Sharing Tissue Factor

Existence of a close relationship between increased clotting and malignancy has been clearly recognized for over a century. Many tumor cell types express tissue factor (TF), a procoagulant protein, on their cell surfaces. Tissue factor is a transmembrane cellular receptor for coagulation factor VII/VIIa. Binding of factor VIIa to TF triggers the activation of coagulation cascade leading ultimately to the generation of thrombin which in turn stimulates platelet activation and cleaves fibrinogen. Thus, there is no surprise that the activation of coagulation by tumor cell TF or by membrane fragments shed from tumor cells carrying TF contributes to cancer-associated thrombotic disorders.1,2 The close association between cancer and TF has also raised the possibility that TF may contribute to the pathogenesis of cancer beyond thrombosis. In fact, there are a number of reports in the literature showing that TF expressed by tumor cells plays an important role in both primary tumor growth and metastasis (see reviews3–5). The prometastatic effect of TF involves both activation of the coagulation pathway (eg, mechanisms linked to thrombin generated by TF) and effects mediated through the direct signaling activity of TF, probably via the cytoplasmic domain of TF.6 Recent studies have shown that direct TF-FVIIa protease-induced cell signaling is a major contributor to tumor growth in breast cancer.7 However, there are a couple of convincing reports in the literature that provide evidence that is contrary to the general belief that tumor-derived TF is crucial for primary tumor growth or metastasis. Toomey et al,8 using embryonic stem (ES) cells that do not express TF, showed that tumor-derived TF was not required for either tumor growth or metastasis. In a more recent study, Palumbo et al9 showed that tumor TF was neither required for primary tumor growth nor necessary for the initial …