Mediated Signaling in the Expression of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Astrocytes Invest. Ophthalmol. Vis. Sci., August 1, 2007; 48(8): 3737 - 3745. [Abstract] [Full Text] [PDF]

				K. K. Kim and H. A. Chapman Endothelin-1 as Initiator of Epithelial-Mesenchymal Transition: Potential New Role for Endothelin-1 during Pulmonary Fibrosis Am. J. Respir. Cell Mol. Biol., July 1, 2007; 37(1): 1 - 2. [Full Text] [PDF]