Cancer Research Articles

Tissue factor, the primary initiator of the coagulation cascade, maintains vascular integrity in response to injury. It is now recognised that, in addition to the role as a procoagulant activator, tissue factor participates in many tumour-related processes that contribute to malignant disease progression. The present review details the recent evidence supporting a role for tissue factor in tumour haemostasis, angiogenesis, metastasis and malignant cell survival. Furthermore, future research directions are discussed that may enhance our understanding of the role and regulation of this protein, which could ultimately lead to the innovative design and development of new anticancer therapies.

Introduction

Angiogenesis, the development of new blood vessels from the existing vasculature, and haemostasis, the coagulation cascade leading to clot formation, are among the most consistent host responses associated with cancer. Tissue factor (TF) normally safeguards the vascular integrity of tissues by initiating the coagulation cascade following vessel injury. Hypercoagulability is exhibited by most cancer patients and contributes to the pathogenesis of tumour growth and metastasis by promoting angiogenesis. Haemostasis and angiogenesis are therefore interrelated processes with important implications for cancer therapy.

TF, similar to a number of haemostatic proteins, participates in many tumour-related processes, including tumour angiogenesis, metastasis, hypercoagulability and tumour cell survival; processes that all contribute to malignant disease progression. The molecular mechanisms responsible for the actions of TF are only just beginning to be elucidated, but it is thought that they occur by the action of intracellular signalling, resulting in gene transcription and subsequent protein synthesis.

Tissue factor

TF – also known as coagulation factor III, thromboplastin, or CD142 – is a 47 kDa transmembrane glycoprotein first cloned independently by four different groups in 1987 [1-4]. The human TF gene spans 12.4 kbp, has six exons and is located on chromosome 1, p21–p22. The TF protein consists of a 219-amino-acid extracellular domain, a 23-amino-acid transmembrane segment and a 21-amino-acid cytoplasmic tail that does not bear significant homology with other proteins [5]. In silico studies have resulted in TF being classified as a member of the class II cytokine/haematopoietic growth factor family [6]. The extracellular domain of TF contains factor VII/activated factor VII (FVIIa) binding sites, but the transmembrane domain plays a crucial role in anchoring the TF–FVIIa complex to the cell surface in addition to complete expression of the procoagulant activity [7].

TF gene expression is complex and is regulated by a number of transcription factors that may be sensitive to hypoxia or anoxia, including activator protein (AP-1), nuclear factor-κB (NF-κB), Sp-1 and early growth response gene-1 (Egr-1) [8,9]. In addition, heparanase and platelet endothelial cell adhesion molecule 1 both participate in the regulation of TF gene expression (via activation of the p38 signalling pathway) [10,11].

Although TF expression can be transiently upregulated in monocytes or macrophages and endothelial cells (ECs) by growth factors and cytokines, vascular ECs and intravascular cells do not express TF in normal physiological situations. Constitutive TF expression is restricted to subendothelial cells (such as pericytes, smooth muscle cells and fibroblasts) that only interact with blood when vascular integrity is compromised [12]. However, it is clear that during tumourigenesis, this strict regulation of TF expression is lost. Upregulation of TF protein by tumour cells and associated stromal cells has been well documented in breast cancer and other malignant tumours [13-17]. TF is now known to exist in several locations: in association with cells (intracellular or surface location) and within the circulation, either associated with microparticles [18] or in a free, soluble form [19,20]. TF-expressing microparticles are membrane vesicles derived from haematopoietic cells (for example, monocytes and platelets) that play a putative role in haemostasis activation in cancer patients [21,22].

Cryptic TF refers to the part of the cellular TF pool that is noncoagulant but retains functional cell signalling. Cryptic TF contains unpaired cysteine thiols and activation involves the formation of the disulphide bond Cys186–Cys209 [23]. Extracellular protein disulphide isomerase has been proposed to target this disulphide bond, inactivating the procoagulant activity of TF [24] while enhancing TF coagulant activity on microparticles shed from cells [25]. Protein disulphide isomerase has therefore been suggested to facilitate a dynamic and reversible switch (conformational change) between two distinct functional TF species: one that initiates coagulation, and an encrypted form that does not – this theory, however, is currently controversial [26].

In normal physiological conditions, initiation of the extrinsic coagulation pathway occurs when TF is exposed to the bloodstream, either following damage to the vascular system integrity or upon activation of monocytes or ECs. FVIIa then binds to TF on the cell surface. Sequential downstream activation of haemostatic protease complexes leads to the generation of thrombin, with subsequent platelet activation and the formation of a fibrin clot that restores vessel integrity (Figure 1) (reviewed in [27]). There is now increasing evidence that, in addition to initiating haemostasis, binding of FVIIa to TF directly cleaves protease-activated receptor (PAR)-2 and results in phosphorylation of the TF cytoplasmic domain. This subsequently inhibits the negative regulatory control of PAR-2-mediated signalling, thereby promoting angiogenesis (Figure 2) [28-30].