Tissue Factor-Factor VII Complex As a Key Regulator of Ovarian Cancer Phenotypes

Abstract

Tissue factor (TF) is an integral membrane protein widely expressed in normal human cells. Blood coagulation factor VII (fVII) is a key enzyme in the extrinsic coagulation cascade that is predominantly secreted by hepatocytes and released into the bloodstream. The TF-fVII complex is aberrantly expressed on the surface of cancer cells, including ovarian cancer cells. This procoagulant complex can initiate intracellular signaling mechanisms, resulting in malignant phenotypes. Cancer tissues are chronically exposed to hypoxia. TF and fVII can be induced in response to hypoxia in ovarian cancer cells at the gene expression level, leading to the autonomous production of the TF-fVII complex. Here, we discuss the roles of the TF-fVII complex in the induction of malignant phenotypes in ovarian cancer cells. The hypoxic nature of ovarian cancer tissues and the roles of TF expression in endometriosis are discussed. Arguments will be extended to potential strategies to treat ovarian cancers based on our current knowledge of TF-fVII function.

Keywords: coagulation factor VII; endometriosis; hypoxia; ovarian cancer; tissue factor; venous thromboembolism.

Figure 1

TF–fVIIa complex formation on the surface of EOC cells results in the activation of the extrinsic coagulation cascade and/or PARs. The serine protease activity of the TF–fVIIa binary complex associated with the plasma membrane initiates activation of downstream coagulation cascades associated with coagulation factors (IX, X, prothrombin, and fibrinogen). Otherwise, this protein complex cleaves the N-terminal end of PARs. PARs are then activated via intramolecular binding between the newly created N-terminus and an extracellular loop region of the receptors. Activation of G-protein-coupled receptors subsequently activates downstream signaling cascades. Phosphorylation of the C-terminal end of TF could also lead to association with PAR2 in a coagulation-independent manner to augment the signaling cascade.

Figure 2

TF–fVIIa-positive MVs released from CCC cells may cause VTE. CCC cells secrete plasma membrane-derived MVs associated with the TF–fVIIa complex. The expression of both TF and fVII is upregulated in CCC cells in response to hypoxia. Production of TF–fVIIa-rich MVs is expected under conditions of hypoxia. These procoagulant MVs released into the bloodstream may cause VTE.

Figure 3

Differential activation mechanisms of the FVII and VEGF genes. Left: activation of conventional hypoxia response genes, such as VEGF. Sp1 regulates the basal promoter activity of the VFGF gene. Right: hypoxic activation of the FVII gene is mediated by the interaction of Sp1 with HIF2a. HDAC4 could function as a coactivator of this transcription. Under conditions of hypoxia, the ARNT–HIF1a complex becomes bound to the HRE region and enhances the basal activity of the distal gene promoter region.

Figure 4

Hypothetical model of the TF–fVIIa-dependent transformation of endometriosis into CCC. Repeated hypoxia and/or inflammation conditions during menstruation cycles could upregulate the expression of TF and fVII in epithelial cells. TF–fVIIa activity on the cell surface is expected to activate PAR2. fX may participate in TF–fVIIa–fXa ternary complex formation, leading to activation of PAR1 (potential fX involvement is designated as a dotted line). These events could facilitate the transformation of endometriosis into CCC. Activation of PAR1 by thrombin because of recurrent bleeding may contribute to this transformation process.