Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis

TY - JOUR

T1 - Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis

AU - Demers, Mélanie

AU - Krause, Daniela S

AU - Schatzberg, Daphne

AU - Martinod, Kimberly

AU - Voorhees, Jaymie R

AU - Fuchs, Tobias A

AU - Scadden, David T

AU - Wagner, Denisa D

PY - 2012/8/7

Y1 - 2012/8/7

N2 - 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.

AB - 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.

KW - Animals

KW - Blotting, Western

KW - Chromatin

KW - DNA

KW - Enzyme-Linked Immunosorbent Assay

KW - Fluorescence

KW - Granulocyte Colony-Stimulating Factor

KW - Histological Techniques

KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive

KW - Mice

KW - Mice, Inbred BALB C

KW - Neutrophils

KW - Statistics, Nonparametric

KW - Thrombosis

U2 - 10.1073/pnas.1200419109

DO - 10.1073/pnas.1200419109

M3 - SCORING: Journal article

C2 - 22826226

VL - 109

SP - 13076

EP - 13081

JO - P NATL ACAD SCI USA

JF - P NATL ACAD SCI USA

SN - 0027-8424

IS - 32

ER -