Role of Alternatively Spliced Tissue Factor in Pancreatic Cancer Growth and Angiogenesis

Signaevsky, Maxim; Hobbs, Jennifer; Doll, Jennifer A.; Liu, Na; Soff, Gerald A.

doi:10.1055/s-2008-1079256

Cited by 28 publications

(26 citation statements)

References 31 publications

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“…asTF is a non-membrane anchored molecule of 27kDa that, while retaining most of the contact sites for coagulation factor VIIa, lacks large portions of an exosite for macromolecular substrates 18 . As a result, asTF has no appreciable procoagulant activity and it is believed to play a more prominent role in promoting angiogenesis 19, 20 . Unlike fl-TF, asTF exhibits angiogenic activity via integrin ligation and activation of Focal Adhesion Kinase (FAK) in a factor VIIa and Protease-Activated Receptor-2 (PAR-2) independent manner 19, 21–23 .…”

Section: Introductionmentioning

confidence: 99%

Alternatively Spliced Tissue Factor Promotes Plaque Angiogenesis Through the Activation of Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor Signaling

Giannarelli¹,

Alique²,

Rodriguez³

et al. 2014

Circulation

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Background Alternatively Spliced Tissue Factor (asTF) is a novel isoform of full-length Tissue Factor (fl-TF) that exhibits angiogenic activity. Although asTF has been detected in human plaques, it is unknown whether its expression in atherosclerosis causes increased neovascularization and an advanced plaque phenotype. Methods and Results Carotid (n=10) and coronary specimens (n=8), from patients with stable or unstable angina, were classified as complicated or uncomplicated based on plaque morphology. Analysis of asTF expression and cell type –specific expression revealed a strong expression and co-localization of asTF with macrophages and neovessels within complicated, but not un-complicated, human plaques. Our results showed that the angiogenic activity of asTF is mediated via HIF-1α up-regulation through integrins and activation of phosphatidylinositol-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways. HIF-1α up-regulation by asTF also was associated with increased VEGF expression in primary human endothelial cells, and VEGF-Trap significantly reduced the angiogenic effect of asTF in vivo. Furthermore, asTF gene transfer significantly increased neointima formation and neovascularization following carotid wire injury in ApoE−/− mice. Conclusions The results of this study provide strong evidence that asTF promotes neointima formation and angiogenesis in an experimental model of accelerated atherosclerosis. Herein, we demonstrate that the angiogenic effect of asTF is mediated via the activation of the HIF-1/VEGF signaling. This mechanism may be relevant to neovascularization, progression and associated complications of human atherosclerosis as suggested by the increased expression of asTF in complicated vs. uncomplicated human carotid and coronary plaques.

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Section: Introductionmentioning

confidence: 99%

Alternatively Spliced Tissue Factor Promotes Plaque Angiogenesis Through the Activation of Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor Signaling

Giannarelli¹,

Alique²,

Rodriguez³

et al. 2014

Circulation

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“…30,31 Recently, alternatively spliced TF has been found to promote tumor growth and to be a proangiogenic factor. 32,33 Alternatively spliced TF, unlike full-length TF, does not affect angiogenesis through proteinactivated receptor-dependent pathways but relies on integrin ligation. 34 We also investigated how TF can directly regulate angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Tissue Factor Regulates Microvessel Formation and Stabilization by Induction of Chemokine (C-C motif) Ligand 2 Expression

Arderiu

Peña

Aledo

et al. 2011

ATVB

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Objective-Tissue factor (TF) triggers arterial thrombosis. TF is also able to initiate cellular signaling mechanisms leading to angiogenesis. Because high cardiovascular risk atherosclerotic plaques show significant angiogenesis, our objective was to investigate whether TF is able to trigger and stabilize atherosclerotic plaque neovessel formation. Methods and Results-In this study, we showed, by real-time confocal microscopy in 3-dimensional basement membrane cocultures, that TF in human microvascular endothelial cells (HMEC-1) and in human vascular smooth muscle cells (HVSMCs) plays an important role in the formation of capillary-like networks. TF silencing in endothelial cells and smooth muscle cells inhibits the formation of tube-like structures with stable phenotype. Using an in vivo model, we observed that TF inhibition in either HMEC-1 or HVSMCs reduced their shared ability to form new capillaries. The phenotypic changes induced by TF silencing were linked to reduced chemokine (C-C motif) ligand 2 (CCL2) expression in endothelial cells. Wound healing and chemotactic assays demonstrated that TF-induced release of CCL2 stimulated HVSMC migration to HMEC-1. Key Words: angiogenesis Ⅲ atherosclerosis Ⅲ cytokines Ⅲ endothelial function Ⅲ vascular biology A therosclerotic plaque angiogenesis, the outgrowth of new capillaries from preexisting vascular networks, is a pathological feature of advanced complicated plaques. 1,2 Interestingly, coronary type VI plaques, according to the American Heart Association classification, are those with higher amount of microvessels and those with higher risk of inducing a clinical cardiovascular event. 3 In advanced plaques, inflammatory cell infiltration and concomitant production of proangiogenic cytokines may be responsible for induction of uncontrolled neointimal microvessel proliferation resulting in production of immature and fragile neovessels. The final stage of microvessel formation occurs when maturation requires the formation of tight endothelial cell-tocell contacts, 4 the downregulation of endothelial proliferation, and the deposition of a basal lamina to which the endothelium tightly adheres, as well as the recruitment of supporting cells to the vessel wall, such as pericytes and smooth muscle cells (SMCs). 5,6 During angiogenesis, the communication between endothelial cells (ECs) and SMCs requires a precise temporal and spatial regulation of pro-and antiangiogenic molecules, but the process is not yet fully understood. Conclusion-Endogenous See accompanying article on page 2364In recent years, it has become clear that the angiogenesis process is highly dependent on components of the blood coagulation cascade. One of these proteins is tissue factor (TF). 7-9 TF is the cellular receptor and cofactor for blood coagulation factor VII (FVII). 10,11 In addition to its primary role in blood coagulation, accumulating evidence has transformed our view of TF from the cellular receptor for activated FVII (FVIIa) to a multifaceted transmembrane signaling receptor. The bioch...

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“…asTF is therefore soluble and has been detected both in the blood circulation and in various normal and cancerous tissues [3][4][5][6][7]. Recent studies have proved that asTF does not play a significant role during coagulation [8,9] but is likely essential during angiogenesis associated with the development of cancer [4,10]. We recently demonstrated that high tumor TF expression in non-small cell lung cancer (NSCLC) was associated with reduced survival of affected patients and that overexpression of TF was linked to oncogenic events, such as KRAS, p53 and PTEN mutations [11,12].…”

mentioning

confidence: 99%

Tumor expression of alternatively spliced tissue factor is a prognostic marker in non‐small cell lung cancer

Rollin

Régina

Gruel

2010

Journal of Thrombosis and Haemostasis

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Role of Alternatively Spliced Tissue Factor in Pancreatic Cancer Growth and Angiogenesis

Cited by 28 publications

References 31 publications

Alternatively Spliced Tissue Factor Promotes Plaque Angiogenesis Through the Activation of Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor Signaling

Alternatively Spliced Tissue Factor Promotes Plaque Angiogenesis Through the Activation of Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor Signaling

Tissue Factor Regulates Microvessel Formation and Stabilization by Induction of Chemokine (C-C motif) Ligand 2 Expression

Tumor expression of alternatively spliced tissue factor is a prognostic marker in non‐small cell lung cancer

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