Formation and activation of fibroblast spheroids depend on fibronectin-integrin interaction |
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Authors: | Salmenperä Pertteli Kankuri Esko Bizik Jozef Sirén Vappu Virtanen Ismo Takahashi Seiichiro Leiss Michael Fässler Reinhard Vaheri Antti |
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Institution: | a Haartman Institute, POB 21, FIN-00014 University of Helsinki, Finland b Institute of Biomedicine, Pharmacology, POB 63, FIN-00014 University of Helsinki, Finland c Cancer Research Institute, Laboratory of Tumor Cell Biology, SK-83391 Bratislava, Slovakia d Institute of Biomedicine, Anatomy, POB 63, FIN-00014 University of Helsinki, Finland e Department of Molecular Medicine, Max Planck Institute for Biochemistry, D-82152 Martinsried, Germany |
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Abstract: | Clustering of fibroblasts into spheroids induces a massive proinflammatory, proteolytic and growth-factor response, named nemosis, which promotes tumor cell invasiveness and differentiation of leukemia cells. We have now sought to investigate mechanisms leading to the formation of multicellular spheroids and subsequent activation of fibroblasts (nemosis). Cell lines either lacking fibronectin expression (FN−/−) or expressing FN with a mutated integrin-binding site (FNRGE/RGE) were unable to form compact spheroids. Furthermore, inhibition of FN synthesis by siRNA or functional inhibition of FN or its integrins impaired spheroid formation (α5, β1) and quenched fibroblast activation (αV). The integrin ligand GRGDSP hexapeptide interfered with spheroid formation and induced activation of fibroblasts. Surprisingly, a 70 kDa FN fragment, which prevents deposition of FN matrix but does not interfere with FN-integrin interaction, prevented spheroid formation only marginally and did not block the activation. Our results present a new mechanism of fibroblast activation, which is initiated by interaction of FN with its integrin receptors. |
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Keywords: | Fibronectin Integrin Nemosis Cyclo-oxygenase-2 Fibroblasts |
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