Osteosarcoma cells induce endothelial cell proliferation during neo-angiogenesis

Authors

  • Filomena de Nigris,

    Corresponding author
    1. Department of General Pathology, U.O.C. Immunohematology, and Excellence Research Centre on Cardiovascular Disease, 1st School of Medicine, Second University of Naples, Naples, Italy
    • Department of General Pathology, School of Medicine Second University of Naples, Via De Crecchio 7, 80138 Naples, Italy.
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  • Francesco Paolo Mancini,

    1. Department of Science for Biology, Geology and Environment, University of Sannio, Benevento, Italy
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  • Concetta Schiano,

    1. Department of General Pathology, U.O.C. Immunohematology, and Excellence Research Centre on Cardiovascular Disease, 1st School of Medicine, Second University of Naples, Naples, Italy
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  • Teresa Infante,

    1. Fondazione Studio Diagnostica Nucleare (SDN), IRCCS, Naples, Italy
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  • Alberto Zullo,

    1. Department of Science for Biology, Geology and Environment, University of Sannio, Benevento, Italy
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  • Pellegrino Biagio Minucci,

    1. Department of General Pathology, U.O.C. Immunohematology, and Excellence Research Centre on Cardiovascular Disease, 1st School of Medicine, Second University of Naples, Naples, Italy
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  • Mohammed Al-Omran,

    1. Peripheral Vascular Disease Research Chair, College of Medicine, King Saud University, Riyadh, Saudi Arabia
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  • Antonio Giordano,

    1. Department of Human Pathology and Oncology, University of Siena, Siena, Italy
    2. Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Technology, Temple University, Philadelphia, Pennsylvania
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  • Claudio Napoli

    1. Department of General Pathology, U.O.C. Immunohematology, and Excellence Research Centre on Cardiovascular Disease, 1st School of Medicine, Second University of Naples, Naples, Italy
    2. Fondazione Studio Diagnostica Nucleare (SDN), IRCCS, Naples, Italy
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Abstract

Understanding the mechanisms inducing endothelial cell (EC) proliferation following tumor microenvironment stimuli may be important for the development of antiangiogenic therapies. Here, we show that cyclin-dependent kinase 2 and 5 (Cdk2, Cdk5) are important mediators of neoangiogenesis in in vitro and in vivo systems. Furthermore, we demonstrate that a specific Yin Yang 1 (YY1) protein-dependent signal from osteosarcoma (SaOS) cells determines proliferation of human aortic endothelial cells (HAECs). Following tumor cell stimuli, HAECs overexpress Cdk2 and Cdk5, display increased Cdk2 activity, undergo enhanced proliferation, and form capillary-like structures. Moreover, Roscovitine, an inhibitor of Cdks, blunted overexpression of Cdk2 and Cdk5 and Cdk2 activity induced by the YY1-dependent signal secreted by SaOS cells. Furthermore, Roscovitine decreased HAEC proliferation and angiogenesis (the latter by 70% in in vitro and 50% in in vivo systems; P < 0.01 vs. control). Finally, the finding that Roscovitine triggers apoptosis in SaOS cells as well as in HAECs by activating caspase-3/7 indicates multiple mechanisms for the potential antitumoral effect of Roscovitine. Present work suggests that Cdk2 and Cdk5 might be pharmacologically accessible targets for both antiangiogenic and antitumor therapy. J. Cell. Physiol. 228: 846–852, 2013. © 2012 Wiley Periodicals, Inc.

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