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.T he contribution of inflammation to primary tumor progression is well documented (1); however, little is known about its role in metastatic outgrowth in distant organs. The lung, which is a frequent site of metastasis from extrapulmonary neoplasms, is susceptible to inflammatory insults. Bacterial infection-induced, metastasis-conducive environments in the lung (2, 3) and cigarette smoke-induced inflammation were associated with pulmonary metastasis from breast cancer (2, 4).Bacterial lipopolysaccharide (LPS) is a well-characterized inducer of inflammation because its binding to toll-like receptor 4 (TLR4) results in nuclear factor kappa B (NF-κB) activation and expression of proinflammatory cytokines, including interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and IL-6 (5). LPS-induced acute lung injury is marked by increased neutrophil influx and up-regulation of proinflammatory cytokines. Similar phenotypes are observed in other lung inflammatory conditions, including asthma (6), chronic obstructive pulmonary disease (7), and pneumonia (8, 9). LPS-mediated lung inflammation is associated with breast and colon cancer metastasis to the lungs (10-12).The mechanisms by which inflammation contributes to metastatic outgrowth in distant organs have remained underexplored. From a clinical perspective, although blocking primary tumor invasion and blocking dissemination are considered effective approaches in suppressing metastasis, an important question is how best to treat patients whose tumor has already metastasized. Thus, approaches are required to block tumor outgrowth in secondary organs for effective treatment of metastatic cancers. In this study, using two independent models of lung inflammation, we show enhanced recruitment of neutrophils, which degranulate to release the Ser proteases, neutrophil elastase (NE) and cathepsin G (CG), to degrade thrombospondin-1 (Tsp-1) in the lung microenvironment, enhancing metastatic outgrowth. Protease deficiency protected Tsp-1 from proteolysis and suppressed metastasis, providing a previously unidentified mechanism of Tsp-1 regulation in the metastatic organ. Results Neutrophil-Mediated Lung Inflammation Enhances MetastaticOutgrowth. To determine the contribu...

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“…However, pro-metastatic neutrophils deactivate TSP1 by elastase-and cathepsin G-mediated degradation after degranulation in lung tissue, and inactivation of TSP1 contributes to metastasis formation 164 …”

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“…Inhibiting TGF‐β can reduce the microvessel density and also decreases the expression of VEGF and of monocyte chemotactic protein 1 (MCP‐1), which are both important for angiogenesis . Of interest, recent findings suggest that cathepsin‐G may, in conjunction with NE, also contribute to the inflammation‐mediated promotion of cancer by degradation of the anti‐tumorigenic thrombospondin‐1 . Finally, cathepsin‐G may be an antigenic target for T‐cell‐mediated immune therapy in AML, which abundantly express the molecule .…”