Lung inflammation promotes metastasis through neutrophil protease-mediated degradation of Tsp-1
Lung inflammation promotes metastasis through neutrophil protease-mediated degradation of Tsp-1
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DOI：
10.1073/pnas.1507294112
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发表时间：
2015-12-29
影响因子：
11.1
通讯作者：
Mittal, Vivek
中科院分区：
文献类型：
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作者：
El Rayes, Tina;Catena, Raul;Mittal, Vivek
炎症与原发性肿瘤进展密不可分。然而，炎症对转移性器官中肿瘤生长的贡献仍有待研究。在这里，我们表明，外源性炎症在肺部导致招募骨髓来源的中性粒细胞，其deepenylazurophilic颗粒释放丝氨酸蛋白酶，弹性蛋白酶和组织蛋白酶G，导致抗肿瘤因子血小板反应蛋白-1（TSP-1）的蛋白水解破坏。这些中性粒细胞蛋白酶的基因消融保护Tsp-1免于降解并抑制肺转移。这些结果提供了对炎性中性粒细胞对转移的贡献的机制见解，并突出了独特的中性粒细胞蛋白酶-Tsp-1轴作为潜在的抗转移治疗靶点。
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.