Document Detail

Endogenous activated protein C limits cancer cell extravasation through sphingosine-1-phosphate receptor 1-mediated vascular endothelial barrier enhancement.
MedLine Citation:
PMID:  19571314     Owner:  NLM     Status:  MEDLINE    
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 (S(1)P(1))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 S(1)P(1) 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 S(1)P(1) 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 S(1)P(1)-mediated VE-cadherin-dependent vascular barrier enhancement.
Geerte L Van Sluis; Tatjana M H Niers; Charles T Esmon; Wikky Tigchelaar; Dick J Richel; Harry R Buller; Cornelis J F Van Noorden; C Arnold Spek
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-07-01
Journal Detail:
Title:  Blood     Volume:  114     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-08-28     Completed Date:  2009-09-22     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1968-73     Citation Subset:  AIM; IM    
Department of Vascular Medicine, Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
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MeSH Terms
Antibodies, Monoclonal / metabolism
Anticoagulants / chemistry
Antigens, CD / metabolism
Cadherins / metabolism
Endothelium, Vascular / metabolism,  pathology*
Evans Blue / pharmacology
Melanoma, Experimental
Models, Biological
Neoplasms / metabolism*,  pathology
Oxadiazoles / pharmacology
Protein C / metabolism*
Receptors, Lysosphingolipid / metabolism*
Signal Transduction
Thiophenes / pharmacology
Grant Support
//Howard Hughes Medical Institute
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Anticoagulants; 0/Antigens, CD; 0/Cadherins; 0/Oxadiazoles; 0/Protein C; 0/Receptors, Lysosphingolipid; 0/SEW2871; 0/Thiophenes; 0/cadherin 5; 314-13-6/Evans Blue

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