Compact spheroid formation by ovarian cancer cells is associated with contractile behavior and an invasive phenotype.
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 TGFbeta-mediated fibrotic response and/or beta1 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 TGFbeta, and by beta1-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.
Sodek
Katharine L
KL
Department of Cell and Systems Biology, University of Toronto, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada.
Ringuette
Maurice J
MJ
Brown
Theodore J
TJ
D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000235:genetics / Q000378:metabolism; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D005353:Fibronectins; D019012:Integrin beta1; D055293:Receptors, Urokinase Plasminogen Activator; C000717608:TGM2 protein, human; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D003094:Collagen; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; C500142:lysyl hydroxylase 1, human; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins