Compact spheroid formation by ovarian cancer cells is associated with contractile behavior and an invasive phenotype

Authors

  • Katharine L. Sodek,

    1. Department of Cell and Systems Biology, University of Toronto, and the Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada
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  • Maurice J. Ringuette,

    1. Department of Cell and Systems Biology, University of Toronto, and the Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada
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    • Maurice J. Ringuette and Theodore J. Brown contributed equally.

  • Theodore J. Brown

    Corresponding author
    1. Department of Obstetrics and Gynecology, University of Toronto, and the Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada
    • Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5
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    • Maurice J. Ringuette and Theodore J. Brown contributed equally.

    • Fax: 416-586-8588


Abstract

Ovarian cancer cells are present in malignant ascites both as individual cells and as multicellular spheroid aggregates. Although spheroid formation affords protection of cancer cells against some chemotherapeutic agents, it has not been established whether a relationship exists between invasive behavior and predisposition to spheroid formation. Aspects of spheroid formation, including cell-matrix adhesion, remodeling and contractility are characteristic myofibroblast-like behaviors associated with fibrosis that contribute to tumor growth and dissemination. We explored the possibility that cell behaviors that promote spheroid formation also facilitate invasion. Our analysis of 6 human ovarian cancer cell lines indicated that ovarian cancer cells possessing myofibroblast-like properties formed compact spheroids and invaded 3D matrices. These cells readily contracted collagen I gels, possessed a spindle-like morphology, and had elevated expression of genes associated with the TGFβ-mediated fibrotic response and/or β1 integrin function, including fibronectin (FN), connective tissue growth factor (CTGF/CCN2), lysyl oxidase (LOX1), tissue transglutaminase 2 (TGM2) and urinary plasminogen activator receptor (uPAR). Whereas cell aggregation was induced by TGFβ, and by β1-integrin overexpression and activation, these treatments did not stimulate the contractile activity required for spheroid compaction. The positive relationship found between compact spheroid formation and invasive behavior implies a preferential survival of an invasive subpopulation of ovarian cancer cells, as cells in spheroids are more resistant to several chemotherapeutics. Preventing the formation of ovarian cancer spheroids may represent a novel strategy to improve the efficacy of existing therapeutics. © 2008 Wiley-Liss, Inc.

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