THROMBOSIS AND HEMOSTASIS Brief report Role of activated protein C and its receptor in inhibition of tumor metastasis

Engagement of endothelial protein C re-ceptor (EPCR) by activated protein C (aPC) decreases expression of endothe-lial adhesion molecules implicated in tumor-endothelium interactions. We ex-amined the role of the aPC/EPCR pathway on tumor migration and metastasis. In vitro, B16-F10 melanoma cells showed decreased adhesion to and transmigra-tion through endothelium treated with recombinant human aPC (rhaPC). In mu-rine B16-F10 metastasis models, trans-genic EPCR overexpressing (Tie2-EPCR) mice exhibited marked reductions in liver (50%) and lung (92%) metastases com-pared with wild-type (WT) animals. Intravi-tal imaging showed reduced B16-F10 en-trapment within livers of Tie2-EPCR compared with WT mice. A similar reduc-tion was observed in WT mice treated with rhaPC. Strikingly, rhaPC treatment resulted in a 44 % reduction in lung metas-tases. This was associated with decreased lung P-selectin and TNF- mRNA levels. These findings support an important role for the aPC/EPCR pathway in reducing metastasis via inhibition of tumor cell adhesion and transmigration. (Blood. 2009;113:3371-3374