Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 52, Pages 16000-16005Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1507294112
Keywords
metastasis; inflammation; neutrophils; proteases; thrombospondin-1
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Funding
- Cornell Center on the Microenvironment and Metastasis [U54CA14387]
- National Lung Cancer Partnership
- Government of Navarra
- Camara Navarra de Comercio (Spain)
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Inflammation is inextricably associated with primary tumor progression. However, the contribution of inflammation to tumor outgrowth in metastatic organs has remained underexplored. Here, we show that extrinsic inflammation in the lungs leads to the recruitment of bone marrow-derived neutrophils, which degranulate azurophilic granules to release the Ser proteases, elastase and cathepsin G, resulting in the proteolytic destruction of the antitumorigenic factor thrombospondin-1 (Tsp-1). Genetic ablation of these neutrophil proteases protected Tsp-1 from degradation and suppressed lung metastasis. These results provide mechanistic insights into the contribution of inflammatory neutrophils to metastasis and highlight the unique neutrophil protease-Tsp-1 axis as a potential antimetastatic therapeutic target.
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