Abstract
Postoperative abdominal infectious complication (AIC) is associated with metastasis in locally advanced gastric cancer (GC) patients after radical gastrectomy. However, the underlying mechanism remains unclear. Herein, we report that neutrophil extracellular traps (NETs), the DNA meshes released by neutrophils in response to infection, could promote GC cells proliferation, invasion, migration and epithelial–mesenchymal transition dependent on TGF-β signaling. Then we model nude mice with cecal puncture without ligation to simulate postoperative AIC and find that NETs in peripheral blood and ascites fluid facilitate GC cells extravasation and implantation into liver and peritoneum for proliferation and metastasis. Notably, TGF-β signaling inhibitor LY 2157299 could effectively impede liver and peritoneal metastasis but not concurrently aggravate sepsis in those AIC-bearing nude mice. These findings implicate that targeting downstream effectors of NETs such as TGF-β signaling might provide potential therapeutic prospect to reduce the risk of GC metastasis.
Highlights
Postoperative abdominal infectious complication (AIC) is associated with metastasis in locally advanced gastric cancer (GC) patients after radical gastrectomy
We show that abdominal infectious complication (AIC) after gastrectomy would stimulate neutrophils to release neutrophil extracellular traps (NETs) both in peripheral blood and abdominal cavity
We find that TGF-β inhibitor LY 2157299 is a potential therapeutic to decrease metastasis without exacerbating sepsis in the setting of liver and peritoneal metastasis nude mice with AIC-induced NETs, which raise the possibility to prolong the survival of GC patients
Summary
Postoperative AIC reduces overall survival (OS) and recurrence-free survival (RFS) in locally advanced GC patients undergoing R0 resection. Immunofluorescence co-staining DNA, Cit-H3 and TGF-β1 in neutrophils (Fig. 4G) and clinical samples (Fig. 4H) further demonstrated that TGF-β1 expression was positively synchronous with NETs release Together, these data implicated that NETs induced proliferation, invasion, migration and EMT of GC cells were dependent on TGFβ signaling activation. Ki[67] immunohistochemistry (IHC) assay displayed that NETs promoted GC cells proliferation in metastatic sites and this effect would be abolished when NETs digested by DNase I or TGF-β signaling inhibited by LY 2157299 (Supplementary Fig. 7E) These data suggested that TGF-β inhibitor effectively counteracts NETs-GC clusters induced metastasis but not aggravated sepsis
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