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 showe...

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Bibliographic Details
Published in:Blood 2009-04, Vol.113 (14), p.3371-3374
Main Authors: Bezuhly, Michael, Cullen, Robyn, Esmon, Charles T., Morris, Steven F., West, Kenneth A., Johnston, Brent, Liwski, Robert S.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Blood Coagulation Factors - genetics
Blood Coagulation Factors - physiology
Cell Adhesion - drug effects
Cell Adhesion - genetics
Cell Movement - drug effects
Cell Movement - genetics
Female
Hematologic and hematopoietic diseases
Medical sciences
Melanoma, Experimental - genetics
Melanoma, Experimental - pathology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neoplasm Metastasis - genetics
Neoplasm Metastasis - prevention & control
Protein C - genetics
Protein C - pharmacology
Protein C - physiology
Receptor, TIE-2 - genetics
Receptors, Cell Surface - genetics
Receptors, Cell Surface - physiology
Recombinant Proteins - pharmacology
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Summary: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-α mRNA levels. These findings support an important role for the aPC/EPCR pathway in reducing metastasis via inhibition of tumor cell adhesion and transmigration.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2008-05-159434