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

被引：213

作者：

El Rayes, Tina ^{[1
,2
,3
]}

Catena, Raul ^{[1
,2
,3
]}

Lee, Sharrell ^{[1
,3
]}

Stawowczyk, Marcin ^{[1
,2
,3
]}

Joshi, Natasha ^{[1
,2
,3
]}

Fischbach, Claudia ^{[4
]}

Powell, Charles A. ^{[5
]}

Dannenberg, Andrew J. ^{[6
]}

Altorki, Nasser K. ^{[1
,3
]}

Gao, Dingcheng ^{[1
,2
,3
]}

Mittal, Vivek ^{[1
,2
,3
]}

机构：

[1] Cornell Univ, Weill Cornell Med Coll, Dept Cardiothorac Surg, New York, NY 10065 USA

[2] Cornell Univ, Weill Cornell Med Coll, Dept Cell & Dev Biol, New York, NY 10065 USA

[3] Cornell Univ, Weill Cornell Med Coll, Neuberger Berman Lung Canc Ctr, New York, NY 10065 USA

[4] Cornell Univ, Nancy E & Peter C Meinig Sch Biomed Engn, Ithaca, NY 14853 USA

[5] Icahn Sch Med Mt Sinai, Div Pulm Crit Care & Sleep Med, New York, NY 10029 USA

[6] Cornell Univ, Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2015年 / 112卷 / 52期

关键词：

metastasis; inflammation; neutrophils; proteases; thrombospondin-1; NF-KAPPA-B; BREAST-CANCER; ELASTASE INHIBITOR; PREMETASTATIC LUNG; PROGENITOR CELLS; TUMOR-GROWTH; MURINE LUNG; THROMBOSPONDIN-1; PNEUMONIA; INJURY;

D O I：

10.1073/pnas.1507294112

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：16000 / 16005

页数：6

共 44 条

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Single residue determines the specificity of neutrophil elastase for Shigelia virulence factors [J].