Neutrophil extracellular traps promote gastric cancer metastasis by inducing epithelial-mesenchymal transition

The risks of tumor recurrence following the successful resection of the primary tumor have been known for decades; however, the precise mechanisms underlying treatment failures remain unknown. The formation of neutrophil extracellular traps (NETs) has increasingly been demonstrated to be associated with thrombi formation in cancer patients, as well as with the development and metastasis of cancer. The present study demonstrated that the level of peripheral blood NETs in patients with gastric cancer (GC) was associated with tumor progression, and patients with stage III/IV disease exhibited significant differences compared with the healthy controls and patients with stage I/II disease, which may be associated with an increased risk of metastasis. In addition, plasma from patients with stage III/IV GC was more prone to stimulate neutrophils to form NETs; thus, it was hypothesized that the formation of NETs may be affected by the tumor microenvironment. A higher deposition of NETs in GC tissues compared with normal resection margins was also identified. In vitro, following treatment with phorbol myristate acetate, which promotes the formation of NETs, or with DNAse-1/GSK-484, which inhibits the formation of NETs, it was found that the tumor migratory ability was altered; however, no significant changes were observed in cell proliferation and cell cycle progression. Epithelial-mesenchymal transition (EMT) is a key event associated with dissemination and metastasis in GC pathogenesis. Finally, the present study demonstrated that NETs promote a more aggressive mesenchymal phenotype and promote the progression of GC in vitro and in vivo. On the whole, to the best of our knowledge, the present study reports a previously unknown role of NETs in the regulation of GC, which is associated with EMT and migration. Therefore, targeting NETs may prove to be therapeutically beneficial.