Endogenous activated protein C limits cancer cell extravasation through sphingosine-1-phosphate receptor 1–mediated vascular endothelial barrier enhancement

Receptor of Activated Protein C Promotes Metastasis and Correlates with Clinical Outcome in Lung Adenocarcinoma

“…In apparent contrast to our findings, in a model of melanoma, APC decreased lung metastasis by the ability to prevent tumor transmigration through the endothelial cells, by the EPCR/PAR1/ S1P1 axis (32,33). This difference is explained by the fact that the melanoma cell line did not expressed EPCR, and therefore APC effects were exclusively mediated by the EPCR expressed in endothelial cells.…”

The APCs of neuroprotection

“…One model from the literature (16) suggests that the location of APC bound to EPCR within caveolae (small invaginations of the plasma membrane) of luminal endothelial cells may help to dictate which G protein is linked to PAR1 and hence the nature of the downstream signaling. The ability of APC to elicit cellular responses that are cytoprotective and antiinflammatory through PAR1 activation may explain why APC is effective in preventing disease progression in many of the disease models mentioned above (6)(7)(8)(9)(10)(11)(12). Indeed, variants of APC with low anticoagulant activity have been generated that retain cytoprotective activity and remain protective in many animal models of disease, including sepsis (17).…”

Chromogranin A Regulates Tumor Self-Seeding and Dissemination

“…For example, VEGF-expressing tumor cells can promote, via VEGF, the disruption of VEcadherin-b-catenin complex in the lung endothelium of mice, facilitating their extravasation (7). Furthermore, the enhancement of VE-cadherin-dependent endothelial barrier function with activated protein C has been shown to limit cancer cell extravasation in normal tissues (8). Thus, whereas the presence of vessels with tight endothelial barriers may represent an impediment for the infiltration of normal tissues, the presence of leaky vessels in tumors might facilitate the shedding of cancer cells in circulation and tumor reinfiltration.…”