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Proc Natl Acad Sci U S A. 2015 Dec 29;112(52):16000-5. doi: 10.1073/pnas.1507294112. Epub 2015 Dec 14.

Lung inflammation promotes metastasis through neutrophil protease-mediated degradation of Tsp-1.

Author information

1
Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, New York, NY 10065; Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, New York, NY 10065; Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, New York, NY 10065;
2
Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, New York, NY 10065; Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, New York, NY 10065;
3
Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853;
4
Division of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
5
Department of Medicine, Weill Cornell Medical College of Cornell University, New York, NY 10065.
6
Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, New York, NY 10065; Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, New York, NY 10065; Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, New York, NY 10065; vim2010@med.cornell.edu.

Abstract

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.

KEYWORDS:

inflammation; metastasis; neutrophils; proteases; thrombospondin-1

PMID:
26668367
PMCID:
PMC4703007
DOI:
10.1073/pnas.1507294112
[Indexed for MEDLINE]
Free PMC Article

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