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Tissue factor, angiogenesis and tumour progression.

Bluff JE, Brown NJ, Reed MW, Staton CA - Breast Cancer Res. (2008)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Microcirculation Research Group, Academic Unit of Surgical Oncology, School of Medicine and Biomedical Sciences, Beech Hill Road, Sheffield S10 2RX, UK. j.bluff@sheffield.ac.uk

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.

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Tissue factor-induced protease-activated receptor 2 signalling. (a) When the cytoplasmic domain is nonphosphorylated, tissue factor (TF) exerts a negative regulatory control on protease-activated receptor (PAR)-2 and inhibits signalling. (b) Binding of activated factor VII (FVIIa) to TF results in proteolytic cleavage of PAR-2 and phosphorylation of the cytoplasmic domain of TF via activation of phosphatidylcholine-specific phospholipase C (PC-PLC) and protein kinase C (PKC) alpha. Phosphorylation releases the negative regulatory control of PAR-2-mediated signalling, resulting in activation of several mitogen-activated protein kinase (MAPK) pathways and subsequent gene transcription. Phosphatidylinositol 3-kinase (PI3K) and Rac1 activation also constitute important signal transduction cascades, mainly related to antiapoptotic and migration processes. The constitutive association of α3β1 integrin with aggressive breast cancer cells (for example, MDA-MB-231 cells) implies that tumour cells have lost the ability to sense extracellular gradients of coagulation proteases and constitutively couple TF and integrin signalling. Although the precise mechanism for this coupling is unknown, it may play a role in tumour cell invasiveness. The overall activation of these signalling pathways is responsible for the induction of angiogenesis, malignant cell survival and metastasis, resulting in tumour growth and disease progression. BTCM, breast tumour cell membrane; Cyr61, cysteine-rich angiogenic inducer 61; CTGF, connective tissue growth factor; EC, endothelial cell; Egr-1, early growth response gene 1; ERK, extracellular signal-related kinase; JNK, c-jun N-terminal kinase; PKB, protein kinase B; TSP, thrombospondin; uPAR, urokinase-type plasminogen activator receptor; VEGF, vascular endothelial growth factor.
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Figure 2: Tissue factor-induced protease-activated receptor 2 signalling. (a) When the cytoplasmic domain is nonphosphorylated, tissue factor (TF) exerts a negative regulatory control on protease-activated receptor (PAR)-2 and inhibits signalling. (b) Binding of activated factor VII (FVIIa) to TF results in proteolytic cleavage of PAR-2 and phosphorylation of the cytoplasmic domain of TF via activation of phosphatidylcholine-specific phospholipase C (PC-PLC) and protein kinase C (PKC) alpha. Phosphorylation releases the negative regulatory control of PAR-2-mediated signalling, resulting in activation of several mitogen-activated protein kinase (MAPK) pathways and subsequent gene transcription. Phosphatidylinositol 3-kinase (PI3K) and Rac1 activation also constitute important signal transduction cascades, mainly related to antiapoptotic and migration processes. The constitutive association of α3β1 integrin with aggressive breast cancer cells (for example, MDA-MB-231 cells) implies that tumour cells have lost the ability to sense extracellular gradients of coagulation proteases and constitutively couple TF and integrin signalling. Although the precise mechanism for this coupling is unknown, it may play a role in tumour cell invasiveness. The overall activation of these signalling pathways is responsible for the induction of angiogenesis, malignant cell survival and metastasis, resulting in tumour growth and disease progression. BTCM, breast tumour cell membrane; Cyr61, cysteine-rich angiogenic inducer 61; CTGF, connective tissue growth factor; EC, endothelial cell; Egr-1, early growth response gene 1; ERK, extracellular signal-related kinase; JNK, c-jun N-terminal kinase; PKB, protein kinase B; TSP, thrombospondin; uPAR, urokinase-type plasminogen activator receptor; VEGF, vascular endothelial growth factor.

Mentions: 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].


Tissue factor, angiogenesis and tumour progression.

