Abstract
The Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is characterized by the infiltration of lymphocytes and a unique tumor microenvironment. Exosomes from cancer cells are essential for intercellular communication. The aims of this study were to investigate the secretion of EBVaGC exosomes and their physiological effect on dendritic cell maturation in vitro and to characterize dendritic cells (DCs) in EBVaGC in vivo. Western blotting analysis of CD63 and CD81 of exosomes from EBV-infected gastric cancer cell lines indicated an increase in exosome secretion. The fraction of monocyte-derived DCs positive for the maturation marker CD86 was significantly suppressed when incubated with exosomes from EBV-infected gastric cancer cell lines. Immunohistochemical analysis of GC tissues expressing DC markers (S100, Langerin, CD1a, CD83, CD86, and BDCA-2) indicated that the density of DCs was generally higher in EBVaGC than in EBV-negative GC, although the numbers of CD83- and CD86-positive DCs were decreased in the group with high numbers of CD1a-positive DCs. A low number of CD83-positive DCs was marginally correlated with worse prognosis of EBVaGC in patients. EBVaGC is a tumor with abundant DCs, including immature and mature DCs. Moreover, the maturation of DCs is suppressed by exosomes from EBV-infected epithelial cells.
Highlights
The Epstein-Barr virus (EBV) is a γ-herpesvirus and has been associated with neoplastic growth of various human cells, including lymphocytes of B, T, and NK-cell lineages and epithelial cells of the nasopharynx and stomach [1]
Exosomes Purified from Gastric Cancer Cell Lines with and without EBV Infection
To evaluate the exosomes of gastric cancer cell lines with EBV-infection (MKN7 + EBV and MKN7 + EBV) and of a cancer cell lines from an EBV gastric carcinoma (SNU719), the presence of EBV was confirmed by positive results of EBNA1-RT-PCR and the absence of lytic infection by negative results of BZLF1-RT-PCR, respectively (Figure 1A)
Summary
The Epstein-Barr virus (EBV) is a γ-herpesvirus and has been associated with neoplastic growth of various human cells, including lymphocytes of B-, T-, and NK-cell lineages and epithelial cells of the nasopharynx and stomach [1]. How EBV initiates and maintains neoplastic growth of latently infected cells that counteract immune surveillance in a specific milieu of each cell type has not yet been elucidated. EBV-associated gastric carcinoma (EBVaGC) is characterized by the clonal growth of EBV-infected stomach epithelial cells, and the frequency of EBVaGC takes up nearly 10% of gastric carcinoma cases [2]. EBVaGC has a unique histologic subtype that is known as gastric carcinoma with lymphoid stroma (GCLS); EBVaGC requires intensive investigation such that its interaction with immune cells, especially in this type of EBV-infected malignant tumor, is elucidated. The elucidation of the characteristics of exosomes and their role in tumor development is expected to contribute on how the tumor microenvironment and cancer growth can be manipulated and suppressed
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