Chronic Stress Accelerates Gastric Cancer Liver Metastasis through Glucocorticoid-GR-NETosis and Hepatocyte-Derived LCN2 [dataset2]

ABSTRACT: Chronic psychological stress is closely associated with metastasis in solid tumors, but its role in gastric cancer liver metastasis has not been fully explored. In this study, we established chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS) mouse models of liver metastasis and found that chronic stress significantly increased corticosterone levels and accelerated gastric cancer liver metastasis. Transcriptomic and immune cell analyses of the liver from stressed mice revealed that stress reshapes the liver immune microenvironment, promoting neutrophil infiltration and inhibiting CD8⁺ T cell function, thereby creating a pro-metastatic immune niche. In vitro Transwell co-culture assays showed that neutrophils pretreated with glucocorticoids (GCs) significantly enhanced tumor cell migration and invasion. In vivo neutrophil depletion significantly reversed stress-induced liver metastasis. Mechanistic studies demonstrated that GCs activated neutrophils through the glucocorticoid receptor (GR) signaling pathway, inducing reactive oxygen species (ROS)-dependent NETosis, which promoted metastasis. Inhibition of GR or clearance of neutrophil extracellular traps (NETs) significantly alleviated the pro-metastatic effects of stress. Furthermore, GR-activated hepatocytes secreted lipocalin 2 (LCN2), which further enhanced neutrophil chemotaxis and the promotion of liver metastasis. Clinical cohort analysis showed that higher serum cortisol and NETs levels in high-stress patients were significantly associated with poorer survival. This study reveals that chronic stress promotes gastric cancer liver metastasis through the glucocorticoid-GR-NETosis pathway and further amplifies the metastatic effect through the LCN2-neutrophil axis within the liver-brain axis. These findings provide potential therapeutic targets, such as GR, NETs and LCN2, and may serve as biomarkers for early diagnosis and survival assessment in clinical settings.

ORGANISM(S): Mus musculus

PROVIDER: GSE313796 | GEO | 2026/09/03

REPOSITORIES: GEO