Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis
Jonathan Cools-Lartigue, … , Paul Kubes, Lorenzo Ferri
Jonathan Cools-Lartigue, … , Paul Kubes, Lorenzo Ferri
Published July 1, 2013
Citation Information: J Clin Invest. 2013;123(8):3446-3458. https://doi.org/10.1172/JCI67484.
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Research Article Oncology

Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis

Abstract

The majority of patients with cancer undergo at least one surgical procedure as part of their treatment. Severe postsurgical infection is associated with adverse oncologic outcomes; however, the mechanisms underlying this phenomenon are unclear. Emerging evidence suggests that neutrophils, which function as the first line of defense during infections, facilitate cancer progression. Neutrophil extracellular traps (NETs) are extracellular neutrophil-derived DNA webs released in response to inflammatory cues that trap and kill invading pathogens. The role of NETs in cancer progression is entirely unknown. We report that circulating tumor cells become trapped within NETs in vitro under static and dynamic conditions. In a murine model of infection using cecal ligation and puncture, we demonstrated microvascular NET deposition and consequent trapping of circulating lung carcinoma cells within DNA webs. NET trapping was associated with increased formation of hepatic micrometastases at 48 hours and gross metastatic disease burden at 2 weeks following tumor cell injection. These effects were abrogated by NET inhibition with DNAse or a neutrophil elastase inhibitor. These findings implicate NETs in the process of cancer metastasis in the context of systemic infection and identify NETs as potential therapeutic targets.

Authors

Jonathan Cools-Lartigue, Jonathan Spicer, Braedon McDonald, Stephen Gowing, Simon Chow, Betty Giannias, France Bourdeau, Paul Kubes, Lorenzo Ferri

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Figure 2

Systemic sepsis promotes the development of gross metastasis, which is attenuated by systemic administration of inhibitors of NET formation.

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Systemic sepsis promotes the development of gross metastasis, which is a...
Mice were subjected to CLP in order to induce sepsis. Intrasplenic injection of H59 Lewis lung cancer cell lines was performed 24 hours later. Administration of DNAse 1 intramuscularly or a NEi per os was started 24 hours prior to CLP and continued daily for 14 days. At 14 days, mice were sacrificed, and the number of gross hepatic metastases was quantified. (A) Representative images of hepatic nodules after necropsy in mice subjected to sham surgery, CLP, CLP with daily DNAse 1 administration, and CLP with daily NEi administration. (B) CLP resulted in a significant increase in the number of gross metastatic nodules compared with sham. Treatment with DNAse or NEi after CLP resulted in a significant decrease in the number of gross metastases. Data are presented as mean ± SEM from n = 5 mice per group. *P < 0.05, **P < 0.01 versus CLP. #P < 0.001 versus sham as determined by 1-way ANOVA with Tukey’s HSD post-hoc analysis.