Interaction with neutrophils promotes gastric cancer cell migration and invasion by inducing epithelial-mesenchymal transition

Abstract

Emerging evidence has revealed that neutrophils have phenotypic and functional plasticity. Neutrophils could be polarized towards a pro-tumor phenotype by tumor-derived factors. In the present study, we investigated the role of the interaction with neutrophils on the functions of gastric cancer cells in vitro. Human promyelocytic leukemia HL-60 cells were induced to differentiate into neutrophil-like cells (HL-60N) using dimethyl sulfoxide (DMSO). Human gastric cancer cells were co-cultured with HL-60N cells or treated with the conditioned medium (CM) of cancer-activated HL-60N cells. The migration and invasion of gastric cancer cells were significantly enhanced while their proliferation was minimally altered. The expression of pro-inflammatory factors including IL-6, IL-8, IL-1β, and TNFα was significantly increased in cancer-activated HL-60N cells, which induced the activation of the ERK pathway and epithelial-mesenchymal transition (EMT) in gastric cancer cells. Blocking the ERK pathway activation reversed the promoting effects of cancer-activated HL-60N cells on gastric cancer cell migration and invasion. In addition, mouse gastric cancer cell derived CM could also increase the expression of pro-inflammatory factors in mouse bone marrow neutrophils, which in turn enhanced the migration and invasion of mouse gastric cancer cells. Collectively, our findings revealed that the interaction with neutrophils promoted gastric cancer cell migration and invasion through the activation of the ERK pathway and the induction of EMT, indicating that neutrophils may play an important role in gastric cancer metastasis. Therefore, targeting neutrophil-cancer cell interaction may provide a new strategy for the treatment of gastric cancer.

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

“…In a gastric cancer microenvironment, macrophages via interaction with mesenchymal stem cells induce differentiation of cancer-associated fibroblasts (CAFs) [232][233][234]. CAFs are crucial in the initiation, growth, and migration properties of gastric cancer cells [235,236]. They are responsible for the release of carcinogenic and proinflammatory factors including interleukin-6 (Il-6), cyclooxygenase-2 (COX-2), chemokine (C-X-C motif) ligand 1 (Cxcl1), chemokine (C-X-C motif) ligand 9 (Cxcl9), interferon gamma-induced protein 10 (Cxcl10), stromal cell-derived factor 1 (Cxcl12), and fibroblast-specific protein 1 (FSP1), which promote the EMT process and induce carcinogenesis, promoting migration and invasion [237][238][239].…”

Tumor-Infiltrating Lymphocyte-Based Risk Score for Predicting Prognosis in Gastric Cancer

“…In this study, infiltration of plasma cells was also shown to prolong survival in gastric cancer as a component of the humoral immune response, consistent with previous studies (18,19); however, the precise role of these cells remains poorly understood. Neutrophils were assigned the highest coefficient in our risk assessment formula, possibly due to their ability to regulate many of the malignancy-associated behaviors of cancer cells, such as migration and invasion (20,21). The difference in infiltration ratio among these four immune cell types may be correlated with leukocyte migration-related pathways, which were enriched in our high risk subgroup; a high risk score was indicative of infiltrates with a high proportion of neutrophils and low proportions of plasma cells, activated CD4 + memory T cells, and Tfh cells.…”

Immunological Aspects of the Tumor Microenvironment and Epithelial-Mesenchymal Transition in Gastric Carcinogenesis

“…Neutrophil-cancer cell interaction can lead to the polarization of neutrophils towards a pro-tumor phenotype [101]. found that bone marrow neutrophils in mice activated by GC cells promote their ability to migrate, thus leading to increased invasiveness.…”

“…Cancer-associated fibroblasts (CAFs) have been shown to have a crucial influence on the initiation, growth, and migration of tumor cells [101]. This is especially due to the reduced cell-to-cell adhesion, enhanced mobility, and constant activation [87,105].…”

“…Macrophages are among a variety of immune cells present in the GC microenvironment. Their plasticity enables them to play a crucial role in the tumor microenvironment [101,139]. Macrophages can acquire either an M1 (classical) or M2 (alternative) phenotype [85].…”