Contribution of platelets to tumor aggressivity.

Abstract

e21156 Background: The interaction between cancer and coagulation process has been shown since many years. The aim of our study is to understand the mechanisms implicated and to propose new therapeutic approaches. Methods: Two breast cancer cell lines were used: a very aggressive (MDA-MB231) and a much less aggressive (MCF-7). Platelet aggregation tests were done with washed platelets, normal or fibrin removed plasma and cancer cells (20 to 2.105 cells/ml). Procoagulant activity of cancer cells was studied. Aspirin, Apyrase (ADPase), a direct thrombin inhibitor (Hirudin), two Xa inhibitors (Fondaparinux, Rivaroxaban) were the inhibitors tested. Interaction between platelets and cancer cells was visualized by confocal microscopy. Angiogenic effect of supernatants from platelets-cancer cells co-incubation was investigated. Results: The data obtained show that a platelet aggregation is induced by cancer cells in the presence of a small amount of plasma. This aggregation depends on both the type and number of cancer cells. Aggressive MDA-MB231 cells have a more potent pro-aggregating activity than MCF-7. This aggregation appears to be due to thrombin generation since it is inhibited by Hirudin. Rivaroxaban, a direct inhibitor of factor Xa, inhibits platelets aggregation but not Fondaparinux, an indirect anti Xa inhibitor which binds to Antithrombin III. Aspirin and Apyrase have no effect. Moreover, the procoagulant activity of cancer cells with plasma is inhibited by Hirudin and Rivaroxaban but not by Fondaparinux. This suggests that the Fondaparinux-Antithrombin III complex cannot access to cell membrane-bound factor Xa. It may be due to its steric hindrance since thromboplastin induced coagulation is inhibited by Rivaroxaban but not by Fondaparinux. The confocal microscopic study shows that platelets protect tumor cells from immune attack via the formation from a protective envelope around cancer cells. Angiogenesis assays show that activation of platelets by cancer cells releases angiogenesis stimulating factors and cytokines. Conclusions: The present work confirms the crucial role of platelets in cancer aggressiveness and reveals that Rivaroxaban or Thrombin inhibitors could be efficient drugs to reduce cancer progression, metastasis and thrombosis.