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

Tina El Rayes, Raúl Catena, Sharrell Lee, Marcin Stawowczyk, Natasha Joshi, Claudia Fischbach, Charles A. Powell, Andrew J. Dannenberg, Nasser K. Altorki, Dingcheng Gao, Vivek Mittal

Research output: Contribution to journalArticle

91 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)16000-16005
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number52
DOIs
StatePublished - Dec 29 2015

Keywords

  • Inflammation
  • Metastasis
  • Neutrophils
  • Proteases
  • Thrombospondin-1

ASJC Scopus subject areas

  • General

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