Role of Tissue Factor in Tumor Progression and Cancer-Associated Thrombosis

2019 ◽  
Vol 45 (04) ◽  
pp. 396-412 ◽  
Author(s):  
Araci M. R. Rondon ◽  
Chantal Kroone ◽  
Maaike Y. Kapteijn ◽  
Henri H. Versteeg ◽  
Jeroen T. Buijs
Keyword(s):  
Tissue Factor ◽  
Cancer Progression ◽  
Coagulation Cascade ◽  
Clinical Phase ◽  
Transmembrane Glycoprotein ◽  
Cancer Models ◽  
Cytotoxic Compounds ◽  
Cancer Associated Thrombosis ◽  
Tumor Types

AbstractIt has been long-established that cancer and thrombosis are linked, but the exact underlying pathological mechanism remains to be unraveled. As the initiator of the coagulation cascade, the transmembrane glycoprotein tissue factor (TF) has been intensely investigated for its role in cancer-associated thrombosis and cancer progression. TF expression is regulated by both specific oncogenes and environmental factors, and it is shown to regulate primary growth and metastasis formation in a variety of cancer models. In clinical studies, TF has been shown to be overexpressed in most cancer types and is strongly associated with disease progression. While TF clearly associates with cancer progression, a prominent role for TF in the development of cancer-associated thrombosis is less clear. The current concept is that cancer-associated thrombosis is associated with the secretion of tumor-derived TF-positive extracellular vesicles in certain tumor types. To date, many therapeutic strategies to target TF—both in preclinical and clinical phase—are being pursued, including targeting TF or the TF:FVIIa complex by itself or by exploiting TF as a docking molecule to deliver cytotoxic compounds to the tumor. In this review, the authors summarize the current understanding of the role of TF in both cancer progression and cancer-associated thrombosis, and discuss novel insights on TF as a therapeutic target as well as a biomarker for cancer progression and VTE.

scholarly journals Inhibition of tissue factor signaling suppresses tumor growth

Blood ◽  
2008 ◽  
Vol 111 (1) ◽  
pp. 190-199 ◽  
Author(s):  
Henri H. Versteeg ◽  
Florence Schaffner ◽  
Marjolein Kerver ◽  
Helle H. Petersen ◽  
Jasimuddin Ahamed ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tissue Factor ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Coagulation Activation ◽  
Inhibitory Antibody ◽  
Unique Pair ◽  
Cancer Associated Thrombosis

Coagulation activation by tissue factor (TF) is implicated in cancer progression, cancer-associated thrombosis and metastasis. The role of direct TF signaling pathways in cancer, however, remains incompletely understood. Here we address how TF contributes to primary tumor growth by using a unique pair of isotype-matched antibodies that inhibit either coagulation (monoclonal antibody [Mab]-5G9) or direct signaling (Mab-10H10). We demonstrate that the inhibitory antibody of direct TF-VIIa signaling not only blocks TF-VIIa mediated activation of PAR2, but also disrupts the interaction of TF with integrins. In epithelial and TF-expressing endothelial cells, association of TF with β1 integrins is regulated by TF extracellular ligand binding and independent of PAR2 signaling or proteolytic activity of VIIa. In contrast, α3β1 integrin association of TF is constitutive in breast cancer cells and blocked by Mab-10H10 but not by Mab-5G9. Mab-5G9 has antitumor activity in vivo, but we show here that Mab-10H10 is at least as effective in suppressing human xenograft tumors in 2 different models. Breast tumor growth was also attenuated by blocking PAR2 signaling. These results show that tumor cell TF-PAR2 signaling is crucial for tumor growth and suggest that anti-TF strategies can be applied in cancer therapy with minor impairment of TF-dependent hemostatic pathways.

The role of monocytes in thrombotic disorders

2009 ◽  
Vol 102 (11) ◽  
pp. 916-924 ◽  
Author(s):  
Gregory Lip ◽  
Eduard Shantsila
Keyword(s):  
Innate Immunity ◽  
Dendritic Cells ◽  
Tissue Factor ◽  
Physiological Role ◽  
Coagulation Cascade ◽  
Pathophysiological Role ◽  
Platelet Aggregates

SummaryAlthough, the main physiological role of monocytes is attributed to innate immunity (that is, phagocytosis) and the development of tissue macrophages and dendritic cells, the pathophysiological role of these goes far behind these (simplistic) limits. Indeed, monocytes constitute a major source of blood tissue factor, a key element of the extrinsic coagulation cascade. Monocytes actively bind to platelets, thus forming very prothrombotic monocyte-platelet aggregates. Additionally, these cells link inflammation and the procoagulant state observed in various prothrombotic conditions. However, monocytes are also crucial for successful thrombus recanalisation. In this article, we review the available data on potential mechanisms that link monocytes with thrombosis-related processes.

scholarly journals Is the C-C Motif Ligand 2–C-C Chemokine Receptor 2 Axis a Promising Target for Cancer Therapy and Diagnosis?

2020 ◽  
Vol 21 (23) ◽  
pp. 9328
Author(s):  
Hiroaki Iwamoto ◽  
Kouji Izumi ◽  
Atsushi Mizokami
Keyword(s):  
Cancer Progression ◽  
Chemokine Receptor ◽  
Anticancer Agents ◽  
Mononuclear Cells ◽  
Chemical Mediator ◽  
Cancer Models ◽  
Promising Target ◽  
Therapy And Diagnosis ◽  
Inflammatory Tissue

C-C motif ligand 2 (CCL2) was originally reported as a chemical mediator attracting mononuclear cells to inflammatory tissue. Many studies have reported that CCL2 can directly activate cancer cells through a variety of mechanisms. CCL2 can also promote cancer progression indirectly through increasing the recruitment of tumor-associated macrophages into the tumor microenvironment. The role of CCL2 in cancer progression has gradually been understood, and various preclinical cancer models elucidate that CCL2 and its receptor C-C chemokine receptor 2 (CCR2) are attractive targets for intervention in cancer development. However, clinically available drugs that regulate the CCL2–CCR2 axis as anticancer agents are not available at this time. The complete elucidation of not only the oncological but also the physiological functions of the CCL2–CCR2 axis is required for achieving a satisfactory effect of the CCL2–CCR2 axis-targeted therapy.

scholarly journals Should We Replace the Terms Intrinsic and Extrinsic Coagulation Pathways With Tissue Factor Pathway?

2016 ◽  
Vol 23 (8) ◽  
pp. 922-927 ◽  
Author(s):  
Jan F. Vojacek
Keyword(s):  
Tissue Factor ◽  
Coagulation Cascade ◽  
Coagulation System ◽  
Bleeding Complications ◽  
Antithrombotic Agents ◽  
Risk Of Bleeding ◽  
Tissue Factor Pathway ◽  
The Common ◽  
Coagulation Pathway

Present review highlights some new aspects of the role of individual components of blood coagulation process and proposes a modified concept of hemocoagulation cascade. The role of FXII in the initiation of the so-called intrinsic coagulation system is currently questioned. Its role has been recently demonstrated mainly in the thrombus propagation and final stabilization together with factors XI and XIII. The edited concept underlines the common part of the tissue factor (TF) in the initiation of both the intrinsic and extrinsic pathways of the coagulation system and therefore may make it not improperly be called the TF coagulation pathway. The search for new antithrombotic agents shows that the level of the coagulation system blockade depends on which step in the coagulation cascade is targeted and results in different degrees of the antithrombotic efficiency and the risk of bleeding complications.

scholarly journals N-cadherin antagonists as oncology therapeutics

2015 ◽  
Vol 370 (1661) ◽  
pp. 20140039 ◽  
Author(s):  
Orest W. Blaschuk
Keyword(s):  
Cell Adhesion ◽  
Cancer Progression ◽  
Structural Integrity ◽  
Cancer Therapies ◽  
Transmembrane Glycoprotein ◽  
Anti Cancer ◽  
Different Types ◽  
Poorly Differentiated ◽  
Novel Strategy

The cell adhesion molecule (CAM), N-cadherin, has emerged as an important oncology therapeutic target. N-cadherin is a transmembrane glycoprotein mediating the formation and structural integrity of blood vessels. Its expression has also been documented in numerous types of poorly differentiated tumours. This CAM is involved in regulating the proliferation, survival, invasiveness and metastasis of cancer cells. Disruption of N-cadherin homophilic intercellular interactions using peptide or small molecule antagonists is a promising novel strategy for anti-cancer therapies. This review discusses: the discovery of N-cadherin, the mechanism by which N-cadherin promotes cell adhesion, the role of N-cadherin in blood vessel formation and maintenance, participation of N-cadherin in cancer progression, the different types of N-cadherin antagonists and the use of N-cadherin antagonists as anti-cancer drugs.

scholarly journals Protease-activated receptor 2 exacerbates cisplatin-induced nephrotoxicity

2019 ◽  
Vol 316 (4) ◽  
pp. F654-F659 ◽  
Author(s):  
Mari Watanabe ◽  
Yuji Oe ◽  
Emiko Sato ◽  
Akiyo Sekimoto ◽  
Hiroshi Sato ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Factor Viia ◽  
Therapeutic Option ◽  
Factor Xa ◽  
Kidney Injury ◽  
Coagulation Cascade ◽  
Expression Levels ◽  
Cisplatin Nephrotoxicity ◽  
Protease Activated Receptor 2

Acute kidney injury (AKI) is associated with hypercoagulability. Tissue factor/factor VIIa complex and factor Xa in the coagulation cascade activate protease-activated receptor 2 (PAR2). Previously, we have shown that PAR2-mediated inflammation aggravates kidney injury in models of diabetic kidney disease and adenine-induced renal fibrosis. However, the role of PAR2 in AKI remains unclear. To clarify the role of PAR2, we administered cisplatin, one of the most common causal factors of AKI, to wild-type and PAR2-deficient mice. The expression levels of tissue factor and PAR2 were significantly increased in the kidneys of mice that were administered cisplatin. A lack of PAR2 corrected the levels of plasma blood urea nitrogen and creatinine as well as ameliorated the acute tubular injury score in the kidney. A lack of PAR2 corrected the infiltration of neutrophils and the gene expression levels of proinflammatory cytokines/chemokines in these mouse kidneys. Similarly, apoptotic markers, such as cleaved caspase-3-positive area and Bax/Bcl2 ratio, were attenuated via PAR2 deletion. Thus, elevated PAR2 exacerbates cisplatin nephrotoxicity, and targeting PAR2 is a novel therapeutic option that aids in the treatment of patients with cisplatin-induced AKI.

Abstract 190: Purinergic Control of Tissue Factor Transcription in Human Coronary Artery Endothelial Cells: New AP-1 Site and Negative Regulator

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Yiwei Liu ◽  
Lingxin Zhang ◽  
Chuan Wang ◽  
Shama Roy ◽  
Jianzhong Shen
Keyword(s):  
Endothelial Cells ◽  
Coronary Artery ◽  
Tissue Factor ◽  
Promoter Activity ◽  
Purinergic Receptor ◽  
Consensus Sequence ◽  
Negative Regulator ◽  
Coagulation Cascade ◽  
Human Coronary Artery

Previously we reported that the P2Y2 receptor (P2Y2R) is one of the predominant purinergic receptors expressed in human coronary artery endothelial cells (HCAEC), and that P2Y2R activation by ATP or UTP induces dramatic up-regulation of tissue factor (TF), key initiator of the coagulation cascade. However, the molecular mechanism of this P2Y2R-TF axis remains unclear. Here we report a role of a newly identified AP-1 consensus sequence along with its new binding components in P2Y2R regulation of TF transcription. We identified with bioinformatics tools that a novel AP-1 site at -1363 bp of human TF promoter region is highly conserved across multiple species. P2Y2R activation increased TF promoter activity and mRNA expression in HCAEC. Truncation, deletion, and mutation of this new distal AP-1 site all significantly supressed TF promoter activity in response to P2Y2R activation. EMSA and ChIP assays further confirmed that upon P2Y2R activation, c-Jun, ATF-2 and Fra-1, but not the typical c-Fos, bound to the new AP-1 site. In addition, loss-of-function studies using siRNAs confirmed a positive transactivation role of c-Jun and ATF-2, but unexpectedly revealed a strong negative role of Fra-1 in P2Y2R-induced TF up-regulation. Furthermore, we found that P2Y2R activation promoted ERK1/2 phosphorylation, leading to Fra-1 activation while JNK activated c-Jun and ATF-2. These findings reveal the basis for P2Y purinergic receptor regulation of endothelial TF expression and indicate that targeting the P2Y2R-Fra-1-TF pathway may be an attractive new strategy in control of vascular thrombogenicity and/or inflammation associated with endothelial dysfunction.

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

Blood ◽  
2012 ◽  
Vol 119 (4) ◽  
pp. 924-932 ◽  
Author(s):  
Yascha W. van den Berg ◽  
Susanne Osanto ◽  
Pieter H. Reitsma ◽  
Henri H. Versteeg
Keyword(s):  
Tumor Growth ◽  
Tissue Factor ◽  
Cancer Progression ◽  
Tumor Angiogenesis ◽  
Factor Viia ◽  
Coagulation Factor ◽  
Coagulation Cascade ◽  
Cancer Subtypes ◽  
Tumor Cell Behavior

Abstract 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 TF-dependent 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.

scholarly journals TMEM88 is a Prognostic Biomarker and Correlates With Immune Infiltrates in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Andrew Liman ◽  
Yang Gu ◽  
Pengpeng Liu ◽  
Quanyan Liu
Keyword(s):  
Liver Cancer ◽  
Cancer Progression ◽  
Prognostic Biomarker ◽  
Progression Free Survival ◽  
Free Survival ◽  
Multiple Tumor ◽  
Normal Tissues ◽  
Tumor Types ◽  
Disease Stages