Bluff JE, Brown NJ, Reed MW, Staton CA - Breast Cancer Res. (2008)

Tissue factor-induced protease-activated receptor 2 signalling. (a) When the cytoplasmic domain is nonphosphorylated, tissue factor (TF) exerts a negative regulatory control on protease-activated receptor (PAR)-2 and inhibits signalling. (b) Binding of activated factor VII (FVIIa) to TF results in proteolytic cleavage of PAR-2 and phosphorylation of the cytoplasmic domain of TF via activation of phosphatidylcholine-specific phospholipase C (PC-PLC) and protein kinase C (PKC) alpha. Phosphorylation releases the negative regulatory control of PAR-2-mediated signalling, resulting in activation of several mitogen-activated protein kinase (MAPK) pathways and subsequent gene transcription. Phosphatidylinositol 3-kinase (PI3K) and Rac1 activation also constitute important signal transduction cascades, mainly related to antiapoptotic and migration processes. The constitutive association of α3β1 integrin with aggressive breast cancer cells (for example, MDA-MB-231 cells) implies that tumour cells have lost the ability to sense extracellular gradients of coagulation proteases and constitutively couple TF and integrin signalling. Although the precise mechanism for this coupling is unknown, it may play a role in tumour cell invasiveness. The overall activation of these signalling pathways is responsible for the induction of angiogenesis, malignant cell survival and metastasis, resulting in tumour growth and disease progression. BTCM, breast tumour cell membrane; Cyr61, cysteine-rich angiogenic inducer 61; CTGF, connective tissue growth factor; EC, endothelial cell; Egr-1, early growth response gene 1; ERK, extracellular signal-related kinase; JNK, c-jun N-terminal kinase; PKB, protein kinase B; TSP, thrombospondin; uPAR, urokinase-type plasminogen activator receptor; VEGF, vascular endothelial growth factor.
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Related In: Results  -  Collection

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Figure 2: Tissue factor-induced protease-activated receptor 2 signalling. (a) When the cytoplasmic domain is nonphosphorylated, tissue factor (TF) exerts a negative regulatory control on protease-activated receptor (PAR)-2 and inhibits signalling. (b) Binding of activated factor VII (FVIIa) to TF results in proteolytic cleavage of PAR-2 and phosphorylation of the cytoplasmic domain of TF via activation of phosphatidylcholine-specific phospholipase C (PC-PLC) and protein kinase C (PKC) alpha. Phosphorylation releases the negative regulatory control of PAR-2-mediated signalling, resulting in activation of several mitogen-activated protein kinase (MAPK) pathways and subsequent gene transcription. Phosphatidylinositol 3-kinase (PI3K) and Rac1 activation also constitute important signal transduction cascades, mainly related to antiapoptotic and migration processes. The constitutive association of α3β1 integrin with aggressive breast cancer cells (for example, MDA-MB-231 cells) implies that tumour cells have lost the ability to sense extracellular gradients of coagulation proteases and constitutively couple TF and integrin signalling. Although the precise mechanism for this coupling is unknown, it may play a role in tumour cell invasiveness. The overall activation of these signalling pathways is responsible for the induction of angiogenesis, malignant cell survival and metastasis, resulting in tumour growth and disease progression. BTCM, breast tumour cell membrane; Cyr61, cysteine-rich angiogenic inducer 61; CTGF, connective tissue growth factor; EC, endothelial cell; Egr-1, early growth response gene 1; ERK, extracellular signal-related kinase; JNK, c-jun N-terminal kinase; PKB, protein kinase B; TSP, thrombospondin; uPAR, urokinase-type plasminogen activator receptor; VEGF, vascular endothelial growth factor.
Mentions: 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].

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Microcirculation Research Group, Academic Unit of Surgical Oncology, School of Medicine and Biomedical Sciences, Beech Hill Road, Sheffield S10 2RX, UK. j.bluff@sheffield.ac.uk

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.

Show MeSH
Related in: MedlinePlus