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Ascites-induced shift along epithelial-mesenchymal spectrum in ovarian cancer cells: enhancement of their invasive behavior partly dependant on αv integrins

Abstract

At least one-third of patients with epithelial ovarian cancer (OC) present ascites at diagnosis and almost all have ascites at recurrence. The presence of ascites, which acts as a dynamic reservoir of active molecules and cellular components, correlates with the OC peritoneal metastasis and is associated with poor prognosis. Since epithelial-mesenchymal transition (EMT) is involved in different phases of OC progression, we have investigated the effect of the unique ascitic tumor microenvironment on the EMT status and the behavior of OC cells. The exposure of three OC cell lines to ascites leads to changes in cellular morphologies. Within ascites, OC cells harboring an initial intermediate epithelial phenotype are characterized by marked dislocation of epithelial markers (E-cadherin, ZO-1 staining) while OC cells initially harboring an intermediate mesenchymal phenotype strengthen their mesenchymal markers (N-cadherin, vimentin). Ascites differentially triggers a dissemination phenotype related to the initial cell features by either allowing the proliferation and the formation of spheroids and the extension of colonies for cells that present an initial epithelial intermediate phenotype, or favoring the migration of cells with a mesenchymal intermediate phenotype. In an ascitic microenvironment, a redeployment of αv integrins into cells was observed and the ascites-induced accentuation of the two different invasive phenotypes (i.e. spheroids formation or migration) was shown to involve αv integrins. Thus, ascites induces a shift toward an unstable intermediate state of the epithelial-mesenchymal spectrum and confers a more aggressive cell behavior that takes on a different pathway based on the initial epithelial-mesenchymal cell features.

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Abbreviations

Asc:

Ascites

CM:

Culture medium

ECM:

Extracellular matrix

EMT:

Epithelial-mesenchymal transition

Fn:

Fibronectin

MET:

Mesenchymal-epithelial transition

MMP:

Matrix metalloproteinases

OC:

Ovarian cancer

TIMP:

Tissue inhibitor of metalloproteinases

Vn:

Vitronectin

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Acknowledgments

This work was supported by the Ligue Contre le Cancer comité du Val d’Oise, France. L. Carduner is a recipient of a fellowship from the Ministère de l’Enseignement Supérieur et de la Recherche, and of the Université de Cergy-Pontoise. The authors thank Dr. C. Blanc-Fournier and M. Briand from F. Baclesse comprehensive center for their support in obtaining ascites samples. We thank Dr. L. Poulain, Dr. C. Denoyelle and Pr. P. Gauduchon (BioTICLA unit from F. Baclesse comprehensive center) for their constant support and advice. We thank Dr. S. Sin (Biology Development lab) for providing some of EMT marker antibodies. The manuscript was revised by Biomedes for English language editing.

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The authors declare that they have no conflict of interest.

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Correspondence to F. Carreiras.

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Carduner, L., Leroy-Dudal, J., Picot, C.R. et al. Ascites-induced shift along epithelial-mesenchymal spectrum in ovarian cancer cells: enhancement of their invasive behavior partly dependant on αv integrins. Clin Exp Metastasis 31, 675–688 (2014). https://doi.org/10.1007/s10585-014-9658-1

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Keywords

  • Ascites
  • Epithelial-mesenchymal transition
  • Ovarian cancer
  • αv integrins
  • Tumor microenvironment