Distinct Pathogenesis of Pancreatic Cancer Microvesicle–Associated Venous Thrombosis Identifies New Antithrombotic Targets In Vivo

Stark, Konstantin; Schubert, Irene; Joshi, Urjita; Kilani, Badr; Hoseinpour, Parandis; Thakur, Manovriti; Grünauer, Petra; Pfeiler, Susanne; Schmidergall, Tobias; Stockhausen, Sven; Bäumer, Markus; Chandraratne, Sue; Brühl, Marie-Luise von; Lorenz, Michael; Coletti, Raffaele; Reese, Sven; Laitinen, Ilina; Wörmann, Sonja M.; Algül, Hana; Bruns, Christiane; Ware, Jerry; Mackman, Nigel; Engelmann, Bernd; Maßberg, Steffen

doi:10.1161/atvbaha.117.310262

Cited by 45 publications

(42 citation statements)

References 74 publications

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“…Disrupting PE dependent activation of factor X suppressed pancreatic MVs induced DVTwithout causing changes in hemostasis. 65 In terms of therapy, this study confirms the observation that low molecular weight heparins are effective for prevention and treatment of CAT 66,67 but also suggests that oral actor Xa inhibitors may also be even more effective and tolerated. 68 In other cancers, TF is not necessary the major pathway by which MVs can promote VTE.…”

Section: Microvesicles and The Diversity Of Cancer Associated Thrombosupporting

confidence: 75%

“…64 Beside TF pathway, another alternative novel pathway was also recently reported, using an IVC flow restricted model and strains of genetically engineered mice lacking GP1b or expressing reduced levels of TF. 65 The mechanisms are independent of platelets and myeloid cells and involve the synergistic activation of coagulation by pancreatic MVs and host TF. A major contribution of the procoagulant activity of pancreatic MVs was provided by phosphatidylethanolamine (PE) externalization which supported robust generation of Xa (►Fig.…”

Section: Microvesicles and The Diversity Of Cancer Associated Thrombomentioning

confidence: 99%

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Microvesicles and Cancer Associated Thrombosis

Lacroix

Vallier

Bonifay

et al. 2019

Semin Thromb Hemost

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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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Section: Microvesicles and The Diversity Of Cancer Associated Thrombosupporting

confidence: 75%

Section: Microvesicles and The Diversity Of Cancer Associated Thrombomentioning

confidence: 99%

Microvesicles and Cancer Associated Thrombosis

Lacroix

Vallier

Bonifay

et al. 2019

Semin Thromb Hemost

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“…Although PS is detectable after activation on macrophages and derived EV, the procoagulant activity of EV is most efficiently inhibited by duramycin, an antagonist of PE, and less so by lactadherin, which specifically blocks PS . PE is emerging as an important lipid in thrombosis because it also supports the prothrombotic activity of cancer cell‐derived EV . A challenge for future translational coagulation research will be the development of assay systems incorporating such lipid components, which in cell‐based and preclinical models emerged as relevant coagulation amplifiers.…”

Section: Myeloid Cell Tf Activation In the Context Of Inflammationmentioning

confidence: 99%

Tissue factor at the crossroad of coagulation and cell signaling

Zelaya

Rothmeier

Ruf

2018

Journal of Thrombosis and Haemostasis

135

123

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The tissue factor (TF) pathway plays a central role in hemostasis and thrombo-inflammatory diseases. Although structure-function relationships of the TF initiation complex are elucidated, new facets of the dynamic regulation of TF's activities in cells continue to emerge. Cellular pathways that render TF non-coagulant participate in signaling of distinct TF complexes with associated proteases through the protease-activated receptor (PAR) family of G protein-coupled receptors. Additional co-receptors, including the endothelial protein C receptor (EPCR) and integrins, confer signaling specificity by directing subcellular localization and trafficking. We here review how TF is switched between its role in coagulation and cell signaling through thiol-disulfide exchange reactions in the context of physiologically relevant lipid microdomains. Inflammatory mediators, including reactive oxygen species, activators of the inflammasome, and the complement cascade play pivotal roles in TF procoagulant activation on monocytes, macrophages and endothelial cells. We furthermore discuss how TF, intracellular ligands, co-receptors and associated proteases are integrated in PAR-dependent cell signaling pathways controlling innate immunity, cancer and metabolic inflammation. Knowledge of the precise interactions of TF in coagulation and cell signaling is important for understanding effects of new anticoagulants beyond thrombosis and identification of new applications of these drugs for potential additional therapeutic benefits.

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“…For example, structural, mechanistic, and disease-specific properties of the clot formation process are generally not factored into prophylactic or therapeutic protocols and neither are the intricacies of regulatory balances in specific cases, spatial distribution of coagulation effectors such as TF, role of microparticles (MPs), myeloid cells and platelets, heterogeneity of the vasculature, fine architecture of the fibrin polymer, or other biologically meaningful but difficult to measure individual variables. 28,33,34 Nonetheless, efforts are underway to understand what is unique about pathological thrombosis versus physiological hemostasis and, more specifically, what are the upstream and more cancerspecific causes (inducers and modulators) of CAT in comparison to cancer-unrelated mechanisms of thrombosis. 4,9 The emerging picture suggests that some of the elements of the coagulation cascade may be nonessential for hemostasis (e.g., FXII) and thereby potentially targetable in the context of CAT.…”

mentioning

confidence: 99%

Oncogenes and Clotting Factors: The Emerging Role of Tumor Cell Genome and Epigenome in Cancer-Associated Thrombosis

Tawil

Bassawon

Rak

2019

Semin Thromb Hemost

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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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Distinct Pathogenesis of Pancreatic Cancer Microvesicle–Associated Venous Thrombosis Identifies New Antithrombotic Targets In Vivo

Cited by 45 publications

References 74 publications

Microvesicles and Cancer Associated Thrombosis

Microvesicles and Cancer Associated Thrombosis

Tissue factor at the crossroad of coagulation and cell signaling

Oncogenes and Clotting Factors: The Emerging Role of Tumor Cell Genome and Epigenome in Cancer-Associated Thrombosis

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