Chronic stress is associated with increased risk of metastasis and poor survival in cancer patients, yet the reasons are unclear. We show that chronic stress increases lung metastasis from disseminated cancer cells 2- to 4-fold in mice. Chronic stress significantly alters the lung microenvironment, with fibronectin accumulation, reduced T cell infiltration, and increased neutrophil infiltration. Depleting neutrophils abolishes stress-induced metastasis. Chronic stress shifts normal circadian rhythm of neutrophils and causes increased neutrophil extracellular trap (NET) formation via glucocorticoid release. In mice with neutrophil-specific glucocorticoid receptor deletion, chronic stress fails to increase NETs and metastasis. Furthermore, digesting NETs with DNase I prevents chronic stress-induced metastasis. Together, our data show that glucocorticoids released during chronic stress cause NET formation and establish a metastasis-promoting microenvironment. Therefore, NETs could be targets for preventing metastatic recurrence in cancer patients, many of whom will experience chronic stress due to their disease.

中文翻译：

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慢性应激通过中性粒细胞介导的微环境变化增加转移

慢性压力与癌症患者转移风险增加和生存率低有关，但其原因尚不清楚。我们发现，慢性压力会使小鼠播散性癌细胞的肺转移增加 2 至 4 倍。慢性应激显着改变肺微环境，导致纤连蛋白积累、T细胞浸润减少和中性粒细胞浸润增加。消耗中性粒细胞可以消除应激诱导的转移。慢性压力会改变中性粒细胞的正常昼夜节律，并通过糖皮质激素的释放导致中性粒细胞胞外陷阱（NET）形成增加。在中性粒细胞特异性糖皮质激素受体缺失的小鼠中，慢性应激无法增加 NET 和转移。此外，用 DNase I 消化 NET 可以预防慢性应激诱导的转移。总之，我们的数据表明，慢性应激期间释放的糖皮质激素会导致 NET 形成并建立促进转移的微环境。因此，NETs 可能成为预防癌症患者转移复发的目标，其中许多人会因疾病而经历慢性压力。