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Critical Reviews in Biochemistry and... 2015The plasma coagulation system in mammalian blood consists of a cascade of enzyme activation events in which serine proteases activate the proteins (proenzymes and... (Review)
Review
The plasma coagulation system in mammalian blood consists of a cascade of enzyme activation events in which serine proteases activate the proteins (proenzymes and procofactors) in the next step of the cascade via limited proteolysis. The ultimate outcome is the polymerization of fibrin and the activation of platelets, leading to a blood clot. This process is protective, as it prevents excessive blood loss following injury (normal hemostasis). Unfortunately, the blood clotting system can also lead to unwanted blood clots inside blood vessels (pathologic thrombosis), which is a leading cause of disability and death in the developed world. There are two main mechanisms for triggering the blood clotting, termed the tissue factor pathway and the contact pathway. Only one of these pathways (the tissue factor pathway) functions in normal hemostasis. Both pathways, however, are thought to contribute to thrombosis. An emerging concept is that the contact pathway functions in host pathogen defenses. This review focuses on how the initiation phase of the blood clotting cascade is regulated in both pathways, with a discussion of the contributions of these pathways to hemostasis versus thrombosis.
Topics: Animals; Blood Coagulation; Hemostasis; Humans; Models, Biological; Platelet Activation; Proteolysis; Thromboplastin; Thrombosis
PubMed: 26018600
DOI: 10.3109/10409238.2015.1050550 -
Thrombosis Research May 2012Tissue factor plays a primary role in both hemorrhage control and thrombosis depending upon whether its presentation is extravascular or intravascular. The molecular... (Review)
Review
Tissue factor plays a primary role in both hemorrhage control and thrombosis depending upon whether its presentation is extravascular or intravascular. The molecular architecture and function of the tissue factor molecule and its role in the activations of factor IX and factor X have been elegantly elucidated but controversies prevail with respect to distinctions between tissue factor sources and tissue factor "activity." This presentation will review data on the architecture and functions of the tissue factor-factor VIIa complex and discuss the elements of the controversies associated with tissue factor presentation in both normal and pathologic milieu.
Topics: Animals; Factor VIIa; Humans; Models, Molecular; Thromboplastin
PubMed: 22401799
DOI: 10.1016/j.thromres.2012.02.018 -
Journal of Atherosclerosis and... 2015Atherosclerosis is a progressive disease characterized by the accumulation of lipids in medium to large sized arteries. Atherothrombosis is a term used to describe... (Review)
Review
Atherosclerosis is a progressive disease characterized by the accumulation of lipids in medium to large sized arteries. Atherothrombosis is a term used to describe formation of a thrombus after rupture of an atherosclerotic plaque. Thrombosis can lead to myocardial infarction and stroke. Risk factors for atherosclerosis include hyperlipidemia, diabetes, smoking and hypertension all of which increase tissue factor (TF) expression. High levels of TF are present in atherosclerotic plaques due to expression by macrophages and vascular smooth muscle cells and the presence of cell-derived TF-positive microvesicles (MVs). In addition, hyperlipidemia leads to the formation of oxidized LDL, which induces TF expression in circulating monocytes and the release of TF-positive MVs. The major source of TF that drives thrombosis after plaque rupture is TF within the plaque. However, TF in the blood on monocytes and MVs may also contribute the thrombosis. Inhibition of the TF/factor VIIa complex is unlikely to be an effective strategy to reduce atherothrombosis due the essential role of the complex in hemostasis. However, selective blockade of pathologic TF without affecting protective TF may be effective in reducing atherothrombosis. For instance, statins have been shown to reduce TF expression in the plaque and in circulating monocytes, which would be expected to reduce thrombosis. Further studies are needed to determine safe strategies to reduce pathologic TF expression and atherothrombosis.
Topics: Animals; Humans; Plaque, Atherosclerotic; Thromboplastin; Thrombosis
PubMed: 26016513
DOI: 10.5551/jat.30940 -
Seminars in Thrombosis and Hemostasis Jun 2019There is a strong relationship between tissue factor (TF) and cancer. Many cancer cells express high levels of both full-length TF and alternatively spliced (as) TF. TF... (Review)
Review
There is a strong relationship between tissue factor (TF) and cancer. Many cancer cells express high levels of both full-length TF and alternatively spliced (as) TF. TF expression in cancer is associated with poor prognosis. In this review, the authors summarize the regulation of TF expression in cancer cells and the roles of TF and asTF in tumor growth and metastasis. A variety of different signaling pathways, transcription factors and micro ribonucleic acids regulate TF gene expression in cancer cells. The TF/factor VIIa complex enhances tumor growth by activating protease-activated receptor 2 signaling and by increasing the expression of angiogenic factors, such as vascular endothelial growth factor. AsTF increases tumor growth by enhancing integrin β1 signaling. TF and asTF also contribute to metastasis via multiple thrombin-dependent and independent mechanisms that include protecting tumor cells from natural killer cells. Finally, a novel anticancer therapy is using tumor TF as a target to deliver cytotoxic drugs to the tumor. TF may be useful in diagnosis, prognosis, and treatment of cancer.
