Lung inflammation promotes metastasis through neutrophil protease mediated degradation of Tsp 1
Significance Lungs are highly susceptible to inflammation. However, molecular insights into how external inflammation enhances metastatic outgrowth in the lungs remain lacking. Clinically, approaches are required to block tumor outgrowth in secondary organs for effective treatment of metastatic cancers. We demonstrate a previously unidentified mechanism of thrombospondin 1 (Tsp 1) regulation by inflammatory neutrophil proteases in the metastatic organ. Our findings suggest the potential of using neutrophil protease inhibitors as antimetastatic therapies. 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.
Proceedings of the National Academy of Sciences