Abstract
BackgroundNeoplastic cells promote a hypercoagulable state by the expression of cell surface proteins, such as tissue factor. In BRAFv600 mutated melanoma patients upon BRAF inhibitors, a hypercoagulable state correlates with prognosis, while a down-regulation of the hemostatic parameters is observed in patients responders as compared to non responders. The present study was intended to better clarify the strict relationship between coagulation mediators and target therapy in melanoma.MethodsThe expression of tissue factor was investigated after the treatment with the BRAF inhibitor Dabrafenib and the MEK inhibitor Trametinib in the BRAFv600e mutated melanoma cell lines A-375 and SK-MEL-28, together with its ability to activate the coagulation cascade.ResultsDabrafenib and Trametinib caused the down-regulation of TF in both cell lines A-375 and SK-MEL-28. For the cell line A-375 the effect was evident both at RNA and procoagulant activity; for the cell line SK-MEL-28 only at RNA level without any variation of the protein. Interestingly, when in contact with plasma deficient of factor VII, both cell lines were not able to activate the coagulation cascade.ConclusionsThe present study provides the first in vitro observation that tissue factor expressed in melanoma cells may contribute to the modulation of the coagulation state of patients in the treatment with BRAF inhibitors.
Highlights
Neoplastic cells promote a hypercoagulable state by the expression of cell surface proteins, such as tissue factor
Dabrafenib and Trametinib decrease tissue factor (TF) expression in BRAFv600e melanoma cell lines Dabrafenib and Trametinib caused the decrease of TF mRNA expression in both A-375 and SK-MEL-28 cell lines
In A-375 cell line there is a significant 7.4-fold reduction of TF mRNA in Dabrafenib treated cells (p < 0.0001); 5.6-fold reduction in Trametinib treated cells (p < 0.0001); and 5.1-fold reduction in cells treated with the combination of Dabrafenib + Trametinib (p = 0.0002) (Fig. 1a)
Summary
Neoplastic cells promote a hypercoagulable state by the expression of cell surface proteins, such as tissue factor. Melanoma cells express TF, contributing to metastatic dissemination through local generated proteolytic activity with the formation of a platelet thrombus, which determines the stable implantation of tumor cells in the microvasculature of target organs [5]. These data strongly suggest that both coagulation and melanoma progression are strictly linked. To clarify the relationship between coagulation mediators and the target therapy in melanoma, and in particular the modulation of the coagulation cascade in B RAFv600 mutated melanoma patients upon BRAF inhibitors, we investigated the effects of BRAF and MEK inhibitors, alone or in association, on TF expression in BRAFv600e mutated melanoma cell lines. TF procoagulant activity was evaluated in plasma in order to better understand the role of TF expressed by melanoma cells in the coagulation cascade
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