Gene/Protein Disease Symptom Drug Enzyme Compound
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 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It 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.
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PMID:Role of Tissue Factor in Tumor Progression and Cancer-Associated Thrombosis. 3109 12

There are emerging linkages between biological and genetic aspects of cancer progression and the mechanisms of cancer-associated thrombosis. It is argued that reciprocal influences between cancer cells, their associated vascular stroma, and the hemostatic system may shape the mechanism of coagulopathy. In this regard, glioblastoma multiforme offers a paradigm where the prevalent occurrence of local microthrombosis and peripheral venous thromboembolism can be linked to the profiles of oncogenic driver mutations and their impact on the expression of coagulation-related genes (coagulome). These relationships can be recapitulated in cellular models of glioblastoma, where the expression of tissue factor, podoplanin, and the release of procoagulant microparticles (extracellular vesicles) remains under the control of oncogenic pathways (epidermal growth factor receptor variant III, isocitrate dehydrogenase 1). These pathways define molecular subtypes of glioblastoma that express differential coagulomes. Moreover, single-cell sequencing of glioblastoma samples reveals a combinatorial rather than common profile of both subtype markers and coagulation-related genes. Based on these emerging observations, the authors suggest that cancers may operate as coagulant composites, where individual cells and their dominant populations express different procoagulant phenotypes, resulting in the net impact on the hemostatic system. They suggest that relating these mechanisms to clinical presentations of thrombosis may facilitate a more causality-based, personalized, and possibly cancer-specific thromboprophylaxis and treatment.
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PMID:Oncogenes and Clotting Factors: The Emerging Role of Tumor Cell Genome and Epigenome in Cancer-Associated Thrombosis. 3109 13

Within tumors, the coagulation-inducing protein tissue factor (TF), a major initiator of blood coagulation, has been shown to play a critical role in the hematogenous metastasis of tumors, due to its effects on tumor hypercoagulability and on the mediation of interactions between platelets and tumor cells. Targeting tumor-associated TF has therefore great therapeutic potential for antimetastasis therapy and preventing thrombotic complication in cancer patients. Herein, we reported a novel peptide-based nanoparticle that targets delivery and release of small interfering RNA (siRNA) into the tumor site to silence the expression of tumor-associated TF. We showed that suppression of TF expression in tumor cells blocks platelet adhesion surrounding tumor cells in vitro. The downregulation of TF expression in intravenously administered tumor cells (i.e., simulated circulating tumor cells [CTCs]) prevented platelet adhesion around CTCs and decreased CTCs survival in the lung. In a breast cancer mouse model, siRNA-containing nanoparticles efficiently attenuated TF expression in the tumor microenvironment and remarkably reduced the amount of lung metastases in both an experimental lung metastasis model and tumor-bearing mice. What's more, this strategy reversed the hypercoagulable state of the tumor bearing mice by decreasing the generation of thrombin-antithrombin complexes (TAT) and activated platelets, both of which are downstream products of TF. Our study describes a promising approach to combat metastasis and prevent cancer-associated thrombosis, which advances TF as a therapeutic target toward clinic applications.
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PMID:Tumor-Specific Silencing of Tissue Factor Suppresses Metastasis and Prevents Cancer-Associated Hypercoagulability. 3118 Jun 84

Recent studies have demonstrated a role of neutrophils in both venous and arterial thrombosis. A key prothrombotic feature of neutrophils is their ability to release web-like structures composed of DNA filaments coated with histones and granule proteins referred to as neutrophil extracellular traps (NETs). NETs were discovered over a decade ago as part of our first line of host defense against invading microorganisms. Although NETs have a protective role against pathogens, recent data suggest that an uncontrolled and excessive NET formation within the vasculature may contribute to pathological thrombotic disorders. In vitro studies suggest that NETs promote vessel occlusion by providing a scaffold for platelets, red blood cells, extracellular vesicles, and procoagulant molecules, such as von Willebrand factor and tissue factor. In addition, NET components enhance coagulation by both activating the intrinsic pathway and degrading an inhibitor of the extrinsic pathway (tissue factor pathway inhibitor). NET formation has, therefore, been proposed to contribute to thrombus formation and propagation in arterial, venous, and cancer-associated thrombosis. This review will describe animal and human studies suggesting a role of NETs in the pathogenesis of various thrombotic disorders. Targeting NETs may be a novel approach to reduce thrombosis without affecting hemostasis.
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PMID:Neutrophil Extracellular Traps: Villains and Targets in Arterial, Venous, and Cancer-Associated Thrombosis 3131 34

