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Review
. 2022 Jan;47(1):13.
doi: 10.3892/or.2021.8224. Epub 2021 Nov 15.

New insights into Epstein‑Barr virus‑associated tumors: Exosomes (Review)

Wei Chen #  1 , Yao Xie #  1 , Tingting Wang  1 , Lin Wang  1
Affiliations
Review

New insights into Epstein‑Barr virus‑associated tumors: Exosomes (Review)

Wei Chen et al. Oncol Rep. 2022 Jan.

Abstract

Epstein‑Barr virus (EBV) is endemic worldwide and is associated with a number of human tumors. EBV‑associated tumors have unique mechanisms of tumorigenesis. EBV encodes multiple oncogenic molecules that can be loaded into exosomes released by EBV+ tumor cells to mediate intercellular communication. Moreover, different EBV+ tumor cells secrete exosomes that act on various target cells with various biological functions. In addition to oncogenicity, EBV+ exosomes have potential immunosuppressive effects. Investigating EBV+ exosomes could identify the role of EBV in tumorigenesis and progression. The present review summarized advances in studies focusing on exosomes and the functions of EBV+ exosomes derived from different EBV‑associated tumors. EBV+ exosomes are expected to become a new biomarker for disease diagnosis and prognosis. Therefore, exosome‑targeted therapy displays potential.

Keywords: Epstein‑Barr virus; biomarker; exosome; immunosuppressive; microRNAs.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1.
Figure 1.
Overview of formation of exosomes and exosomes in the TME. EBV-encoded molecules, such as EBER and LMP-1, are loaded into exosomes and regulate the formation of exosomes. The endosomal sorting complex required for transport pathway and associated proteins, including CD63, Syntenin-1, Alix, TSG101 and Hrs, interact with LMP-1, inducing LMP-1 loading in exosomes. Tumor-derived exosomes target surrounding cells or enter the fluid circulation. Stress from the TME, such as hypoxia and acidic microenvironment, stimulates the synthesis and secretion of exosomes. TME, tumor microenvironment; EBV, Epstein-Barr virus; EBER, EBV-encoded RNA; LMP, latent membrane protein; Alix, programmed cell death 6 interacting protein; TSG101, tumor susceptibility 101; Hrs, human growth factor-regulated tyrosine kinase substrate; UCH-L1, ubiquitin C-terminal hydrolase L1; TRAF2, TNF receptor associated factor 2; CHMPs, charged multivesicular body proteins; MVE, multivesicular endosome; La, Lupus antigen; MHC, major histocompatibility complex; TCR, T cell receptor.
Figure 2.
Figure 2.
Role of EBV+ exosomes in the TME of B cell lymphoma, NPC and EBVaGC. For B cell lymphoma, EBV+ exosomes primarily act on lymphocytes with immunomodulatory functions. The EBV+ exosomes induce the proliferation and differentiation of naive B cells into plasmablast-like B cells. EBV+ exosomes also target macrophages, leading to transformation into TAMs and stimulating the secretion of immunosuppressive cytokines to inhibit CD8+ T cells. Moreover, EBV+ exosomes inhibit T cell synthesis of IL-1β. In the TME of NPC, EBV+ exosomes exert a strong immunosuppressive function, which is induced by recruiting Tregs and promoting CD8+ T cell apoptosis. In addition, EBV+ exosomes from NPC target endothelium, fibroblasts and epithelium to stimulate cell growth by delivering EGFR. EBV+ exosomes from NPC also stimulate EMT, promoting tumor metastasis and angiogenesis. The immunosuppressive effects of EBV+ exosomes from EBVaGC are primarily achieved via inhibiting pDCs. miR-BART15-3p is enriched in exosomes from EBVaGC cells and can induce the apoptosis of target cells, including tumor cells. EBV, Epstein-Barr virus; TME, tumor microenvironment; NPC, nasopharyngeal carcinoma; EBVaGC, EBV-associated gastric cancer; TAM, tumor-associated macrophages; EGFR, epidermal growth factor receptor; EMT, epithelial-mesenchymal transition; pDC, plasmacytoid dendritic cells; miR, microRNA; BART, BamHI-A rightward transcripts; NLRP, NLR family pyrin domain; ARG1, arginase 1; IL, interleukin; EBER, EBV-encoded RNA; TCR, T cell receptor; MHC, major histocompatibility complex; LMP, latent membrane protein; FGF, fibroblast growth factor; EGFR, epidermal growth factor receptor; HIF, hypoxia-inducible factor; CCL, C-C motif chemokine ligand; EBNA, Epstein-Barr nuclear antigen; La, lupus antigen; BHFR, BamHI fragment H rightward open reading frame; BRUCE, baculovirus inhibitor of apoptosis repeat-containing ubiquitin-conjugating enzyme; DC, dendritic cell.
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References

    1. Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet. 1964;1:702–703. doi: 10.1016/S0140-6736(64)91524-7. - DOI - PubMed
    1. Vockerodt M, Yap LF, Shannon-Lowe C, Curley H, Wei W, Vrzalikova K, Murray PG. The Epstein-Barr virus and the pathogenesis of lymphoma. J Pathol. 2015;235:312–322. doi: 10.1002/path.4459. - DOI - PubMed
    1. Tsao SW, Tsang CM, To KF, Lo KW. The role of Epstein-Barr virus in epithelial malignancies. J Pathol. 2015;235:323–333. doi: 10.1002/path.4448. - DOI - PMC - PubMed
    1. Niller HH, Banati F, Salamon D, Minarovits J. Epigenetic alterations in Epstein-Barr virus-associated diseases. Adv Exp Med Biol. 2016;879:39–69. doi: 10.1007/978-3-319-24738-0_3. - DOI - PubMed
    1. Lyu X, Wang J, Guo X, Wu G, Jiao Y, Faleti OD, Liu P, Liu T, Long Y, Chong T, et al. EBV-miR-BART1-5P activates AMPK/mTOR/HIF1 pathway via a PTEN independent manner to promote glycolysis and angiogenesis in nasopharyngeal carcinoma. PLoS Pathog. 2018;14:e1007484. doi: 10.1371/journal.ppat.1007484. - DOI - PMC - PubMed

Grants and funding

The present study was supported by the Department of Science and Technology of Sichuan Province (grant no. 2019YFS0250 and 2018SZ0162).