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

Rollin, Jérôme; Régina, Sandra; Gruel, Yves

doi:10.1111/j.1538-7836.2009.03713.x

Cited by 17 publications

(14 citation statements)

References 16 publications

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“…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 . In addition to its expression in pancreatic, lung, breast and cervical cancer 19, 21, 24 , asTF has been detected in human plaques 25, 26 ; however, limited evidence exists beyond analysis of lipid-rich aortic lesions 26 . Whereas asTF is expressed by monocytes/macrophages and vascular smooth muscle cells 17, 27 , the main cellular components of plaques, it is unknown whether asTF expression in atherosclerotic plaques is related to a more advanced phenotype and if so, what its functional relevance is.…”

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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“…A comprehensive overview of the studies that we selected for this review is provided in Table 1. 78,79 Studies of the upstream oncogenic events that lead to enhanced flTF expression have been conducted in colorectal 8 and lung cancer, 13,14 and associations were identified between flTF expression and p53 and K-ras mutations for both lung and colorectal cancers, and PTEN as well, for lung cancer.The majority of the cited studies support the notion that flTF expression is an independent predictor of poor overall or relapsefree survival, 13,54,55,[59][60][61]63,70,72,75,80 although some studies failed to find such a relation. 57,76,77 Furthermore, associations have been found with invasiveness in breast cancer 15 and melanomas, 15,76 high clinical staging in lung, 13,14,40,57 pancreas, 62,63 colorectal, 65,66 and prostate cancer, 74 and metastases in cancers of breast, 53 lung, 56 esophagus, 59 gastric, 60 hepatic, 61 pancreatic, 63 and colorectal 67 tissues.…”

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confidence: 84%

“…38 Increasing evidence supports a role for asTF in cancerous processes. 5,6,39,40 The affinity of asTF for FVII(a) is low, which is also reflected in an absence of asTF-dependent FVIIa signaling. On the other hand, asTF activates ␣6␤1 and ␣V␤3 integrins on endothelial cells, thus acting as a pro-angiogenic stimulus.…”

Section: Tf Isoforms and Their Cellular Effects On Cancermentioning

confidence: 99%

“…40 In another study, high asTF mRNA levels conferred an impaired survival to non-small cell lung cancer patients, but the relation with staging and tumor size could not be confirmed. 80 Most of the aforementioned cancers are of epithelial origin, but this does not exclude a role for aberrant flTF expression in cancer of other origins. Mouse studies indicate that flTF expression influences fibrosarcoma progression, 41 and rat osteosarcoma cells display flTF-dependent coagulant activity, 82 but data on human sarcomas are lacking.…”

Section: Tf Isoforms In Human Cancermentioning

confidence: 99%

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The relationship between tissue factor and cancer progression: insights from bench and bedside

Berg¹,

Osanto

Reitsma³

et al. 2012

Blood

307

243

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It is now widely recognized that a strong correlation exists between cancer and aberrant hemostasis. Patients with various types of cancers, including pancreatic, colorectal, and gastric cancer, often develop thrombosis, a phenomenon commonly referred to as Trousseau syndrome. Reciprocally, components from the coagulation cascade also influence cancer progression. The primary initiator of coagulation, the transmembrane receptor tissue factor (TF), has gained considerable attention as a determinant of tumor progression. On complex formation with its ligand, coagulation factor VIIa, TF influences protease-activated receptor-dependent tumor cell behavior, and regulates integrin function, which facilitate tumor angiogenesis both in vitro and in mouse models. Furthermore, evidence exists that an alternatively spliced isoform of TF also affects tumor growth and tumor angiogenesis. In patient material, TF expression and TF cytoplasmic domain phosphorylation correlate with disease outcome in many, but not in all, cancer subtypes, suggesting that TFdependent signal transduction events are a potential target for therapeutic intervention in selected types of cancer. In this review, we summarize our current understanding of the role of TF in tumor growth and metastasis, and speculate on anticancer therapy by targeting TF. (Blood. 2012; 119(4):924-932) IntroductionAfter Trousseau's description of thrombophlebitis as a complication of pancreatic cancer in the 19th century, the notion that increased expression of tissue factor (TF) underlies the relation between coagulation and cancer has become generally accepted. Full-length TF (flTF) is a 47-kDa membrane-bound glycoprotein that is present on subendothelial cells. 1 In the classic concept of coagulation, it is thought that endothelial disruption leads to exposure of flTF to the bloodstream. Exposed flTF can bind to its natural ligand factor VII (FVII), which then becomes activated FVII (FVIIa). The thus formed flTF/FVIIa complex converts factor X (FX) to factor Xa (FXa), and FXa in turn activates prothrombin leading to formation of thrombin (factor IIa). Thrombin subsequently activates platelets and converts fibrinogen into fibrin, 2 essential components of a stable hemostatic plug. 1 The primary function of subendothelial flTF is to serve as a hemostatic envelope surrounding the vasculature. However, under certain conditions, the expression of flTF is induced in monocytes and endothelial cells. flTF is also often expressed on cancer cells and the tumor vasculature, 2 and flTF-bearing microparticles can become shed by these cells. 3 These flTF-bearing microparticles are important contributors to the thrombotic phenotype in cancer patients. 3 The flTF/FVIIa complex also influences pathways that do not lead to blood coagulation, but rather activate cell-bound proteaseactivated receptors (PARs) that are of importance during the inflammatory and angiogenic response to injury. 4 Furthermore, a soluble variant of flTF, known as alternatively spliced TF (asTF), stimulates angiogen...

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“…These alterations seems to be linked to the RNA binding protein FOX2 whose expression is downregulated in ovarian cancer and whose splicing results extensively changed in breast cancer samples. More recently, it has been reported that the presence of an alternatively spliced isoform of the receptor for factor VII/VIIa, named Tissue Factor (TF), is a prognostic marker in patients with non-small cell lung cancer [7]. Indeed, this soluble isoform of TF lacking exon 5 that encodes the transmembrane domain has been detected in various cancerous tissues and several studies suggested that its expression promotes tumor growth and is associated with increased tumor cell proliferation and angiogenesis in vivo [8].…”

Section: Introductionmentioning

confidence: 99%

Identification of tumor-associated cassette exons in human cancer through EST-based computational prediction and experimental validation

et al. 2010

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BackgroundMany evidences report that alternative splicing, the mechanism which produces mRNAs and proteins with different structures and functions from the same gene, is altered in cancer cells. Thus, the identification and characterization of cancer-specific splice variants may give large impulse to the discovery of novel diagnostic and prognostic tumour biomarkers, as well as of new targets for more selective and effective therapies.ResultsWe present here a genome-wide analysis of the alternative splicing pattern of human genes through a computational analysis of normal and cancer-specific ESTs from seventeen anatomical groups, using data available in AspicDB, a database resource for the analysis of alternative splicing in human. By using a statistical methodology, normal and cancer-specific genes, splice sites and cassette exons were predicted in silico. The condition association of some of the novel normal/tumoral cassette exons was experimentally verified by RT-qPCR assays in the same anatomical system where they were predicted. Remarkably, the presence in vivo of the predicted alternative transcripts, specific for the nervous system, was confirmed in patients affected by glioblastoma.ConclusionThis study presents a novel computational methodology for the identification of tumor-associated transcript variants to be used as cancer molecular biomarkers, provides its experimental validation, and reports specific biomarkers for glioblastoma.

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

Cited by 17 publications

References 16 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

The relationship between tissue factor and cancer progression: insights from bench and bedside

Identification of tumor-associated cassette exons in human cancer through EST-based computational prediction and experimental validation

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