Diagnostic, Therapeutic Predictive, and Prognostic Value of Neutrophil Extracellular Traps in Patients With Gastric Adenocarcinoma

Abstract

Neutrophils are a significant population of infiltrated immune cells in the tumor microenvironment. Neutrophil extracellular traps (NETs) are implicated in the biological behavior of many malignant tumors. NETs can be degraded into soluble nucleosomes, leading to the release of fragments containing DNA and granule proteins into the peripheral blood (PB). Using human gastric cancer (GC) biopsies and PB samples, we investigated the specific value of NETs in GC from a clinical perspective. In summary, the formation of NETs was discovered in the tissue microenvironment and PB of GC patients. The amounts of NETs and neutrophil accumulation decreased from tumor tissue to paratumor tissue. In addition, the level of NETs in the PB gradually declined through the following patient populations: advanced disease patients, preoperative patients, postoperative patients, benign disease patients, and healthy controls. The levels of NETs in the plasma and serum were significantly correlated. As a serum biomarker, NETs had a better diagnostic value than carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) in GC. The neutrophil count and neutrophil to lymphocyte ratio (NLR) were significantly associated with the level of NETs in the PB. The existence of lymph node metastasis indicated a high level of NETs in the serum. Moreover, the level of NETs in the PB was inversely correlated with short-term efficacy in GC patients who had received advanced first-line treatment. The higher baseline level of NETs in the PB of patients with negative HER2 status was correlated with worse progression-free survival (PFS). And the level of NETs in the PB was a unfavorable independent prognostic factor for PFS in patients with advanced GC who had received first-line treatment. Thus, NETs have novel diagnostic, therapeutic predictive, and prognostic value in GC patients.

Heterogenous presence of neutrophil extracellular traps in human solid tumours is partially dependent on IL‐8

“…Previous reports on single parameter staining indicated that the abundance of NETs in lymphoma as well as pancreatic and ovarian cancer, correlates with worse overall prognosis [19–21]. Mouse data are supportive of pathogenic mechanisms exerted by NETs, but this remains unresolved in humans.…”

“…B-cell lymphoma patients show increased circulating levels of NETs that correlate with serum IL-8 and worse prognosis [19]. Moreover, reports suggest the presence of NETs in pancreatic, gastric, and ovarian cancer where they correlate with worse prognosis [20][21][22][23]. However, accurate analytical studies supporting reliable measurement of NETs are needed [20,23].…”

Neutrophil extracellular traps in cancer: not only catching microbes

“…For example, elevated NET levels, measured as serum MPO-DNA molecules, correlates with metastatic phenotype of colorectal cancer patients [27]. Moreover, the levels of circulating NE-DNA complexes increased with the stage of the disease in breast and gastric cancers [28,29]. Increased levels of plasma biomarkers of activated neutrophils and NETs, such as cfDNA, NE and citH3, have also recently been detected in a mouse model of pancreatic cancer [30].…”

“…High neutrophil infiltration is associated with breast cancer aggressiveness and therapy resistance mediated by pro-tumor neutrophil characteristics due to the cancer cell-neutrophil interactions [39]. Tumor cells release cytokines and chemokines such as IL-8, IL-17 and G-CSF, CXCL5 and CXCL6 [18,40] that attract neutrophils from the bone marrow to tumor sites [29,39,41,42]. It has been demonstrated that significant neutrophil heterogeneity exists.…”

Neutrophil Extracellular Traps in Colorectal Cancer Progression and Metastasis

“…In gastric cancer (GC), the analysis of blood samples has revealed higher levels of NETs in patients with benign gastric disease than healthy controls [ 69 ]. The results indicate a better diagnostic value of NETs than carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9).…”