Tissue Factor and PAR2 Signaling in the Tumor Microenvironment

Abstract

Abstract-Diverse oncogenic transformations result in the constitutive expression of tissue factor (TF) in cancer cells. The local and systemic activation of the coagulation cascade has long been a recognized hallmark for aggressive cancer, but genetic mouse models and new experimental therapeutics have only recently demonstrated crucial roles for TF initiated cell signaling in the pathogenesis of cancer. On tumor cells, the TF-VIIa binary complex mediates activation of protease activated receptor (PAR) 2 and thereby shapes the tumor microenvironment by inducing an array of proangiogenic and immune modulating cytokines, chemokines, and growth factors. PAR2 also uniquely triggers tumor cell migration by G protein-independent pathways through ␤-arrestin scaffolding. Metastatic tumor cells use additional signaling networks of the coagulation cascade by activating PAR1 through thrombin or the ternary TF-VIIa-Xa signaling complex in the vascular and potentially lymphatic system. Selective antagonists of TF-VIIa-PAR2 signaling may be used as antiangiogenic therapy without increasing the risk of bleeding, whereas coagulation and associated signaling pathways on platelets and other host cells may be targeted for therapeutic benefit in advanced cancer and metastatic disease. Key Words: thrombosis Ⅲ cancer Ⅲ G protein-coupled receptor Ⅲ coagulation signaling A prothrombotic state is one of the hallmarks of advanced cancer, and thromboembolic disease contributes significantly to the mortality of cancer patients (reviewed in 1 ). Tissue factor (TF), the cellular activator of the coagulation cascade, is central to the hypercoagulable state of cancer patients and responsible for local thrombin generation and fibrin deposition in the tumor stroma. TF also triggers remote thrombotic complications involving procoagulant TF ϩ microparticles 2 with potential contribution from other cancer procoagulants (reviewed in 3 ). TFdependent coagulation generates thrombin and induces pleiotrophic cellular effects of thrombin on platelets through G protein-coupled protease-activated receptors (PARs) 4 as well as thrombin-initiated vascular-protective signaling of the endogenous activated protein C-EPCR-PAR1 pathway. 5 Direct signaling by TF-associated proteases are mediated by the binary TF-VIIa enzyme complex that activates PAR2 or the ternary TF-VIIa-Xa coagulation initiation complex in which Xa efficiently cleaves PAR2 as well as PAR1. 6 These signaling complexes involve distinct cellular pools of TF. 7 Oncogenic mutations of K-ras, upregulation of oncogenic epidermal growth factor receptors (EGFR), or loss of tumor suppressors p53 and PTEN result in constitutive upregulation of TF, and hypoxia can amplify tumor cell TF expression in certain cancers (reviewed in 8 ). Furthermore, hypoxia induces the synthesis of coagulation factor VIIa in various cancer types and ectopically synthesized VII by TF-expressing cells can trigger X activation and tumor cell migration and invasion. 9 Potentially, the ectopic synthesis of VIIa may turn on direct ...

The wound healing, chronic fibrosis, and cancer progression triad

“…However, PAR-2 can be activated by other molecules from the coagulation cascade such as the tissue factor (TF) and activated factor X (FX A ) (47). TF is expressed by many types of cancer cells (169), and TF or FX A -induced PAR-2 signaling has been implicated in both chronic fibrosis and tumor progression (33,34,151,169,318,347). Interestingly, TF, FX A , thrombin, and activation of PAR-1 or PAR-2 may possibly promote myofibroblastic differentiation (Supplemental Table S1).…”

Cooperation of tissue factor cytoplasmic domain and PAR2 signaling in breast cancer development

“…1,2 Cancer cell-expressed tissue factor (TF) is a major procoagulant stimulus in cancer-associated thrombosis, and tumor cell TF expression is correlated with tumor progression in several experimental tumor models (reviewed in Schaffner and Ruf 3 ). Although thrombin generated in the course of coagulation supports hematogenous metastasis 4 and regulates angiogenesis and the tumor microenvironment, 5 several lines of pharmacological and genetic evidence show that direct signaling of TF plays a pivotal role in cancer progression and angiogenesis.…”

“…3 Host cell-derived TF makes independent contributions to tumor development of transplanted teratomas, 22 and in models of hypoxia-induced angiogenesis, TF cytoplasmic domain-deleted mice (TF ⌬CT mice) display accelerated angiogenesis, a phenotype that is reversed by simultaneous deficiency in PAR2. 23 Although the TF cytoplasmic domain has been implicated in the growth of certain tumors 24 and hematogenous tumor dissemination, 25,26 it is unknown whether signaling of the TF cytoplasmic domain is restricted to the host compartment in breast cancer progression.…”

Tissue Factor-Dependent Chemokine Production Aggravates Experimental Colitis

“…Interestingly, a major difference between wild-type animals and TFlow mice in response to DSS-induced colitis is the influx of granulocytes into the inflamed colon. This is particularly interesting because TF is known to influence cell migration (mainly in the setting of tumor cells) (35,36). Consequently, we determined whether TFlow granulocytes (obtained from TFlow mice) are affected in their migratory response compared with wild-type granulocytes.…”

“…This is particularly interesting, since granulocytes are of pivotal relevance in the clinical setting of inflammatory bowel disease, as evident from, for instance, the promising effect of Natalizumab and MLN02 for the treatment of Crohn's disease and ulcerative colitis (38,39). Moreover, it is well know that TF induces migration of a large variety of cells (35,36). Although the presence of TF on granulocytes is under debate (40), we determined whether granulocytes derived from TFlow mice did have a hampered migratory capacity compared with granulocytes from wild-type mice.…”