The relationship between tissue factor and cancer progression: insights from bench and bedside

Abstract

It is now widely recognized that a strong correlation exists between cancer and aberrant hemostasis. Patients with various types of cancers, including pancreatic, colorectal, and gastric cancer, often develop thrombosis, a phenomenon commonly referred to as Trousseau syndrome. Reciprocally, components from the coagulation cascade also influence cancer progression. The primary initiator of coagulation, the transmembrane receptor tissue factor (TF), has gained considerable attention as a determinant of tumor progression. On complex formation with its ligand, coagulation factor VIIa, TF influences protease-activated receptor-dependent tumor cell behavior, and regulates integrin function, which facilitate tumor angiogenesis both in vitro and in mouse models. Furthermore, evidence exists that an alternatively spliced isoform of TF also affects tumor growth and tumor angiogenesis. In patient material, TF expression and TF cytoplasmic domain phosphorylation correlate with disease outcome in many, but not in all, cancer subtypes, suggesting that TFdependent signal transduction events are a potential target for therapeutic intervention in selected types of cancer. In this review, we summarize our current understanding of the role of TF in tumor growth and metastasis, and speculate on anticancer therapy by targeting TF. (Blood. 2012; 119(4):924-932) IntroductionAfter Trousseau's description of thrombophlebitis as a complication of pancreatic cancer in the 19th century, the notion that increased expression of tissue factor (TF) underlies the relation between coagulation and cancer has become generally accepted. Full-length TF (flTF) is a 47-kDa membrane-bound glycoprotein that is present on subendothelial cells. 1 In the classic concept of coagulation, it is thought that endothelial disruption leads to exposure of flTF to the bloodstream. Exposed flTF can bind to its natural ligand factor VII (FVII), which then becomes activated FVII (FVIIa). The thus formed flTF/FVIIa complex converts factor X (FX) to factor Xa (FXa), and FXa in turn activates prothrombin leading to formation of thrombin (factor IIa). Thrombin subsequently activates platelets and converts fibrinogen into fibrin, 2 essential components of a stable hemostatic plug. 1 The primary function of subendothelial flTF is to serve as a hemostatic envelope surrounding the vasculature. However, under certain conditions, the expression of flTF is induced in monocytes and endothelial cells. flTF is also often expressed on cancer cells and the tumor vasculature, 2 and flTF-bearing microparticles can become shed by these cells. 3 These flTF-bearing microparticles are important contributors to the thrombotic phenotype in cancer patients. 3 The flTF/FVIIa complex also influences pathways that do not lead to blood coagulation, but rather activate cell-bound proteaseactivated receptors (PARs) that are of importance during the inflammatory and angiogenic response to injury. 4 Furthermore, a soluble variant of flTF, known as alternatively spliced TF (asTF), stimulates angiogen...

Quantitative PET Imaging of Tissue Factor Expression Using 18F-Labeled Active Site–Inhibited Factor VII

“…Many tumors express various levels of cell surface TF, and the TF:FVIIa complex has been shown to activate protease-activated receptor 2 and through intracellular signaling to induce an antiapoptotic effect as well as to enhance tumor growth, migration, and angiogenesis. In addition, TF:FVIIa more indirectly facilitates metastatic dissemination through thrombin generation and PAR1 signaling (1)(2)(3)(4).…”

A preliminary estimation of tissue factor pathway inhibitor (TFPI) and protein C in patients with intracranial tumors

“…TF also assists the tumor cells in the metastasis of these cells, and the escape from the control of the host immune system via tumor microenvironment modulation. 17 The test used in our study to measure the TF concentration in the plasma allows for identifying both TF forms, fltF and asTF. The TF source in patients with intracranial tumors is not only the endothelial cells damaged by tumor cells but also the tumor cells themselves, as seen from an extremely high TF conin those patients.…”

Gene therapy-based prophylaxis to rescue the “prima ballerina”

“…Defined oncogenic transformations drive TF expression in cancer via hypoxia-induced signaling, EGFR-and PTEN-dependent pathways as well as Src-signaling pathways (6). Moreover, various cancer cells ectopically synthesize FVII, which could result in activation of cell motility and invasion.…”