Endogenous activated protein C is essential for immune-mediated cancer cell elimination from the circulation

Fibrinogen and platelets play an important role in cancer cell survival in the circulation by protecting cancer cells from the immune system. Moreover, endogenous activated protein C (APC) limits cancer cell extravasation due to sphingosine-1-phosphate receptor-1 (S1P1) and VE-cadherin-dependent vascular barrier enhancement. We aimed to study the relative contribution of these two mechanisms in secondary tumor formation in vivo. We show that fibrinogen depletion limits pulmonary tumor foci formation in an experimental metastasis model in C57Bl/6 mice but not in NOD-SCID mice lacking a functional immune system. Moreover, we show that in the absence of endogenous APC, fibrinogen depletion does not prevent cancer cell dissemination and secondary tumor formation in immune-competent mice. Overall, we thus show that endogenous APC is essential for immune-mediated cancer cell elimination.