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

Abstract

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.

The regulatory mechanism of neutrophil extracellular traps in cancer biological behavior

“…NETs promote migration ability in breast cancer through EMT [ 90 ]. This result is consistent with another study in GC [ 106 ]. It shows that process of EMT is significant for NETs induced tumor metastasis.…”

Neutrophil extracellular traps in cancer: not only catching microbes

“…NETs also promote the process of metastasis by contributing to migration and invasion by tumor cells [18,24,44]. It has been recently shown that, in gastric cancer, NETs promote a more aggressive mesenchymal phenotype [45]. Park et al [41] demonstrated that more neutrophils were recruited in the context of murine metastatic breast cancer cells (4 T1) when compared with cells that did not metastasize.…”

Role of Cell-Free DNA and Deoxyribonucleases in Tumor Progression

“…A study comparing triple-negative human breast cancer (oestrogen− progesterone−, HER-2−) with luminal HER-2+ breast cancer found excessive NET formation in the case of triple-negative human breast cancer that correlated with the spread of metastases [103]. In patients with stage III/IV gastric cancer, the NET density was significantly higher compared with healthy donors and patients with stage I/II of the disease, while no significant differences in NET density were found between patients with stage III or IV of the disease [98]. The late stages of breast and lung cancer were characterized by higher NET density compared with the early stage [99,103].…”

“…Large accumulations of dead neutrophils and NETs have been found in the microenvironment of haemorrhagic lungs in LLC mice, Ewing's sarcoma, small bowel cancer, colorectal cancer, breast cancer and lymphoma [92][93][94][95][96][97]. Patients with advanced lung, breast or gastric cancer are characterized by excessive formation of NETs and, moreover, research also indicates that NET levels may be associated with metastasis [98,99]. Some authors suggest that NET deposition in tumor tissue may have a cytotoxic effect.…”