Casting a NET on cancer: the multiple roles for neutrophil extracellular traps in cancer

Wolach, Ofir; Martinod, Kimberly

doi:10.1097/moh.0000000000000690

Cited by 10 publications

(8 citation statements)

References 128 publications

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“…Apart from a potential diagnostic value in DCI detection, NETs might serve as therapeutic targets. DNase or janus kinase inhibitors in humans and neonatal NET inhibitory factor in mice have shown promise to reduce NET formation and NET-mediated ischemic injury ( 32 , 48 ).…”

Section: Discussionmentioning

confidence: 99%

Neutrophil Extracellular Traps and Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage

Witsch

Spalart

Martinod

et al. 2022

Critical Care Explorations

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IMPORTANCE: Myeloperoxidase (MPO)-DNA complexes, biomarkers of neutrophil extracellular traps (NETs), have been associated with arterial and venous thrombosis. Their role in aneurysmal subarachnoid hemorrhage (aSAH) is unknown. OBJECTIVES: To assess whether serum MPO-DNA complexes are present in patients with aSAH and whether they are associated with delayed cerebral ischemia (DCI). DESIGN, SETTING, AND PARTICIPANTS: Post-hoc analysis of a prospective, observational single-center study, with de novo serum biomarker measurements in consecutive patients with aSAH between July 2018 and September 2020, admitted to a tertiary care neuroscience ICU. MAIN OUTCOMES AND MEASURES: We analyzed serum obtained at admission and hospital day 4 for concentrations of MPO-DNA complexes. The primary outcome was DCI, defined as new infarction on brain CT. The secondary outcome was clinical vasospasm, a composite of clinical and transcranial Doppler parameters. We used Wilcoxon signed-rank-test to assess for differences between paired measures. RESULTS: Among 100 patients with spontaneous subarachnoid hemorrhage, mean age 59 years (sd ± 13 yr), 55% women, 78 had confirmed aSAH. Among these, 29 (37%) developed DCI. MPO-DNA complexes were detected in all samples. The median MPO-DNA level was 33 ng/mL (interquartile range [IQR], 18–43 ng/mL) at admission, and 22 ng/mL (IQR, 11–31 ng/mL) on day 4 (unpaired test; p = 0.015). We found a significant reduction in MPO-DNA levels from admission to day 4 in patients with DCI (paired test; p = 0.036) but not in those without DCI (p = 0.17). There was a similar reduction in MPO-DNA levels between admission and day 4 in patients with (p = 0.006) but not in those without clinical vasospasm (p = 0.47). CONCLUSIONS AND RELEVANCE: This is the first study to detect the NET biomarkers MPO-DNA complexes in peripheral serum of patients with aSAH and to associate them with DCI. A pronounced reduction in MPO-DNA levels might serve as an early marker of DCI. This diagnostic potential of MPO-DNA complexes and their role as potential therapeutic targets in aSAH should be explored further.

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Section: Discussionmentioning

confidence: 99%

Neutrophil Extracellular Traps and Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage

Witsch

Spalart

Martinod

et al. 2022

Critical Care Explorations

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“…Targeting polyanions (cfDNA from NETs or other origin, polyphosphate and GAGs) in arterial, venous, infection-associated and cancer-associated thrombosis will remain a promising therapeutic approach with the hope of developing antithrombotics that do not interfere with physiological hemostasis [40 ▪▪ ,41,42 ▪▪ ,43 ▪ ]. Exploration of appropriate tools to eliminate the harmful effects of cfDNA and polyphosphates, or construction of a polyanion of optimal size and charge to confer potent histone-neutralizing properties would be of great clinical benefit.…”

Section: Discussionmentioning

confidence: 99%

Fibrin structure, viscoelasticity and lysis face the interplay of biorelevant polyions

Komorowicz

Kolev

2022

Current Opinion in Hematology

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Purpose of review In the past 5 decades, heparins have been widely used as anticoagulants in the prevention and treatment of thrombosis. Subsequent development of heparin variants of various size and charge facilitated the discovery of their multiple biological actions and nonanticoagulant benefits. Platelet-derived or microbial polyphosphates, as well as DNA released in the course of neutrophil extracellular trap-formation are additional polyanions, which can modulate the development and stability of thrombi associated with cancer or inflammation. In this review, we focus on the size-dependent and electric charge-dependent modulatory effects of the three polyanions of different chemical structure. Recent findings The polycationic histones have been recognized as potential biomarkers and therapeutic targets in several diseases related to inflammation and thrombosis. Since combating histones with activated protein C or heparin could cause unwanted bleeding, the quest for nonanticoagulant histone-neutralizing agents is ongoing. Polyanions may neutralize or exaggerate certain histone-mediated effects depending on their electric charge, size and histone effects under investigation. Several prothrombotic effects of polyphosphates and DNA are also size-dependent. Summary The efficiency of future therapeutics targeting prothrombotic polyanions or histones is not a simple matter of electric charge, but may rely on a delicate combination of size, charge and chemical composition.

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“…The exposed phosphatidylserine on TF-positive EVs appears to promote the binding of coagulation factors, rather than TF. NETs serve as a scaffold for various procoagulants and act as mediators of CAT ( 149 ). It has been shown that 4T1-derived exosome range EVs induce NET formation in the neutrophils of granulocyte colony-stimulating factor-treated mice ( 150 ).…”

Section: Roles Of Pcsk9 In Thrombosis and Haemostasis Under Disease S...mentioning

confidence: 99%

Effects of PCSK9 on thrombosis and haemostasis in a variety of metabolic states: Lipids and beyond (Review)

Chong,

Mu,

Cen

et al. 2024

Int J Mol Med

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Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are widely recognised as being able to induce a potent reduction in low-density lipoprotein-cholesterol. An increasing number of studies have suggested that PCSK9 also influences the haemostatic system by altering platelet function and the coagulation cascade. These findings have significant implications for anti-PCSK9 therapy in patients with specific coagulation conditions, including expanded indications, dose adjustments and drug interactions. The present review summarises the changes in PCSK9 levels in individuals with liver diseases, chronic kidney diseases, diabetes mellitus, cancer and other disease states, and discusses their impact on thrombosis and haemostasis. Furthermore, the structure, effects and regulatory mechanisms of PCSK9 on platelets, coagulation factors, inflammatory cells and endothelial cells during coagulation and haemostasis are described.

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Casting a NET on cancer: the multiple roles for neutrophil extracellular traps in cancer

Cited by 10 publications

References 128 publications

Neutrophil Extracellular Traps and Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage

Neutrophil Extracellular Traps and Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage

Fibrin structure, viscoelasticity and lysis face the interplay of biorelevant polyions

Effects of PCSK9 on thrombosis and haemostasis in a variety of metabolic states: Lipids and beyond (Review)

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