Abstract
BackgroundPeritoneal dissemination often develops in gastric cancer. Tumor-associated macrophages (TAMs) are present in the peritoneal cavity of gastric cancer patients with peritoneal dissemination, facilitating tumor progression. However, the mechanism by which macrophages differentiate into tumor-associated macrophages in the peritoneal cavity is not well understood. In this study, the interplay between gastric cancer-derived extracellular vesicles (EVs) and macrophages was investigated.MethodsThe association between macrophages and EVs in peritoneal ascitic fluid of gastric cancer patients, or from gastric cancer cell lines was examined, and their roles in differentiation of macrophages and potentiation of the malignancy of gastric cancer were further explored.ResultsImmunofluorescent assays of the ascitic fluid showed that M2 macrophages were predominant along with the cancer cells in the peritoneal cavity. EVs purified from gastric cancer cells, as well as malignant ascitic fluid, differentiated peripheral blood mononuclear cell-derived macrophages into the M2-like phenotype, which was demonstrated by their morphology and expression of CD163/206. The macrophages differentiated by gastric cancer-derived EVs promoted the migration ability of gastric cancer cells, and the EVs carried STAT3 protein.ConclusionEVs derived from gastric cancer play a role by affecting macrophage phenotypes, suggesting that this may be a part of the underlying mechanism that forms the intraperitoneal cancer microenvironment.
Highlights
Peritoneal dissemination often develops in gastric cancer
CD163 + macrophages and extracellular vesicles were detected in cytology-positive peritoneal washings or malignant ascitic fluid from gastric cancer patients Since it has been reported that intraperitoneal macrophages are preferentially differentiated into M2 macrophages in Gastric cancer (GC) patients, cellular components in peritoneal washings in a case of a peritoneal cytology-positive GC patient were investigated
extracellular vesicles (EVs) were purified from malignant ascitic fluid derived from GC patients with cancer dissemination (Fig. 1d-f) or peritoneal washings collected during surgery for a GC patient (Fig. S1 A, B), indicating that a certain amount of EVs existed in the peritoneal cavity in GC patients
Summary
Peritoneal dissemination often develops in gastric cancer. Tumor-associated macrophages (TAMs) are present in the peritoneal cavity of gastric cancer patients with peritoneal dissemination, facilitating tumor progression. The mechanism by which macrophages differentiate into tumor-associated macrophages in the peritoneal cavity is not well understood. The interplay between gastric cancer-derived extracellular vesicles (EVs) and macrophages was investigated. Peritoneal dissemination is one of the most common metastatic patterns of GC [2], and it results in a poor prognosis, but its underlying mechanism remains unclear. M1 type macrophages have a role in anti-tumor immunity and the inflammatory response. M2 type macrophages are involved in the anti-inflammatory response, wound healing, and pro-tumorigenic properties. TAMs are generally considered to more closely resemble the M2-type and thereby modulate the pro-tumor microenvironment [6]. Targeting TAMs has been investigated in clinical studies [7,8,9]
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