Cancer enhances the risk of venous thromboembolism, but a hypercoagulant microenvironment also promotes cancer progression. Although anticoagulants have been suggested as a potential anticancer... Show moreCancer enhances the risk of venous thromboembolism, but a hypercoagulant microenvironment also promotes cancer progression. Although anticoagulants have been suggested as a potential anticancer treatment, clinical studies on the effect of such modalities on cancer progression have not yet been successful for unknown reasons. In normal physiology, complex formation between the subendothelial-expressed tissue factor (TF) and the blood-borne liver-derived factor VII (FVII) results in induction of the extrinsic coagulation cascade and intracellular signaling via protease-activated receptors (PARs). In cancer, TF is overexpressed and linked to poor prognosis. Here, we report that increased levels of FVII are also observed in breast cancer specimens and are associated with tumor progression and metastasis to the liver. In breast cancer cell lines, tumor-expressed FVII drives changes reminiscent of epithelial-to-mesenchymal transition (EMT), tumor cell invasion, and expression of the prometastatic genes, SNAI2 and SOX9. In vivo, tumorexpressed FVII enhanced tumor growth and liver metastasis. Surprisingly, liver-derived FVII appeared to inhibit metastasis. Finally, tumor-expressed FVII-induced prometastatic gene expression independent of TF but required a functional endothelial protein C receptor, whereas recombinant activated FVII acting via the canonical TF:PAR2 pathway inhibited prometastatic gene expression. Here, we propose that tumor-expressed FVII and liverderived FVII have opposing effects on EMT and metastasis. Show less
Bijkerk, R.; Solingen, C. van; Boer, H.C. de; Pol, P. van der; Khairoun, M.; Bruin, R.G. de; ... ; Zonneveld, A.J. van 2014
Full-length tissue factor (flTF) initiates coagulation, but also exerts non-hemostatic functions such as inflammation and angiogenesis through protease activated receptors (PARs). In 2003 a soluble... Show moreFull-length tissue factor (flTF) initiates coagulation, but also exerts non-hemostatic functions such as inflammation and angiogenesis through protease activated receptors (PARs). In 2003 a soluble variant of flTF was described which results from alternative splicing. Since its discovery the role of alternatively spliced tissue factor (asTF) in coagulation has been debated. asTF may have pro-coagulant properties but due to structural differences when compared to flTF, asTF coagulant function may be relatively low. Nevertheless, similar to flTF, asTF appears to have non-hemostatic properties; asTF expression in tumors correlates with increased tumor size, vessel number and poor survival in some cancer types, and drives tumor growth in animal models. Interestingly, unlike flTF, asTF does not promote angiogenesis through activating PARs but rather via integrin ligation. flTF is a critical determinant in cardiovascular disease but little is known about asTF in cardiovascular disease. asTF is produced by monocytes and macrophages, thus macrophage-derived asTF may contribute to atherosclerotic disease. In conclusion, unraveling asTF's non-hemostatic properties may generate new insights in the pathophysiology and diagnostics of cancer and cardiovascular disease. Show less
Full-length tissue factor (fITF) initiates coagulation, but also exerts non-hemostatic functions such as inflammation and angiogenesis I through,protease activated receptors (PARs) In 2003 a... Show moreFull-length tissue factor (fITF) initiates coagulation, but also exerts non-hemostatic functions such as inflammation and angiogenesis I through,protease activated receptors (PARs) In 2003 a soluble variant of fITF was described which results from alternative splicing Since its discovery the role of alternatively spliced; tissue factor (asTF) in coagulation has been debated. asTF may have pro-coagulant propeites, but due to structural differences when compared to fITF, asTF coagulant function may be relatively low. Nevertheless, similar to I fITF, asTF appears to have non-hemostatic properties, asTF expression in tumors correlates with increased tumor size, vessel I number and poor survival in some cancer I types, and drives tumor growth in animal I models Interestingly, unlike fITF, asTF does not promote angiogenesis through activating PARs but:rather:via integrin ligation. fITF is a critical determinant'in cardiovascular disease but little is known about asTF in cardiovascular disease asTF is,Produced by monocytes. and macrophages thus macrophage-derived asTF may contribute:to atherosclerotic disease In conclusion, unraveling asTF's non-hemostatic, properties may generate new insights in the pathophysiology and diagnostics of cancer and cardiovascular disease. Show less
