SEARCH:   Advanced

Blood, 27 August 2009, Vol. 114, No. 9, pp. 1968-1973. Prepublished online as a Blood First Edition Paper on July 1, 2009; DOI 10.1182/blood-2009-04-217679. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2009-04-217679v1 114/9/1968    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Van Sluis, G. L. Articles by Spek, C. A. PubMed PubMed Citation Articles by Van Sluis, G. L. Articles by Spek, C. A. Related Collections Thrombosis and Hemostasis Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  VASCULAR BIOLOGY Endogenous activated protein C limits cancer cell extravasation through sphingosine-1-phosphate receptor 1–mediated vascular endothelial barrier enhancement Geerte L. Van Sluis14, Tatjana M.H. Niers4, Charles T. Esmon5, Wikky Tigchelaar3, Dick J. Richel4, Harry R. Buller1, Cornelis J.F. Van Noorden3, and C. Arnold Spek2 1 Department of Vascular Medicine, 2 Center for Experimental and Molecular Medicine, 3 Department of Cell Biology and Histology, and 4 Department of Clinical Oncology, Academic Medical Center, Amsterdam, The Netherlands; and 5 Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, and Howard Hughes Medical Institute, Oklahoma City Activated protein C (APC) has both anticoagulant activity and direct cell-signaling properties. APC has been reported to promote cancer cell migration/invasion and to inhibit apoptosis and therefore may exacerbate metastasis. Opposing these activities, APC signaling protects the vascular endothelial barrier through sphingosine-1-phosphate receptor-1 (S1P1)activation, which may counteract cancer cell extravasation. Here, we provide evidence that endogenous APC limits cancer cell extravasation, with in vivo use of monoclonal antibodies against APC. The protective effect of endogenous APC depends on its signaling properties. The MAPC1591 antibody that only blocks anticoagulant activity of APC does not affect cancer cell extravasation as opposed to MPC1609 that blocks anticoagulant and signaling properties of APC. Combined administration of anti-APC antibodies and S1P1 agonist (SEW2871) resulted in a similar number of pulmonary foci in mice in presence and absence of APC, indicating that the protective effect of APC depends on the S1P1 pathway. Moreover, endogenous APC prevents cancer cell–induced vascular leakage as assessed by the Evans Blue Dye assay, and SEW2871 treatment reversed MPC1609-dependent vascular leakage. Finally, we show that cancer cells combined with MPC1609 treatment diminished endothelial VE-cadherin expression. In conclusion, endogenous APC limits cancer cell extravasation because of S1P1-mediated VE-cadherin–dependent vascular barrier enhancement. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

	Copyright © 2009 by American Society of Hematology         Online ISSN: 1528-0020