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Science. 2018 Sep 28;361(6409). pii: eaao4227. doi: 10.1126/science.aao4227.

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

Author information

1
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
2
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
3
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02215, USA.
4
Center for Health and the Environment, University of California, Davis, Davis, CA 95616, USA.
5
Watson School of Biological Sciences, Cold Spring Harbor, NY 11724, USA.
6
Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
7
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
8
Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10021, USA.
9
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. egeblad@cshl.edu.

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.

PMID:
30262472
DOI:
10.1126/science.aao4227
[Indexed for MEDLINE]

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