title: The role of tissue factor pathway inhibitor in tumor growth and metastasis.
abstract: Clotting activation occurs frequently in cancer. Tissue factor (TF), the most potent initiator of coagulation, is expressed aberrantly in many types of malignancy and is involved not only in tumor-associated hypercoagulability but also in promoting tumor angiogenesis and metastasis via coagulation-dependent and coagulation-independent (signaling) mechanisms. Tissue factor pathway inhibitor (TFPI) is the natural inhibitor of TF coagulant and signaling activities. Studies have shown that TFPI exhibits antiangiogenic and antimetastatic effects in vitro and in vivo. In animal models of experimental metastasis, both circulating and tumor cell-associated TFPI are shown to significantly reduce tumor cell-induced coagulation activation and lung metastasis. Heparins and heparin derivatives, which induce the release of TFPI from the vascular endothelium, also exhibit antitumor effects, and TFPI may contribute significantly to those effects. Indeed, a non-anticoagulant low-molecular-weight heparin with intact TFPI-releasing capacity has been shown to have significant antimetastatic effect in a similar experimental mouse model. The evidence supporting the dual inhibitory functions on TF-driven coagulation and signaling strengthen the rationale for considering TFPI as a potential anticancer agent. This article primarily summarizes the evidence for antiangiogenic and antimetastatic effects of TFPI and describes its potential mechanisms of action. The possible application of TFPI and other inhibitors of TF as potential anticancer agents is described, and information regarding potential antitumor properties of TFPI-2 (which has structural similarities to TFPI) is also included.
authors.affiliation: Institute of Translational Research, Florida Hospital, Orlando, Florida 32804, USA. ali.amirkhosravi@flhosp.org
authors.forename: Ali
authors.initials: A
authors.lastname: Amirkhosravi
authors.forename: Todd
authors.initials: T
authors.lastname: Meyer
authors.forename: Mildred
authors.initials: M
authors.lastname: Amaya
authors.forename: Monica
authors.initials: M
authors.lastname: Davila
authors.forename: Shaker A
authors.initials: SA
authors.lastname: Mousa
authors.forename: Theresa
authors.initials: T
authors.lastname: Robson
authors.forename: John L
authors.initials: JL
authors.lastname: Francis
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000378:metabolism / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000378:metabolism / Q000494:pharmacology; D006487:Hemostasis; D006495:Heparin, Low-Molecular-Weight / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism* / Q000494:pharmacology*; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009369:Neoplasms / Q000097:blood* / Q000098:blood supply / Q000473:pathology*; D009389:Neovascularization, Pathologic; D015842:Serine Proteinase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D013925:Thromboplastin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D008074:Lipoproteins; D015842:Serine Proteinase Inhibitors; C051928:lipoprotein-associated coagulation inhibitor; D013925:Thromboplastin