Venous thromboembolism is known to be associated with an increase in morbidity and mortality in patients with malignancy. Predictive laboratory biomarkers of venous thromboembolism (VTE) have long been sought after to improve outcomes and help guide clinical decision making. Previously studied biomarkers include C reactive protein (CRP), tissue factor expressing microparticles (TF MP), D-dimer, soluble P-selectin (sP-selectin), plasminogen activator inhibitor 1 (PAI-1), factor VIII, platelet count, and leukocyte counts. This chapter will focus on these possible biomarkers for cancer-associated thrombosis (CAT) with particular emphasis on the pathophysiology behind thrombosis formation as well as data from clinical studies in patients with malignancy. The incorporation of the above biomarkers into risk assessment tools to predict CAT will also be reviewed, as will risk factors for recurrent VTE in patients with malignancy. Further studies are ongoing to develop readily available biomarkers that can be incorporated into future risk assessment models with the goal of reducing morbidity and mortality due to cancer-associated thrombosis.
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PMID:Biomarkers of Cancer-Associated Thromboembolism. 3131 81

It has long been recognised that pancreatic cancer induces a hypercoagulable state that may lead to clinically apparent thrombosis. Although the relationship between pancreatic cancer and hypercoagulability is well described, the underlying pathological mechanism(s) and the interplay between these pathways remain a matter of intensive study. This review summarises existing data on epidemiology and pathogenesis of thrombotic complications in pancreatic cancer with a particular emphasis on novel pathophysiological pathways. Pancreatic cancer is characterised by high tumoural expression of tissue factor, activation of leukocytes with the release of neutrophil extracellular traps, the dissemination of tumour-derived microvesicles that promote hypercoagulability and increased platelet activation. Furthermore, other coagulation pathways probably contribute to these processes, such as those that involve heparanase, podoplanin and hypofibrinolysis. In the era in which heparin and its derivatives-the currently recommended therapy for cancer-associated thrombosis-might be superseded by direct oral anticoagulants, novel data from mouse models of cancer-associated thrombosis suggest the possibility of future personalised therapeutic approaches. In this dynamic era for cancer-associated thrombosis, the discovery of novel prothrombotic and proinflammatory mechanisms will potentially uncover pharmacological targets to prevent and treat thrombosis without adversely affecting haemostasis.
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PMID:The relationship between pancreatic cancer and hypercoagulability: a comprehensive review on epidemiological and biological issues. 3132 67

The establishment of prothrombotic states during cancer progression is well reported but the precise mechanisms underlying this process remain elusive. A number of studies have implicated the presence of the clotting initiator protein, tissue factor (TF), in circulating tumor-derived extracellular vesicles (EVs) with thrombotic manifestations in certain cancer types. Tumor cells, as well as tumor-derived EVs, may activate and promote platelet aggregation by TF-dependent and independent pathways. Cancer cells and their secreted EVs may also facilitate the formation of neutrophil extracellular traps (NETs), which may contribute to thrombus development. Alternatively, the presence of polyphosphate (polyP) in tumor-derived EVs may promote thrombosis through a TF-independent route. We conclude that the contribution of EVs to cancer coagulopathy is quite complex, in which one or more mechanisms may take place in a certain cancer type. In this context, strategies that could attenuate the crosstalk between the proposed pro-hemostatic routes could potentially reduce cancer-associated thrombosis.
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PMID:Novel Aspects of Extracellular Vesicles as Mediators of Cancer-Associated Thrombosis. 3133 34

