Antiapoptotic effect of coagulation factor VIIa

Sørensen, Brit B.; Rao, L. Vijaya Mohan; Tornehave, Ditte; Gammeltoft, Steen; Petersen, Lars C.

doi:10.1182/blood-2003-01-0157

Cited by 106 publications

(102 citation statements)

References 46 publications

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“…The TF-FVIIa complex is known to activate PARs, promoting cell survival and proliferation (38). The antiapoptotic role of TF was demonstrated previously in TF-positive BHK cells where FVIIa binding to TF protected against apoptosis induced by growth factor deprivation (39). The TF/FVIIa complex in another study also activated antiapoptotic proteins like Bcl2, and TF inhibition enhanced apoptotic cell death in certain tumor cells (40).…”

Section: Discussionmentioning

confidence: 77%

Tissue Factor Signals Airway Epithelial Basal Cell Survival via Coagulation and Protease-Activated Receptor Isoforms 1 and 2

Ahmad

Ahmad²,

Rancourt³

et al. 2013

Am J Respir Cell Mol Biol

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Tissue factor (TF) initiates the extrinsic coagulation cascade and is a high-affinity receptor for coagulation factor VII. TF also participates in protease-activated receptor (PAR)1 and PAR2 activation. Human epithelial basal cells were previously purified on the basis of TF expression. The purpose of this study was to determine if tracheobronchial epithelial basal cell-associated TF drives coagulation and/ or activates PARs to promote basal cell functions. We used human tracheobronchial tissues to isolate human airway epithelial cells using specific cell surface markers by flow cytometry and studied TF expression by immunostaining. TF-dependent fibrin network formation was observed by confocal and scanning electron microscopy. TF knockdown was done using short hairpin RNA, and TF mRNA was measured using quantitative RT-PCR. We found that 97 6 5% of firstpassage human tracheobronchial epithelial cells were basal cells, and 100% of these basal cells expressed TF. Basal cell-associated TF was active, but TF activity was dependent on added extrinsic coagulation cascade factors. TF inhibition caused basal cell apoptosis and necrosis. This was due to two parallel but interdependent TFregulated processes: failure to generate a basal cell-associated fibrin network and suboptimal PAR1 and PAR2 activity. The data indicate that membrane surface TF mediates airway epithelial basal cell attachment, which maintains cell survival and mitotic potential. The implications of these findings are discussed in the context of basal cell-associated TF activity in normal and injured tissues and of the potential for repair of airway epithelium in lung disease.Keywords: tissue factor; epithelium; clotting; fibrin; tracheobronchial Tissue factor (TF) is a transmembrane cell receptor and cofactor for factor VII (FVII) and serves biological functions beyond its established role in blood coagulation (1). TF may act as a transmembrane signaling molecule by activating and delivering coagulation factors for signaling, and the TF-coagulation FVIIa complex activates G protein-coupled receptors, including the protease-activated receptors (PARs) (2). Under pathologic conditions, TF can be expressed by circulating blood elements (monocytes, neutrophils, and platelets) and by an associated elevated number of cell-derived circulating microparticles. The role of TF in epithelial cell function is much less well understood than its role in the circulation and in hemostasis.In acute lung injury, increased coagulation and decreased fibrinolysis result in diffuse alveolar fibrin deposition, potentially increasing lung inflammation (3). Recent evidence indicates that the damaged alveolar epithelium expresses TF (4) and that FVII-activating protein expression is increased (5). Alveolar procoagulant microparticles are also elevated (6), and intrinsic elevation of tissue factor pathway inhibitor (TFPI) expression is insufficient to inhibit this procoagulant effect (7). Coagulation pathologies also occur in conducting airways. For example, the sulfur mustard ana...

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Section: Discussionmentioning

confidence: 77%

Tissue Factor Signals Airway Epithelial Basal Cell Survival via Coagulation and Protease-Activated Receptor Isoforms 1 and 2

Ahmad

Ahmad²,

Rancourt³

et al. 2013

Am J Respir Cell Mol Biol

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“…TF triggers a procoagulant state in advanced cancer when tumor cells come in contact with the blood or when TF-positive microvesicles are increasingly shed into the circulation (2). The evidence is increasing that the TF/fVIIa complex also initiates key pathogenetic mechanisms in cancer, including angiogenesis (3)(4)(5)(6), cell migration and invasion (3,7), and cell survival (8,9). Although activation of coagulation is critical for TF-dependent hematogenous cancer metastasis (10), it is likely that TF activities in cancer progression also involve direct cell signaling triggered by TF/fVIIa complex formation on cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Activation of Cancer Cell Migration and Invasion by Ectopic Synthesis of Coagulation Factor VII

