Tissue factor as a tumor procoagulant

Abstract

Tissue factor is a cell surface glycoprotein responsible for initiating the extrinsic pathway of coagulation. Many tumor cell homogenates and intact tumor cells have been shown to contain tissue factor activity. Immunohistochemical studies show that many tumors associated with Trousseau's syndrome express tissue factor on their cell surfaces. Tumor cells shed membrane fragments which carry tissue factor that can account for the activation of the clotting system. Tumor cells also produce soluble substances that can induce tissue factor expression on host cells, such as endothelium and monocytes, at sites distant from the tumor. Although, all the functional TF molecules are localized on the outer cell membrane in many tumor cells, the procoagulant activity on the intact cell surface is largely dormant and can be greatly enhanced upon cell injury or damage. Tissue factor procoagulant activity on the cell surface can be modulated by alterations in the plasma membrane without loss of cell viability. Tissue factor activity on cell surfaces is largely regulated by a plasma inhibitor, tissue factor pathway inhibitor. This inhibitor binds to both functional and non-functional tissue factor/VIIa complexes on the cell surface and prevents non-functional tissue factor/VIIa complexes from becoming functional after cell injury or lysis. Heparin, but not warfarin, therapy is effective in preventing the occurrence of devastating thrombotic events in patients with Trousseau's syndrome and the reason(s) for this are still unknown.

Effect of tissue factor deficiency on mouse and tumor development

“…In general, TF expression does not appear to correlate with malignant transformation (20,22). However, several reports suggest a role for TF in tumor angiogenesis and metastasis.…”

“…Most tumor cells express TF (20)(21), and the hypercoagulable state seen in many cancer patients has been attributed in large part to this expression (22). In general, TF expression does not appear to correlate with malignant transformation (20,22).…”

The Thrombophilic State in Cancer Patients

“…Two procoagulant activities have been described and well documented: (1) tissue factor (TF), a 47-kD transmembrane glycoprotein which forms a complex with factor VIIa to activate both factors X and IX and (2) cancer procoagulant (CP), a 68-kD cysteine protease that directly activates factor X independently of factor VIIa [8, 9, 10, 11, 12](table 1). …”

Thrombin Inhibitor, Argatroban, Prevents Tumor Cell Migration and Bone Metastasis

“…Thrombin, a serine protease, is a multifunctional protein involved in a variety of biologic functions and plays a very important role in tumor metastasis. Although the expression of procoagulant activity by malignant cells is a well-established phenomenon [7, 8, 9, 10, 11], therapy in relation to the coagulation system is not well established.…”