E-cadherin induces mesenchymal-to-epithelial transition in human ovarian surface epithelium

Abstract

Ovarian carcinomas are thought to arise in the ovarian surface epithelium (OSE). Although this tissue forms a simple epithelial covering on the ovarian surface, OSE cells exhibit some mesenchymal characteristics and contain little or no E-cadherin. However, E-cadherin is present in metaplastic OSE cells that resemble the more complex epithelia of the oviduct, endometrium and endocervix, and in primary epithelial ovarian carcinomas. To determine whether E-cadherin was a cause or consequence of OSE metaplasia, we expressed this cell-adhesion molecule in simian virus 40-immortalized OSE cells. In these cells the exogenous E-cadherin, all three catenins, and F-actin localized at sites of cell-cell contact, indicating the formation of functional adherens junctions. Unlike the parent OSE cell line, which had undergone a typical mesenchymal transformation in culture, E-cadherin-expressing cells contained cytokeratins and the tight-junction protein occludin. They also formed cobblestone monolayers in two-dimensional culture and simple epithelia in three-dimensional culture that produced CA125 and shed it into the culture medium. CA125 is a normal epithelial-differentiation product of the oviduct, endometrium, and endocervix, but not of normal OSE. It is also a tumor antigen that is produced by ovarian neoplasms and by metaplastic OSE. Thus, E-cadherin restored some normal characteristics of OSE, such as keratin, and it also induced epithelial-differentiation markers associated with weakly preneoplastic, metaplastic OSE and OSE-derived primary carcinomas. The results suggest an unexpected role for Ecadherin in ovarian neoplastic progression.

Putting tumours in context

“…Loss of Ecadherin can be accompanied by increased expression of alternate cadherin isoforms that promote inappropriate survival signals and enhance the malignant phenotype 14 . However, as all cellular responses are tissue-and context-dependent, there can be no universal generalizations, as shown by the fact that E-cadherin gain of function is an early step in ovarian carcinoma 15 .…”

Ascites induces modulation of α6β1 integrin and urokinase plasminogen activator receptor expression and associated functions in ovarian carcinoma

“…HOSE cells immortalised by transfection with SV-40 antigen (Auersperg et al, 1999) were obtained from Professor Nelly Auersperg, University of British Columbia, Vancouver, Canada. HOSE cells were maintained in Medium 199/MCDB (1 : 1), while ovarian cancer cell lines were maintained in RPMI 1640.…”

Transforming Growth Factor-β1, Transforming Growth Factor-β2, and Transforming Growth Factor-β3 Enhance Ovarian Cancer Metastatic Potential by Inducing a Smad3-Dependent Epithelial-to-Mesenchymal Transition

“…In fact, normal OSE have a more uncommitted phenotype than malignant epithelia, and ovarian cancer cells acquire expression of the epithelial marker E-cadherin after neoplastic transformation. Expression of E-cadherin in SV40-immortalized OSE cells induced a mesenchymal-to-epithelial transition, which resulted in the formation of simple epithelia (in three-dimensional culture) that secreted CA125, a protein produced by metaplastic and neoplastic OSE (23). Normal OSE seldom express E-cadherin (24-26), but do express N-cadherin (27,28), which may play a role in the mesenchymal conversion of OSE that occurs when cultured in vitro.…”