Tissue Factor and Cancer

Abstract

Tissue factor (TF), the key regulator of haemostasis and angiogenesis, is also involved in the pathology of several diseases, including cardiovascular, inflammatory and neoplastic conditions. In the latter, TF is upregulated by cancer cells, as well as by certain host cells, and it is the interactions between these distinct pools of TF-expressing cells that likely influence tumour progression in several ways. Furthermore, the release of TF microparticles into the circulation is thought to contribute to the systemic coagulopathies commonly observed in cancer patients. The direct regulation of TF by oncogenic events has provided a plausible explanation for the relatively common overexpression of TF in various cancers and its involvement in tumour growth, angiogenesis, metastasis and coagulopathy. However, this constitutive influence is modified by the tumour microenvironment, cellular interactions and host factors rendering TF expression patterns complex and heterogeneous. It appears that in many biological contexts TF plays a central role in disease progression and thereby potentially constitutes an attractive therapeutic target, especially in scenarios where the risk of bleeding can be avoided by selecting appropriate medications, refined dosing or by targeting the signalling component of TF activity. The efficacy and safety of such approaches still awaits clinical verification.

Breast cancer phenotypes regulated by tissue factor-factor VII pathway: Possible therapeutic targets

“…Therefore, TF-fVIIa complex formation may represent a major cause of thromboembolic events. Numerous studies have also suggested that TF-fVIIa complex formation on the cell surface also contributes to the malignant phenotypes of cancer, including an increase in cell motility, invasiveness, cell survival, and angiogenesis [12,13] . Recently, there is growing experimental evidence to suggest that TF also contributes to tumor initiation [13] .…”

“…Numerous studies have also suggested that TF-fVIIa complex formation on the cell surface also contributes to the malignant phenotypes of cancer, including an increase in cell motility, invasiveness, cell survival, and angiogenesis [12,13] . Recently, there is growing experimental evidence to suggest that TF also contributes to tumor initiation [13] . Therefore, therapeutic strategies targeting TF may be advantageous to breast cancer, although the possible impairment of the physiological hemostatic process should be considered.…”

“…Indeed, TF-fVIIa is capable of transmitting intracellular signals via multiple pathways, predominantly those involving the activation of protease-activated receptors (PARs) (Figure 2). To date, a number of studies have made significant advances towards our understanding of how TF-fVIIa complex formation contributes to cancer progression [12,13,25] . Until now, many studies concerning the biology of TF-fVIIa-dependent signaling were performed using breast cancer cell lines, possibly owing to their functional dependency on TF signaling [26][27][28][29] .…”

“…Inducible gene expression may also account for high TF expression in cancer tissues, although such mechanisms may not necessarily apply to breast cancer cells. For example, F3 gene expression may be regulated by exposure to various environmental stimuli including cytokines [13] , growth factors [13] , and hypoxia [13] , resulting in the activation of AP-1 and NFκB.…”

Ectopic Synthesis of Coagulation Factor VII in Breast Cancer Cells: Mechanisms, Functional Correlates, and Potential for a New Therapeutic Target

“…Inducible expression of the F3 gene is another plausible cause of high TF expression in cancer tissues. Expression of TF is known to be affected by various environmental stimuli such as exposure to cytokines, growth factors, and hypoxia (Milsom & Rak 2009), leading to activation of AP-1 and NFB. Therefore, expression levels of TF can be varied depending on the tumor microenvironment.…”