Tissue Factor as a Novel Target for Treatment of Breast Cancer

Abstract

CME Learning Objectives Explain the process by which tissue factor (TF) initiates blood coagulation and is implicated in tumor progression. Describe the proposed mechanisms of targeting TF in malignancy. Discuss the applications of TF targets in developing new treatments for aggressive cancers including triple‐negative breast cancer. Tissue factor (TF), a 47‐kDa transmembrane glycoprotein that initiates blood coagulation when complexed with factor VIIa (FVIIa), is expressed in several tumor types. TF has been shown to play a role in cell signaling, inflammation, angiogenesis, as well as tumor growth and metastasis. Activation of the TF signaling pathway has been implicated in mediating the function of many tumor cell types and has led to TF as a potential target in the treatment of several malignancies. Formation of the TF‐FVIIa complex in breast cancer cells has been shown to exert an antiapoptotic effect and play a key role in tumor growth and metastasis. Breast cancer growth is suppressed by inhibition of TF‐mediated PAR2 signaling, and deficiency in PAR2 delays spontaneous breast cancer development in mice. TF is expressed in triple‐negative breast cancer (TNBC), an aggressive type of breast cancer in which there is currently a paucity of available targets. Various methods of targeting TF have been investigated and include immunoconjugates or icons, anti‐TF antibodies, TF pathway inhibitors, targeted photodynamic therapy, and microRNAs. These investigations may give way to promising clinical therapies for breast cancer, especially in TNBC, for which there are relatively few effective treatment options.

Tissue Factor Induced by Epithelial–Mesenchymal Transition Triggers a Procoagulant State That Drives Metastasis of Circulating Tumor Cells

“…Tissue factor (TF), a membrane-associated glycoprotein, has emerged as the central player in the relationship between the hemostatic system and cancer progression (13,14,(22)(23)(24)(25)(26). TF binds and activates coagulation factor FVII, which in turn triggers the downstream coagulation cascade leading to thrombin generation and clot formation.…”

“…Early screening studies have identified TF as a differentially expressed gene in invasive cell lines such as MDA-MB-231 breast cancer cell line. Enhanced TF expression has also been found in a variety of solid tumors including breast cancers, in which it associates with decreased overall survival or shorter recurrence-free survival (26). TF is a downstream target of several oncogenic pathways (RAS, HER2, MET, SHH), of the loss of tumor suppressors such as PTEN or p53, and of transcriptional regulation by NFkB, AP-1, or Egr-1 transcription factors (24,25).…”

“…Experimental data point to a determinant role of TF in facilitating both tumor growth and metastasis, involving both coagulation-dependent and -independent mechanisms. Indeed, in addition to its role in coagulation, TF is directly involved, through its cytoplasmic tail, in signaling events that modulate several cellular processes such as adhesion and migration, apoptosis, and angiogenesis (22,23,26,28).…”

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

“…The comparison of the TF concentration in the plasma of the subjects, expressed per mg of protein, with the TF concentration in tumor tissue homogenates presented that, in the case of meningiomas, the TF concentration was 157-fold higher in tumor tissue homogenate than in the plasma The examination of the TF concentration in the blood of patients with various types of cancer (breast cancer, pancreatic cancer, colon cancer) demonstrates a high TF concentration, which was seen as the presence of thrombotic risk or even overt thrombosis. 10 Also, patients with gliomas demonstrated high TF levels, which significantly correlated with the degree of malignancy. 11 The histochemical and immunological tests of the tissue fragments derived from gliomas indicated a TF expression in tumor cells and in endothelium in new vessels created in the process of angiogenesis.…”

Effects of Tissue Factor, PAR-2 and MMP-9 Expression on Human Breast Cancer Cell Line MCF-7 Invasion

“…TF has become one of the targets of targeted therapy for breast cancer cells (Cole et al, 2013), and is considered an important aspect of breast cancer research (Santos et al, 2013). Studies have shown that TF and MMP -9 expression is significantly correlated with breast cancer cells in humans and dogs (Zhao et al, 2008;Hu et al, 2013).…”