Abstract
A correlation between cancer and prothrombotic states has long been described. More recently, a number of studies have focused on the procoagulant mechanisms exhibited by tumor cells. In the present study, we dissected the molecular mechanisms responsible for the procoagulant activity of MV3, a highly aggressive human melanoma cell line. It was observed that tumor cells strongly accelerate plasma coagulation as a result of: i) expression of the blood clotting initiator protein, a tissue factor, as shown by flow cytometry and functional assays (factor Xa formation in the presence of cells and factor VIIa), and ii) direct activation of prothrombin to thrombin by cells, as evidenced by hydrolysis of the synthetic substrate, S-2238, and the natural substrate, fibrinogen. This ability was highly potentiated by the addition of exogenous factor Va, which functions as a co-factor for the enzyme factor Xa. In contrast, prothrombin activation was not observed when cells were previously incubated with DEGR-factor Xa, an inactive derivative of the enzyme. Moreover, a monoclonal antibody against bovine factor Xa reduced the prothrombin-converting activity of tumor cells. In conclusion, the data strongly suggest that MV3 cells recruit factor Xa from the culture medium, triggering an uncommon procoagulant mechanism.
Highlights
Blood coagulation involves a series of zymogen activation reactions that are mainly performed by enzymatic complexes consisting of a serine protease, a protein co-factor and membranes containing anionic phospholipids [1]
Previous studies employing other human melanoma cell lines have demonstrated this ability as a result of Tissue factor (TF) expression [18,23]
Several lines of evidence indicate that the procoagulant properties of cancer cells play a significant role in tumor biology, with this observation being evident in melanoma
Summary
Blood coagulation involves a series of zymogen activation reactions that are mainly performed by enzymatic complexes consisting of a serine protease, a protein co-factor and membranes containing anionic phospholipids [1]. A correlation between cancer and procoagulant states has been described for more than a century [4,5] and a number of mechanisms have been proposed to explain such observations, including [6]: i) increased expression of procoagulant proteins by tumor cells; ii) production of inflammatory cytokines by tumor cells and/or the host with subsequent activation of vascular cells, including platelets, endothelial cells and monocytes; iii) direct tumor-cell interactions resulting in activation of vascular cells; iv) exposure of procoagulant lipids, in particular phosphatidylwww.bjournal.com.br serine, by tumor cells [7,8]. Aberrant expression and activation of the coagulation enzyme receptors (proteinase-activated receptors) on tumor cells have been associated with many aspects of tumor biology including migration, survival and production of angiogenic factors, enzymes and cytokines [15,16,17]
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