Role of Tissue Factor in Cancer

Tissue Factor (TF) has classically been identified as a receptor protease in the initiation phase of blood coagulation. However, it is now recognized that TF, a member of the cytokine receptor family, has a far broader range of functions. The functions include regulation of angiogenesis, tumor growth, metastasis and inflammation, and are most often mediated via TF-activated transmembrane signaling. These observations are associated with the upregulation of TF seen in different types of cancers and its elevation with progression of the disease. Interestingly, oncogenic transforming events such as activation of the K-ras oncogene and inactivation of the p53 tumor suppressor are also responsible for increased TF expression. Taken together, these studies point to an important role for TF in cancer-related processes that contribute to malignant disease progression.TF activates FVII and goes on to form a TF-FVIIa complex. The TF-VIIa complex can then activate the coagulation cascade or initiate intracellular signaling, each process involving a distinct cellular pool of TF. The surface-accessible, extracellular Cys186-Cys209 disulfide bond of TF is critical for coagulation; protein disulfide isomerase disables coagulation by targeting this disulfide, thus directing the TF-FVIIa complex to cleave and activate the GPCR protease activated receptor-2 (PAR2). PAR2 activation triggers GPCR intracellular signaling as well as G protein-independent signaling pathways. PAR2 has been shown to activate p38 MAPK and ERK signaling pathways which induce the transcription of genes such as VEGF-A, CTGF and hbEGF which regulate angiogenesis, as well as genes such as CXCL-1 and IL-8 which regulate proliferation and migration. In an alternate pathway which invokes EGFR, transduction of the TF/FVIIa signal works via transactivation of EGFR with the help of kinases such as Yes and PYK2. EGFR activates the translational regulator EIF4E. Thus TF initiates various signal transduction pathways that result in increased angiogenesis and cell growth.TF is known to regulate the process of metastasis through intracellular signal transduction as well an extracellular mechanism which involves fibrin. Intracellularly, TF-FVIIa-PAR2 activates the JAK/STAT, ERK, PI3K and p38 MAPK pathways leading to the expression of apoptosis-related genes such as Caspase 3 and Bcl-XL. PAR2 also recruits the intracellular adaptor β-arrestin, leading to dephosphorylation of cofilin by activating chronophin. Activation of the cofilin pathway results in cytoskeleton reorganization that is crucial for invasion and metastasis. Furthermore, there is constitutive association of TF with integrins α3/6β1 and αVβ3 in cancer cells which is crucial for TF-VIIa-PAR2 signaling. In the extravascular space, TF enhances metastasis by inducing the coating of fibrin on tumor cells so as to trap the cells in the vasculature, thereby aiding metastasis.Tumor cells have been shown to shed procoagulant plasma membranes called microparticles which are often TF-positive. MPs may gain access to the blood stream via leaky vessels within the tumor vasculature. TF on the surface of such MPs activates FVIIa and triggers the coagulation cascade thus leading to increased thrombosis in cancer patients.