Abstract
BackgroundTumor-Associated Neutrophils (TANs) may be able to induce lymphangiogenesis and angiogenesis, although the detailed roles of TANs remain unclear. The Neutrophil-Lymphocyte Ratio (NLR) is an inflammation-based prognostic factor for gastric cancer. This study aimed to investigate the distribution of CD15+neutrophils in the primary tumor and Tumor-Draining Lymph Nodes (TDLNs), and to examine the association of TANs with the clinicopathological features (including NLR) of patients with gastric cancer.ResultsImmunohistochemical staining showed that the median number of CD15+TANs was 18 and 24 per high-power field (HPF) in primary tumors and TDLNs, respectively. Patients were divided into high and low infiltration groups based on the median number. A high number of infiltrating CD15+TANs in the primary tumors and in the TDLNs were associated with depth of invasion and lymph node metastasis. Kaplan-Meier analysis revealed that a poor overall survival was associated with high numbers of CD15+TANs, and the multivariate analyses revealed that a high number of CD15+TANs in the TDLNs was an independent prognostic factor. The numbers of CD15+TANs in the primary tumors and TDLNs showed weak positive correlation. The number of CD15+TANs in the primary tumors was positively correlated with the preoperative NLR, (P = 0.001, R = 0.327) and immunohistochemical staining revealed that C-X-C motif chemokine receptor 2 (CXCR2) +neutrophils might be the origin of the CD15+TANs. Flow cytometry analysis indicated that infiltrating neutrophils increased in the tumor and TDLN compared to non-cancerous tissue. Neutrophils treated with cancer supernatant upregulated TWIST and IL-6 genes in vitro.ConclusionOur findings suggested that local infiltration of CD15+TANs may be correlated with inflammation in TDLNs and systemic response to cause metastasis in gastric carcinoma.
Highlights
Tumor-Associated Neutrophils (TANs) may be able to induce lymphangiogenesis and angiogenesis, the detailed roles of TANs remain unclear
He et al reported that peritumoral neutrophils up-regulate Programmed cell death ligand-1 (PDL-1) expression and suppress T-cell proliferation in hepatocellular carcinoma [10, 11], while Wang et al have reported that tumor-derived Granulocyte macrophage colony-stimulating factor (GM-CSF) activates neutrophils and induces neutrophil PD-L1 expression through the Janus kinase and signal transducer and activator of transcription 3 (JAK-STAT3) pathway [11]
Other researchers have demonstrated that intratumoral neutrophils have prognostic value in cases of renal cell carcinoma, colorectal cancer, and non-small cell lung cancer [22,23,24], and we have reported that neutrophil infiltration is associated with lymph node micrometastasis and intranodal lymphangiogenesis [3]
Summary
Tumor-Associated Neutrophils (TANs) may be able to induce lymphangiogenesis and angiogenesis, the detailed roles of TANs remain unclear. The Neutrophil-Lymphocyte Ratio (NLR) is an inflammation-based prognostic factor for gastric cancer. This study aimed to investigate the distribution of CD15+neutrophils in the primary tumor and Tumor-Draining Lymph Nodes (TDLNs), and to examine the association of TANs with the clinicopathological features (including NLR) of patients with gastric cancer. We have previously reported that lymphangiogenesis was augmented in both of the primary gastric carcinoma and the tumour-draining lymph nodes (TDLNs) [3,4,5]. Systemic inflammatory markers, including the Neutrophil-lymphocyte ratio (NLR), are prognostic factors in several cancers [13,14,15]. The present study aimed to explore the relationships of CD15+TANs with gastric cancer and systemic inflammation, based on the microenvironments in the primary tumor and TDLNs
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