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

Abstract

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.

Priming of neutrophils toward NETosis promotes tumor growth

“…2,21 The systemic activation of neutrophils and neutrophilia may also initiate cancer-associated thrombosis as demonstrated in mice. 7 Importantly, our results demonstrate that G-CSF does not have to be locally produced in the tumor to prime neutrophils toward NETosis. Indeed, the systemic neutrophil priming following G-CSF infusion in the B16 melanoma model results in the accumulation of NETs in the tumor and increases tumor growth.…”

“…14 Interestingly, LLC tumor, Ewing sarcomas and pancreatic carcinomas have all been reported to express G-CSF. 7,18,19 Moreover, pancreatic carcinomas are associated with myeloid systemic and intratumoral accumulations. 20 In cancer patients, increase in neutrophil count and elevated blood G-CSF have been frequently observed and associated with poor outcome.…”

“…7 We therefore evaluated the presence of G-CSF in B16 melanomas compared to LLC tumor-bearing mice. Plasma analysis showed only a minor amount of G-CSF in the B16 tumor-bearing mice and the level did not increase with tumor growth (Fig 3B).…”

“…6 We previously showed that cancer, through the release of G-CSF, can prime neutrophils toward NETosis and identified NETs as a new player in cancer-associated thrombosis. 7 NETs could play a role in many steps of tumor progression and their release could enhance tumor growth/invasion, or induce cytotoxicity. 8 Using PAD4-deficient mice, which fail to release NETs, 9,10 we now address the role of the host PAD4/NETs in PAD4 WT tumors and report that the systemic priming of neutrophils induces the accumulation of NETting neutrophils in the tumor microenvironment.…”

High glucose modulates IL‐6 mediated immune homeostasis through impeding neutrophil extracellular trap formation

“…Besides being beneficial for antimicrobial processes, NETs are also associated with autoimmune diseases such as lupus erythematous and small vessel vasculitis, where either excess NETs are produced or impairment in its clearance is noted [6,7]. A recent study indicates NETs as a causative factor for tumor associated thrombosis [8]. Stimulus dependent role of several key molecules for NETosis has been proposed.…”