Topics: Gene Expression Regulation, Neoplastic; Humans; Immunoconjugates; Molecular Targeted Therapy; Neoplasm Metastasis; Neoplasms; Prognosis; Signal Transduction; Thromboplastin; Vascular Endothelial Growth Factor A
PubMed: 31096306
DOI: 10.1055/s-0039-1687894 -
Yakugaku Zasshi : Journal of the... 2017Recent advances in antibody-drug conjugate (ADC) technology have shown considerable promise in targeted cancer therapy. The ADC strategy should be confined to highly... (Review)
Review
Recent advances in antibody-drug conjugate (ADC) technology have shown considerable promise in targeted cancer therapy. The ADC strategy should be confined to highly toxic anticancer agents and not to ordinary anti-cancer agents (ACAs) because the affinity of monoclonal antibodies (mAbs) diminishes if more than three ACA molecules are conjugated. According to this principle, higher amounts of ADC should be administered so that each of the ACAs is conjugated to the mAbs. Therefore for an ordinary ACA, nanoparticles should be the preferred drug delivery system (DDS). A large body of clinical evidence indicates that abnormal coagulation occurs in a variety of cancer patients, especially in invasive cancers. Tissue factor (TF), expressed on the surface of various cancer cells and tumor vascular endothelial cells, is the trigger protein of extrinsic coagulation resulting in insoluble fibrin formation. We have developed mAbs against TF and human fibrin that reacted only with human fibrin and not with human fibrinogen. We now propose cancer stromal targeting (CAST) therapy and diagnosis, using a cytotoxic agent or radioisotope conjugated to a monoclonal Ab directed at a specific inert constituent of the tumor stroma, as a new modality especially for invasive cancer.
Topics: Antibodies, Monoclonal; Drug Delivery Systems; Fibrin; Humans; Immunoconjugates; Molecular Targeted Therapy; Nanoparticles; Neoplasms; Thromboplastin
PubMed: 28458284
DOI: 10.1248/yakushi.16-00255-2 -
Blood Advances Mar 2021Vascular anomalies, including local and peripheral thrombosis, are a hallmark of glioblastoma (GBM) and an aftermath of deregulation of the cancer cell genome and...
Vascular anomalies, including local and peripheral thrombosis, are a hallmark of glioblastoma (GBM) and an aftermath of deregulation of the cancer cell genome and epigenome. Although the molecular effectors of these changes are poorly understood, the upregulation of podoplanin (PDPN) by cancer cells has recently been linked to an increased risk for venous thromboembolism (VTE) in GBM patients. Therefore, regulation of this platelet-activating protein by transforming events in cancer cells is of considerable interest. We used single-cell and bulk transcriptome data mining, as well as cellular and xenograft models in mice, to analyze the nature of cells expressing PDPN, as well as their impact on the activation of the coagulation system and platelets. We report that PDPN is expressed by distinct (mesenchymal) GBM cell subpopulations and downregulated by oncogenic mutations of EGFR and IDH1 genes, along with changes in chromatin modifications (enhancer of zeste homolog 2) and DNA methylation. Glioma cells exteriorize their PDPN and/or tissue factor (TF) as cargo of exosome-like extracellular vesicles (EVs) shed from cells in vitro and in vivo. Injection of glioma-derived podoplanin carrying extracelluar vesicles (PDPN-EVs) activates platelets, whereas tissue factor carrying extracellular vesicles (TF-EVs) activate the clotting cascade. Similarly, an increase in platelet activation (platelet factor 4) or coagulation (D-dimer) markers occurs in mice harboring the corresponding glioma xenografts expressing PDPN or TF, respectively. Coexpression of PDPN and TF by GBM cells cooperatively affects tumor microthrombosis. Thus, in GBM, distinct cellular subsets drive multiple facets of cancer-associated thrombosis and may represent targets for phenotype- and cell type-based diagnosis and antithrombotic intervention.
Topics: Animals; Extracellular Vesicles; Glioblastoma; Glioma; Humans; Mice; Thromboplastin; Thrombosis
PubMed: 33720339
DOI: 10.1182/bloodadvances.2020002998 -
International Journal of Cancer Aug 2015Tissue Factor (TF) is an evolutionary conserved glycoprotein, which is of immense importance for a variety of biologic processes. TF is expressed in two naturally... (Review)
Review
Tissue Factor (TF) is an evolutionary conserved glycoprotein, which is of immense importance for a variety of biologic processes. TF is expressed in two naturally occurring protein isoforms, membrane-bound "full-length" (fl)TF and soluble alternatively spliced (as)TF. The TF isoform expression is differentially modulated on post-transcriptional level via regulatory factors, such as serine/arginine-rich (SR) proteins, SR protein kinases and micro (mi)RNAs. Both isoforms mediate a variety of physiologic- and pathophysiologic-relevant functions, such as thrombogenicity, angiogenesis, cell signaling, tumor cell proliferation and metastasis. In this review, we will depict the main mechanisms regulating the TF isoform expression in cancer and under other pathophysiologic-relevant conditions. Moreover, we will summarize and discuss the latest findings regarding the role of TF and its isoforms in cancer biology.
Topics: Alternative Splicing; Animals; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Protein Isoforms; RNA Interference; RNA Processing, Post-Transcriptional; Signal Transduction; Thromboplastin
PubMed: 24806794
DOI: 10.1002/ijc.28959 -
Thrombosis Research May 2012Tissue factor (TF)-initiated coagulation plays a critical role in both hemostasis and thrombosis. It is generally believed that most of the tissue factor expressed on... (Review)
Review
Tissue factor (TF)-initiated coagulation plays a critical role in both hemostasis and thrombosis. It is generally believed that most of the tissue factor expressed on cell surfaces is maintained in a cryptic, i.e., coagulantly inactive state and an activation step (decryption) is required for the expression of maximum TF procoagulant activity. However, what exactly constitutes cryptic or procoagulant TF, molecular differences between these two forms and mechanisms that are responsible for transformation from one to the other form are not entirely clear and remain highly controversial, thus are a matter of ongoing debate. This brief review discusses pertinent literature on TF encryption/decryption with specific emphasis on the role of membrane phospholipids and reduction/oxidation of the TF Cys186-Cys209 disulfide bond in regulating TF activity at cell surfaces.
Topics: Factor VIIa; Humans; Protein Binding; Signal Transduction; Thromboplastin
PubMed: 22398016
DOI: 10.1016/j.thromres.2012.02.021 -
Current Atherosclerosis Reports Oct 2012Tissue factor (TF) is abundantly present in atherosclerotic plaques and it is the primary source of TF that triggers the rapid activation of the coagulation cascade... (Review)
Review
Tissue factor (TF) is abundantly present in atherosclerotic plaques and it is the primary source of TF that triggers the rapid activation of the coagulation cascade after plaque rupture. While much of this TF is associated with monocyte/macrophages and vascular smooth muscle cells, recent studies suggests TF-positive microparticles (MPs) are the most abundant source in plaques. Further, while intravascular TF is largely absent in healthy patients, cardiovascular disease patients have increased TF expression in circulating monocytes, which can result in increased levels of TF-positive MPs. This brief review describes how TF is the primary initiator of atherothrombosis and how TF-positive MPs may serve as a biomarker to identify patients at greater risk of forming an occlusive thrombus. In addition, currently used therapeutics, such as statins and inhibitors of the renin angiotensin system, may have additional benefits by reducing TF expression and subsequent thrombosis.
Topics: Biomarkers; Blood Coagulation; Hemostasis; Humans; Plaque, Atherosclerotic; Thromboplastin; Thrombosis
PubMed: 22886473
DOI: 10.1007/s11883-012-0269-5 -
Cells Mar 2023Syndecan-1 (Sdc-1) upregulation is associated with poor prognosis in breast cancer. Sdc-1 knockdown results in reduced angiogenesis and the dysregulation of tissue...
Syndecan-1 (Sdc-1) upregulation is associated with poor prognosis in breast cancer. Sdc-1 knockdown results in reduced angiogenesis and the dysregulation of tissue factor (TF) pathway constituents. Here, we evaluate the regulatory mechanisms and functional consequences of the Sdc-1/TF-axis using Sdc-1 knockdown and overexpression approaches in MCF-7 and MDA-MB-231 breast cancer cells. Gene expression was analyzed by means of qPCR. Thrombin generation and cell migration were detected. Cell-cycle progression and apoptosis were investigated using flow cytometry. In MDA-MB-231 cells, IL6, IL8, VEGF, and IGFR-dependent signaling affected TF pathway expression depending on Sdc-1. Notably, Sdc-1 depletion and TF pathway inhibitor (TFPI) synergistically affected PTEN, MAPK, and STAT3 signaling. At the functional level, the antiproliferative and pro-apoptotic effects of TFPI depended on Sdc-1, whereas Sdc-1's modulation of cell motility was not affected by TFPI. Sdc-1 overexpression in MCF-7 and MDA-MB-231 cells led to increased TF expression, inducing a procoagulative phenotype, as indicated by the activation of human platelets and increased thrombin formation. A novel understanding of the functional interplay between Sdc-1 and the TF pathway may be compatible with the classical co-receptor role of Sdc-1 in cytokine signaling. This opens up the possibility of a new functional understanding, with Sdc-1 fostering coagulation and platelet communication as the key to the hematogenous metastatic spread of breast cancer cells.
Topics: Female; Humans; Breast Neoplasms; Signal Transduction; Syndecan-1; Thrombin; Thromboplastin
PubMed: 36980251
DOI: 10.3390/cells12060910