title: Lung inflammation promotes metastasis through neutrophil protease-mediated degradation of Tsp-1.
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.
authors.affiliation: 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;
authors.forename: Tina
authors.initials: T
authors.lastname: El Rayes
authors.affiliation: 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;
authors.forename: Raúl
authors.initials: R
authors.lastname: Catena
authors.affiliation: 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;
authors.forename: Sharrell
authors.initials: S
authors.lastname: Lee
authors.affiliation: 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;
authors.forename: Marcin
authors.initials: M
authors.lastname: Stawowczyk
authors.affiliation: 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;
authors.forename: Natasha
authors.initials: N
authors.lastname: Joshi
authors.affiliation: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853;
authors.forename: Claudia
authors.initials: C
authors.lastname: Fischbach
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Charles A
authors.initials: CA
authors.lastname: Powell
authors.affiliation: Department of Medicine, Weill Cornell Medical College of Cornell University, New York, NY 10065.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dannenberg
authors.affiliation: 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;
authors.forename: Nasser K
authors.initials: NK
authors.lastname: Altorki
authors.affiliation: 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;
authors.forename: Dingcheng
authors.initials: D
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: Vivek
authors.initials: V
authors.lastname: Mittal
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D056649:Cathepsin G / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D019272:Leukocyte Elastase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000378:metabolism* / Q000556:secondary; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D011014:Pneumonia / Q000378:metabolism*; D059748:Proteolysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D057057:Serine Proteases / Q000378:metabolism; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D019700:Thrombospondin 1; D010447:Peptide Hydrolases; D057057:Serine Proteases; D056649:Cathepsin G; D019272:Leukocyte Elastase
keywords: inflammation; metastasis; neutrophils; proteases; thrombospondin-1