Extracellular vesicles shed from gastric cancer mediate protumor macrophage differentiation

Abstract

Background 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. 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. Methods The 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. Results Immunofluorescent 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. Conclusion EVs 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.

Cancer stem cell-derived extracellular vesicles preferentially target MHC-II– macrophages and PD1+ T cells in the tumor microenvironment

“…Numerous studies have shown the ability of tEVs to polarize TAMs towards pro-tumorigenic MHC-II-phenotypes. 63–66 In this respect, our data suggest that tEVs CSC may be the main tEV subset responsible for the reported TAMs polarization.…”

Molecular Mechanisms and Potential Rationale of Immunotherapy in Peritoneal Metastasis of Advanced Gastric Cancer

“…In the study, patients with PM showed an increased number of TAM and M2 macrophages, upregulated levels of angiogenesis in the peritoneum and macrophages, and increased levels of epidermal growth factor and vascular endothelial growth factor-expressing macrophages. Although the mechanical aspect of TAM as a potential therapeutic target is still not well understood, previous studies have shown that M2-like macrophage infiltration is highly associated with PD-L1 expression in GC cells, and that extracellular vesicles derived from GC play a role by affecting macrophage phenotypes [ 97 , 98 ]. Considering these results, immunotherapy or cancer vaccines targeting TAM may be a promising strategy for PM treatment.…”

Anti-Cancer Role and Therapeutic Potential of Extracellular Vesicles

“…These EVs stimulate the motility, invasiveness, and stemness of colorectal cancer cell lines. Cancer cells communicate with the microenvironment for progression through EVs [ 61 , 162 , 163 , 164 ]. MiR-370-3p-containing EVs from breast cancer cells induce IL-6, IL-8, and IL-1β secretion by suppressing the cylindromatosis-/NF-κB-signaling pathway in fibroblasts [ 58 ].…”