Activation of blood coagulation in cancer: implications for tumour progression

Abstract

Several studies have suggested a role for blood coagulation proteins in tumour progression. Herein, we discuss (1) the activation of the blood clotting cascade in the tumour microenvironment and its impact on primary tumour growth; (2) the intravascular activation of blood coagulation and its impact on tumour metastasis and cancer-associated thrombosis; and (3) antitumour therapies that target blood-coagulation-associated proteins. Expression levels of the clotting initiator protein TF (tissue factor) have been correlated with tumour cell aggressiveness. Simultaneous TF expression and PS (phosphatidylserine) exposure by tumour cells promote the extravascular activation of blood coagulation. The generation of blood coagulation enzymes in the tumour microenvironment may trigger the activation of PARs (protease-activated receptors). In particular, PAR1 and PAR2 have been associated with many aspects of tumour biology. The procoagulant activity of circulating tumour cells favours metastasis, whereas the release of TF-bearing MVs (microvesicles) into the circulation has been correlated with cancer-associated thrombosis. Given the role of coagulation proteins in tumour progression, it has been proposed that they could be targets for the development of new antitumour therapies.

Figure 1. Extravascular activation of blood coagulation in cancer

(A) Neoplastic cells stimulate vascular permeability in the tumour microenvironment through the generation of proangiogenic factors such as VEGF. In this way, blood coagulation proteins can leave the plasma circulation and reach the extravascular tumour microenvironment, getting in contact with the plasma membrane of tumour cells, which is rich in procoagulant molecules such as (B) TF and (C) PS. The assembly of different blood coagulation complexes thus culminates in the local generation of thrombin and fibrin.

Figure 2. Intravascular activation of blood coagulation in cancer

Tumour cells may secrete TF-bearing MVs that also expose PS on their surface. Procoagulant MVs released by tumour cells can reach the plasma circulation and activate blood coagulation reactions thus contributing to thrombus formation in the intravascular environment.