Tissue factor, angiogenesis and tumour progression

Abstract

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. IntroductionAngiogenesis, 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 factorTF -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][2][3][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 regula...

Anti-tissue factor short hairpin RNA inhibits breast cancer growth in vivo

“…VEGF is known to up-regulate the expression of TF in cancer cells and associated endothelial cells, potentially creating a feedback loop whereby TF in turn up-regulates VEGF expression [1]. It has therefore been proposed that inhibition of TF in breast cancer may result in reduced angiogenesis due to down-regulation of VEGF expression.…”

“…These interrelated processes have important implications for cancer therapy as hypercoagulability is exhibited by most cancer patients and contributes to the pathogenesis of tumour growth and metastasis by promoting angiogenesis [1].…”

“…Tissue factor (TF) is a 47kDa transmembrane glycoprotein that safeguards the vascular integrity of tissues by initiating the coagulation cascade following vessel injury [1].…”

Angiogenesis is associated with the onset of hyperplasia in human ductal breast disease

“…Upregulation of TF protein by tumour cells and associated stromal cells has been well documented in breast cancer and other malignant tumours, and may contribute to tumour angiogenesis, metastasis, hypercoagulability and tumour cell survival (reviewed by Bluff et al, 2008). Furthermore, correlations of elevated TF expression with advanced stages of malignancy have been reported in different cancers, including colon (Nakasaki et al, 2002) and breast (Ueno et al, 2000), suggesting that TF may have a role in tumour progression.…”

“…Many cancer patients display a hypercoagulable state leading to complications, such as deep vein thrombosis and pulmonary embolism (reviewed by Bluff et al, 2008). Upregulation of tissue factor (TF), the primary initiator of the coagulation cascade, has a key role in this process (Molnar et al, 2007).…”