NETing cancer cells
Surgical resection is a primary treatment for many solid tumors; however, patients frequently develop post-surgical infections, which are associated with adverse oncologic outcomes. Jonathan Cools-Lartigue and colleagues examined the role of infection-responsive neutrophils in post-surgical cancer progression. Post-surgery, there is an increase in the number of circulating neutrophils, which play a role in pathogen elimination. Cools-Lartigue and colleagues found that circulating cancer cells become entrapped in neutrophil extracellular traps (NETs), DNA webs that are released from neutrophils in response to inflammation. Using a murine model of post-surgical infection, they found that NET trapping was associated with increased metastatic burden; treatment with NET inhibitors decreased metastases. These findings demonstrate that NETs play a role in metastasis and indicate that NET-targeting therapeutics could potentially reduce post-surgical metastasis. The accompanying immunofluorescent microscopy image shows accumulation of cancer cells (green) in the hepatic sinusoids (red) after sham surgery, surgery that induced an infection, and infection-inducing surgery in the presence of a NET inhibitor.
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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
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)