Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis
Open accessAbstract
Cancer-associated thrombosis often lacks a clear etiology. However, it is linked to a poor prognosis and represents the second-leading cause of death in cancer patients. Recent studies have shown that chromatin released into blood, through the generation of neutrophil extracellular traps (NETs), is procoagulant and prothrombotic. Using a murine model of chronic myelogenous leukemia, we show that malignant and nonmalignant neutrophils are more prone to NET formation. This increased sensitivity toward NET generation is also observed in mammary and lung carcinoma models, suggesting that cancers, through a systemic effect on the host, can induce an increase in peripheral blood neutrophils, which are predisposed to NET formation. In addition, in the late stages of the breast carcinoma model, NETosis occurs concomitant with the appearance of venous thrombi in the lung. Moreover, simulation of a minor systemic infection in tumor-bearing, but not control, mice results in the release of large quantities of chromatin and a prothrombotic state. The increase in neutrophil count and their priming is mediated by granulocyte colony-stimulating factor (G-CSF), which accumulates in the blood of tumor-bearing mice. The prothrombotic state in cancer can be reproduced by treating mice with G-CSF combined with low-dose LPS and leads to thrombocytopenia and microthrombosis. Taken together, our results identify extracellular chromatin released through NET formation as a cause for cancer-associated thrombosis and unveil a target in the effort to decrease the incidence of thrombosis in cancer patients.
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G-CSF can prime neutrophils for NET formation and is secreted by 4T1 cells.
“G-CSF can prime neutrophils for NET formation and is secreted by 4T1 cells (23).”
From Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps (2016) · cites this paper as [23]
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- Authors
- Demers, M., Krause, D. S., Schatzberg, D., Martinod, K., Voorhees, J. R., Fuchs, T. A., Scadden, D. T., & Wagner, D. D.
- Affiliations
- Boston Children's Hospital (US)
- Massachusetts General Hospital (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-07-23
- Volume
- 109
- Issue
- 32
- Pages
- 13076-13081
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3420209
- OpenAlex
- W2070117107
- Cited by
- 883
- References
- 47
- Citations by year
- 2026: 41 · 2025: 60 · 2024: 83 · 2023: 79 · 2022: 87 · 2021: 101 · 2020: 82 · 2019: 70 · 2018: 55 · 2017: 51 · 2016: 55 · 2015: 49 · 2014: 35 · 2013: 29 · 2012: 6
- FWCI
- 16.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Amgen
- Genentech
- National Heart, Lung, and Blood Institute (R01HL102101, R01HL044851)
- National Cancer Institute (K08CA138916)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Health Sciences › Medicine › Internal Medicine › Venous Thromboembolism Diagnosis and Management
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Keywords
- cancer-associated thrombosis, neutrophil extracellular traps, NETosis, procoagulant activity, granulocyte colony-stimulating factor, chronic myeloid leukemia, breast cancer, lung cancer, venous thrombosis, thrombocytopenia, microvascular thrombosis, systemic infection
- MeSH terms
- Animals, Chromatin, DNA, Enzyme-Linked Immunosorbent Assay, Fluorescence, Histological Techniques, Mice, Inbred BALB C, Neutrophils, Thrombosis, Blotting, Western, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Granulocyte Colony-Stimulating Factor, Statistics, Nonparametric, Mice
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