Cancer-related venous thromboembolism (VTE) is frequent and constitutes the second leading cause of death in patients with cancer. High platelet count is one of independent predictive factors of cancer-associated VTE. Besides the implication of platelets in cancer-associated VTE, recent clinical and experimental evidences support that platelets play several roles in the progression of malignancies and inversely, cancer can also influence platelet count and activity. The objective of this report is to review the current literature regarding the role of platelets in cancer through experimental results and population-based studies. Platelets are implicated in cancer progression and metastasis through proangiogenic factors (growth factors and signaling pathways), antiangiogenic factors (angiostatin, endostatin, thrombospondin-1), and matrix metalloproteinases. In addition, platelets are involved in cancer-associated thrombosis and thus tumor cell-induced platelet activation, through anionic phospholipids on their surface, released soluble factors, such as P-selectin, CD40 ligand, platelet factor 4, thrombospondin-1 or beta-thromboglobulin, tumor cell procoagulant proteins (tissue factor, urokinase-type plasminogen activator, plasminogen activator inhibitor type 1), and microparticles. Due to these different mechanisms, platelets may represent a potential therapeutic target. The main current treatments against platelets are: (1) acetylsalicylic acid (aspirin) and nonsteroidal anti-inflammatory drugs, nonselective cyclo-oxygenase (COX)-1 and COX-2 inhibitors, which are associated with decreased cancer incidence and better overall survival and (2) irreversible inhibitor of P2Y12 subtype which decreases cancer incidence. Platelets are key players in tumor growth, metastasis, and cancer-associated thrombosis. This multifaceted role identifies them as a relevant therapeutic target for prevention of cancer occurrence and treatment of cancer.
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PMID:Involvement of Platelets in Cancers. 3138 5

Microvesicles (MVs) are small membrane enclosed structures released into the extracellular space by virtually all cell types. Their composition varies according to the cell origin and the stimulus which caused their formation. They harbor functional molecules and participate in intercellular communication. Endothelium, inflammatory cells, and cancer cells produce procoagulant MVs which contribute to cancer-associated thrombosis (CAT) in animal models. The tissue factor (TF) conveyed by these MVs was shown to play a key role in different animal models of experimental CAT. Alternatively, other molecular mechanisms involving polyphosphates or phosphatidylethanolamine could also be involved. In clinical practice, an association between an increase in the number of TF-positive or the procoagulant activity of these MVs and the occurrence of CAT has indeed been demonstrated in pancreatic-biliary cancers, suggesting that they could behave as a biomarker predictive for CAT. However, to date, this association was not confirmed in other types of cancer. Potential causes explaining this limited associated between MVs and CAT are (1) the diversity of mechanisms associating MVs and different types of cancer; (2) a more complex role of MVs in hemostasis integrating their anticoagulant and fibrinolytic activity; and (3) the lack of sensitivity, reproducibility, and standardization of current methodologies permitting measurement of MVs. Each of these hypotheses constitutes an interesting exploration path for a future reassessment of the clinical interest of the MVs in CAT.
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PMID:Microvesicles and Cancer Associated Thrombosis. 3143 Jul 86

Cancer patients have an increased risk of venous thromboembolism (VTE). The rate of VTE varies with cancer type, with pancreatic cancer having one of the highest rates, suggesting that there are cancer type-specific mechanisms of VTE. Risk assessment scores, such as the Khorana score, have been developed to identify ambulatory cancer patients at high risk of VTE. However, the Khorana score performed poorly in discriminating pancreatic cancer patients at risk of VTE. Currently, thromboprophylaxis is not recommended for cancer outpatients. Recent clinical trials showed that factor Xa (FXa) inhibitors reduced VTE in high-risk cancer patients but also increased major bleeding. Understanding the mechanisms of cancer-associated thrombosis should lead to the development of safer antithrombotic drugs. Mouse models can be used to study the role of different prothrombotic pathways in cancer-associated thrombosis. Human and mouse studies support the notion that 2 prothrombotic pathways contribute to VTE in pancreatic cancer patients: tumor-derived, tissue factor-positive (TF+) extracellular vesicles (EVs), and neutrophils and neutrophil extracellular traps (NETs). In pancreatic cancer patients, elevated levels of plasma EVTF activity and citrullinated histone H3 (H3Cit), a NET biomarker, are independently associated with VTE. We observed increased levels of circulating tumor-derived TF+ EVs, neutrophils, cell-free DNA, and H3Cit in nude mice bearing human pancreatic tumors. Importantly, inhibition of tumor-derived human TF, depletion of neutrophils, or administration of DNAse I to degrade cell-free DNA (including NETs) reduced venous thrombosis in tumor-bearing mice. These studies demonstrate that tumor-derived TF+ EVs, neutrophils, and cell-free DNA contribute to venous thrombosis in a mouse model of pancreatic cancer.
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PMID:Update from the laboratory: mechanistic studies of pathways of cancer-associated venous thrombosis using mouse models. 3180 71


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