Role of activated protein C and its receptor in inhibition of tumor metastasis.
Engagement of endothelial protein C receptor (EPCR) by activated protein C (aPC) decreases expression of endothelial adhesion molecules implicated in tumor-endothelium interactions. We examined the role of the aPC/EPCR pathway on tumor migration and metastasis. In vitro, B16-F10 melanoma cells showed decreased adhesion to and transmigration through endothelium treated with recombinant human aPC (rhaPC). In murine B16-F10 metastasis models, transgenic EPCR overexpressing (Tie2-EPCR) mice exhibited marked reductions in liver (50%) and lung (92%) metastases compared with wild-type (WT) animals. Intravital imaging showed reduced B16-F10 entrapment within livers of Tie2-EPCR compared with WT mice. A similar reduction was observed in WT mice treated with rhaPC. Strikingly, rhaPC treatment resulted in a 44% reduction in lung metastases. This was associated with decreased lung P-selectin and TNF-alpha mRNA levels. These findings support an important role for the aPC/EPCR pathway in reducing metastasis via inhibition of tumor cell adhesion and transmigration.
Bezuhly
Michael
M
Department of Anatomy and Neurobiology, Dalhousie University, Halifax, NS, Canada.
Cullen
Robyn
R
Esmon
Charles T
CT
Morris
Steven F
SF
West
Kenneth A
KA
Johnston
Brent
B
Liwski
Robert S
RS
D000818:Animals; D001779:Blood Coagulation Factors / Q000235:genetics / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D005260:Female; D008546:Melanoma, Experimental / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000517:prevention & control; D011486:Protein C / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D042787:Receptor, TIE-2 / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology
D001779:Blood Coagulation Factors; D011486:Protein C; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C091963:activated protein C receptor; D042787:Receptor, TIE-2