Koizume¹,

Jin²,

et al. 2006

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Blood coagulation factor VII ( fVII) is physiologically synthesized in the liver and released into the blood. Binding of fVII to tissue factor (TF) at sites of vascular injury triggers coagulation and hemostasis. TF/fVIIa complex formation on the surface of cancer cells plays important roles in cancer biology. Although fVII is synthesized by hepatocellular carcinoma, it remained unclear how TF/fVIIa complex formation and promigratory signaling can occur for most other cancers in extravascular locations. Here, we show by reverse transcription-PCR analysis that nonhepatic cancer cell lines constitutively express fVII mRNA and that endogenously synthesized fVIIa triggers coagulation activation on these cells. fVIIa expression in cancer cells is inducible under hypoxic conditions and hypoxia-inducible factor-2A bound the promoter region of the FVII gene in chromatin immunoprecipitation analyses. Constitutive fVII expression in an ovarian cancer cell line enhanced both migration and invasion. Enhanced motility was blocked by anti-TF antibodies, factor Xa inhibition, and anti-protease-activated receptor-1 antibody treatment, confirming that TF/fVIIa stimulated migration by triggering cell signaling. This study shows that ectopic synthesis of fVII by cancer cells is sufficient to support proinvasive factor Xa-mediated protease-activated receptor-1 signaling and that this pathway is inducible under hypoxia.

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“…Thus, prosurvival modulation and the apoptotic machinery pathway are both key in forming the appropriate balance for normal cell maintenance. For example, factor VIIa/tissue factor, apart from its role in coagulation, also induces tumor progression partly via eliciting a survival pathway and inhibiting apoptosis (15,16).…”

Section: Introductionmentioning

confidence: 99%

Protease-Activated Receptor-1 (hPar1), A Survival Factor Eliciting Tumor Progression

Salah

Maoz

Pokroy

et al. 2007

Molecular Cancer Research

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Although ample evidence point to the central involvement of protease activated receptor-1 (PAR1) in tumor progression, little is known about the fate of the tumor when hPar1 is being silenced. We observed that hPar1 antisense clones exhibit low PAR1 levels, attenuated cell proliferation and invasion in vitro, and tumor formation in vivo. These clones showed noticeably reduced paxillin phosphorylation compared with the parental A375SM cells, whereas no change in the integrin levels was noticed. Antisense clones injected into the mice resulted in very few and only occasional small tumors, whereas advanced and vascularized tumors were observed in A375SM cells. The antisense-derived tumor sections expressed active caspase-3, increased terminal deoxynucleotidyl transferase -mediated nick-end labeling staining, and a markedly reduced proliferating cell nuclear antigen level compared with A375SM cell -derived tissue sections. Likewise, ablation of the hPar1 gene in a tetracyclineinducible hPar1 system leads to apoptosis in immature blood vessels, whereas mature vessels were unaffected. The activation of PAR1-induced pAkt/protein kinase B abrogated serum-deprived Bim EL induction and also markedly inhibited Bax levels. On the other hand, small interfering RNA silencing of the hPar1 gene induced the expression of Bim EL , a direct substrate of Akt/protein kinase B and also induced expression of active caspase-9 and caspase-3. These results altogether identify PAR1 as a survival factor that protects cells from undergoing apoptosis. We conclude that whereas PAR1 gene expression correlates with tumor progression, its neutralization effectively initiates an apoptotic pathway leading at least in part to significantly reduced tumor formation. (Mol Cancer Res 2007;5(3):229 -40)

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Antiapoptotic effect of coagulation factor VIIa

Cited by 106 publications

References 46 publications

Tissue Factor Signals Airway Epithelial Basal Cell Survival via Coagulation and Protease-Activated Receptor Isoforms 1 and 2

Tissue Factor Signals Airway Epithelial Basal Cell Survival via Coagulation and Protease-Activated Receptor Isoforms 1 and 2

Activation of Cancer Cell Migration and Invasion by Ectopic Synthesis of Coagulation Factor VII

Protease-Activated Receptor-1 (hPar1), A Survival Factor Eliciting Tumor Progression

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