Fibrin as the mediator of tumor cell interaction with platelets.

Metastasis, a major complication in cancer, is known to depend on the interaction of tumor cells with platelets. However, anti-platelet therapy does not reliably increase survival rates. To address this, here we use light transmission aggregometry, flow cytometry, and confocal microscopy for characterization of human platelets interaction with six lines of tumor cell cultures. A murine model of Lewis carcinoma was used to test the effects of antiplatelet and anticoagulation therapy. Tumor-cell-induced platelet aggregation (TCIPA) correlated with the cell line invasive potential, required calcium and plasma proteins, and was only mildly suppressed by platelet inhibition. However, TCIPA was completely abolished by heparin, rivaroxaban, or dabigatran. For pre-fixed platelets, TCIPA was completely inhibited by the fibrin polymerization inhibitor GPRP. Tumor cells directly induced spatial fibrin polymerization in a factor X-dependent manner. Confocal microscopy confirmed platelet entrapment in the fibrin mesh formed around tumor cells. In the murine model of tumor cell injection, both anticoagulation and antiplatelet treatment reduced lung metastasis. These data suggest that formation of the fibrin mesh associated with a circulating tumor cell, with platelet entrapped in it (not necessarily in the activated state), could be an important early step in the metastasis development. KEY MESSAGES: Platelet-tumor cell heteroaggregates are stabilized by the fibrin network. Thrombin formation is induced by tumor cells, while platelet activation is less essential. Anticoagulant treatment prevents this interaction and may suppress metastasis.