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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice.

Authors: Albrengues, Jean; Shields, Mario A; Ng, David; Park, Chun Gwon; Ambrico, Alexandra; Poindexter, Morgan E; Upadhyay, Priya; Uyeminami, Dale L; Pommier, Arnaud; Küttner, Victoria; Bružas, Emilis; Maiorino, Laura; Bautista, Carmelita; Carmona, Ellese M; Gimotty, Phyllis A; Fearon, Douglas T; Chang, Kenneth; Lyons, Scott K; Pinkerton, Kent E; Trotman, Lloyd C; Goldberg, Michael S; Yeh, Johannes T-H; Egeblad, Mikala

Published In Science, (2018 09 28)

Abstract: Cancer cells from a primary tumor can disseminate to other tissues, remaining dormant and clinically undetectable for many years. Little is known about the cues that cause these dormant cells to awaken, resume proliferating, and develop into metastases. Studying mouse models, we found that sustained lung inflammation caused by tobacco smoke exposure or nasal instillation of lipopolysaccharide converted disseminated, dormant cancer cells to aggressively growing metastases. Sustained inflammation induced the formation of neutrophil extracellular traps (NETs), and these were required for awakening dormant cancer. Mechanistic analysis revealed that two NET-associated proteases, neutrophil elastase and matrix metalloproteinase 9, sequentially cleaved laminin. The proteolytically remodeled laminin induced proliferation of dormant cancer cells by activating integrin α3β1 signaling. Antibodies against NET-remodeled laminin prevented awakening of dormant cells. Therapies aimed at preventing dormant cell awakening could potentially prolong the survival of cancer patients.

PubMed ID: 30262472 Exiting the NIEHS site

MeSH Terms: Animals; Carcinogenesis/metabolism*; DNA/metabolism; Extracellular Traps/enzymology*; Humans; Inflammation/chemically induced; Inflammation/microbiology; Integrin alpha3beta1/metabolism; Lamins/metabolism*; Leukocyte Elastase/metabolism; Lipopolysaccharides; Lung Neoplasms/pathology*; Lung/pathology; MCF-7 Cells; Matrix Metalloproteinase 9/metabolism; Mice; Mice, Inbred BALB C; Neoplasms, Experimental/pathology; Neutrophils/enzymology*; Pneumonia, Bacterial/etiology; Pneumonia, Bacterial/pathology; Pneumonia/chemically induced; Pneumonia/microbiology; Pneumonia/pathology*; Protein-Arginine Deiminases/antagonists & inhibitors; Protein-Arginine Deiminases/metabolism; Proteolysis; Rats; Signal Transduction; Smoking; Tobacco

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