Abstract BackgroundTransmembrane protein 88 (TMEM88) has emerged as a newly discovered cancer-related protein that acts as a cancer-promoting or cancer-inhibiting regulator in multiple tumor types. However, the exact role of TMEM88 in liver cancer is undetermined. The current study was designed to determine the expression of TMEM88 in liver cancer. ResultsTMEM88 expression was significantly lower in several human cancers, but higher in liver and bile cancer, than in corresponding normal tissues. TMEM88 expression in HCC tissues correlated with prognosis. Low TMEM88 expression associated with poorer overall survival, disease-specific survival, progression-free survival, and relapse-free survival in multiple cohorts of HCC patients, particularly at late disease stages (grade 2 and 3). TMEM88 showed strong correlation with tumor-infiltrating B cells, CD4+ and CD8+ T cells, macrophages, neutrophils, and dendritic cells. ConclusionThese findings demonstrate that TMEM88 is a potential prognostic biomarker that determines cancer progression and correlated with tumor immune cells infiltration in HCC.

Tissue Factor Internalization and Trafficking in Fibroblasts: Involvement of Protease Activated Receptors-Mediated Cell Signaling.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 541-541
Author(s):  
Samir K. Mandal ◽  
Usha R. Pendurthi ◽  
L. Vijaya Mohan Rao
Keyword(s):  
Cell Surface ◽  
Cell Signaling ◽  
Tissue Factor ◽  
Protease Activity ◽  
Lung Epithelial Cells ◽  
Lung Fibroblasts ◽  
Coagulation Cascade ◽  
Clotting Factor ◽  
Outer Cell

Abstract Tissue factor (TF) is the cellular receptor for clotting factor VIIa (FVIIa) and the formation of TF-FVIIa complexes on cell surfaces triggers the activation of coagulation cascade and cell signaling. TF is constitutively expressed in many extravascular cells, including fibroblasts and pericytes in and surrounding blood vessel walls, and lung epithelial cells. Our recent studies (Blood2006; 107:4746–4753) show that a majority of TF resides in various intracellular compartments, predominantly in the Golgi. FVIIa binding to cell surface TF induces the internalization of TF, and interestingly, mobilizes the Golgi TF pool and transports it to the outer cell surface. This process is dependent on FVIIa protease activity. This present study is aimed to elucidate potential mechanisms involved in TF internalization and the mobilization from the Golgi. Since studies from our laboratory and others showed that TF-FVIIa could activate protease-activated receptor (PAR)-mediated cell signaling and FVIIa protease activity is required for FVIIa-dependent internalization and trafficking of TF, we hypothesize that TF-VIIa activation of PAR1 or PAR2 plays a role in TF internalization and trafficking. To test this hypothesis, we first examined the role of PAR activation in TF-internalization and trafficking. Lung fibroblasts (WI-38 cells) were exposed to a variety of PAR activators, PAR activating peptide agonists (AP) and various proteases, and TF internalization and trafficking was evaluated by measuring the cell surface TF antigen and activity levels, internalization of cell surface TF (by using biotinylation of cell surface receptors and immunoprecipitation techniques) and mobilization of TF from the Golgi (by immunofluorescence confocal microscopy). PAR1 AP and PAR2 AP treatments increased the TF activity and antigen levels at the cell surface by 20 to 50% whereas PAR3 AP and PAR4 AP had no effect on cell surface TF activity and antigen levels. Cell surface TF activity and antigen levels were also increased slightly in fibroblasts exposed to thrombin and trypsin. Confocal microscopic image analysis of distribution of TF and the Golgi protein (golgin-97) revealed that about 85% of the untreated cells possess intact Golgi TF pool with high degree of colocalization with golgin-97 whereas as only 20–30% of FVIIa, thrombin, trypsin, PAR1 AP or PAR2 AP-treated cells had TF pool in the Golgi. Plasmin and FXa had moderate effect on TF mobilization from the Golgi. No detectable differences were found between control (untreated) cells and cells treated with either FFR-FVIIa, APC, PAR3 AP or PAR4 AP. Next, we investigated the role of PAR1 and PAR2 activation in FVIIa-mediated TF internalization and trafficking. Pretreatment of fibroblasts with PAR2 but not PAR1 activation blocking antibodies attenuated FVIIa-mediated Golgi TF mobilization. Consistent with these data, silencing PAR2 receptor by siRNA technique completely blocked FVIIa-mediated Golgi TF mobilization whereas PAR1 siRNA transfection had no effect (in control studies, we showed PAR1 antibodies or PAR1si RNA transfection blocked thrombin-mediated TF mobilization). Additional studies showed a significant internalization of TF in cells exposed to FVIIa which was completely blocked by silencing PAR2 but not PAR1. Overall the data provided herein suggest a novel mechanism by which tissue factor expression is regulated at the cell surface.

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