Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice
Top Cited Papers
- 28 September 2018
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 361 (6409), 1353-+
- https://doi.org/10.1126/science.aao4227
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.Keywords
Funding Information
- U.S. Department of Defense (W81XWH-14-1-0078)
- National Cancer Institute
- Susan G. Komen for the Cure (PDF16376754)
- European Molecular Biology Organization (ALTF 1425-2015)
- Lustgarten Foundation
- Association pour la Recherche sur le Cancer (AE20141202131)
- Northwell Health
- Northwell Health
- Cold Spring Harbor Laboratory Cancer Center Support Grant
- Deutsche Forschungsgemeinschaft (KU 3264/1-1)
- Cold Spring Harbor Laboratory Cancer Center Support Grant (P30-CA045508)
- George A. and Marjorie H. Anderson Fellowship from the Watson School
- R01 NIH Research Grant Program (5R01CA137050-07)
- Terri Brodeur Breast Cancer Foundation
- Northwell Health
- Starr Centennial Scholarship from the Watson School of Biological Sciences (21090249)
- Cold Spring Harbor Laboratory Cancer Center Support Grant (P30-CA045508)
- Cold Spring Harbor Laboratory Cancer Center Support Grant (P30-CA045508)
- Cold Sprint Harbor Laboratory Cancer Center Grant (P30-CA045508)
- Cold Spring Harbor Laboratory Cancer Center Grant (P30-CA045508)
- Cedar Hill Foundation
- Cold Spring Harbor Laboratory Cancer Center Grant (P30-CA045508)
- Boehringer Ingelheim Fonds Ph.D. Fellowship
- Northwell Health
- AACR-Bayer Healthcare Basic Cancer Research Fellowship (15-40-44-SHIE)
- R01 NIH Research Grant (5R01CA137050-07)
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