Exosomes released by EBV-infected nasopharyngeal carcinoma cells convey the viral Latent Membrane Protein 1 and the immunomodulatory protein galectin 9

The Epstein–Barr virus (EBV) latent membrane protein 1 (LMP1) is expressed in multiple human malignancies and has potent effects on cell growth. It has been detected in exosomes and shown to inhibit immune function. Exosomes are small secreted cellular vesicles that contain proteins, mRNAs, and microRNAs (miRNAs). When produced by malignant cells, they can promote angiogenesis, cell proliferation, tumor-cell invasion, and immune evasion. In this study, exosomes released from nasopharyngeal carcinoma (NPC) cells harboring latent EBV were shown to contain LMP1, signal transduction molecules, and virus-encoded miRNAs. Exposure to these NPC exosomes activated the ERK and AKT signaling pathways in the recipient cells. Interestingly, NPC exosomes also contained viral miRNAs, several of which were enriched in comparison with their intracellular levels. LMP1 induces expression of the EGF receptor in an EBV-negative epithelial cell line, and exosomes produced by these cells also contain high levels of EGF receptor in exosomes. These findings suggest that the effects of EBV and LMP1 on cellular expression also modulate exosome content and properties. The exosomes may manipulate the tumor microenvironment to influence the growth of neighboring cells through the intercellular transfer of LMP1, signaling molecules, and viral miRNAs.

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“…All cells were maintained at 37°C with 5% CO 2 . The C15 xenograft tumor was cultured in vitro for 2 d as previously described (12).…”

Section: Methodsmentioning

confidence: 99%

“…Exosomes are a recently discovered mechanism through which cancer cells and virally infected cells can manipulate their microenvironment. Viruses can use the exosome pathway for virus egress and immune evasion (11)(12)(13). Interestingly, EBV-infected cells release exosomes containing LMP1 that induce T-cell anergy (14).…”

mentioning

confidence: 99%

Human tumor virus utilizes exosomes for intercellular communication

Meckes

Shair

Marquitz

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

479

498

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“…There are still many puzzles of ovarian cancer, including the relationship between the tumor and the host immune system, and the mechanisms of the development, invasion and metastasis of the tumor. Exosomes are a kind of microvesicles released by many types of cells such as tumor cell (1)(2)(3)(4), antigen presenting cells (APC) (5,6) and epithelial cells (7,8). Recent research revealed that exosomes purified from the ascites of patient with ovarian cancer contain some immunological-effect molecules (9).…”

Section: Introductionmentioning

confidence: 99%

Exosomes in the ascites of ovarian cancer patients: origin and effects on anti-tumor immunity

2011

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Abstract. This study was performed to identify the origin of the ascites-derived exosomes from patients with ovarian cancer and to observe the effect of exosomes on anti-tumor immunity. Exosomes were isolated from the ascites of patients with ovarian epithelial cancer by ultracentrifugation plus density gradient centrifugation. The origin of exosomes was identified by immunoelectronmicroscopy (IEM). The growth curve of the tumor cell line SKOV3 cultured with or without exosomes was analyzed. The apoptosis of autogeneic tumor cells (ATCs) and SKOV3 cells affected by exosomes was measured by flow cytometry (FCM) and light phase contrast microscopy. The cytotoxic effect of the peripheral blood mononuclear cells (PBMCs) stimulated by exosomes and/or dendritic cells (DCs) on ovarian cancer cells was measured using a CCK-8 assay. The levels of IFN-Á released by PBMCs stimulated by exosomes and/or DCs were measured by ELISA. The apoptosis of PBMCs and DCs affected by exosomes was measured by FCM and light microscopy. Whether the mature process of DCs was affected by exosomes was studied by FCM. The ratio of CD4 + T cell and CD8 + T cell were measured by FCM. FasL and TRAIL molecules on exosomes were detected by Western blot analysis. The human FasL antagonistic antibody was used to block the apoptosis of DCs and PBMCs induced by exosomes. The receptors of TRAIL DR4 and DR5 on PBMCs and DCs were detected by FCM. In 41 patients examined, we isolated exosomes from the ascites of 35 patients. We detected TCR, CD20, HLA-DR, B7-2, HER2/neu, CA125 and Histone H 2 A on exosomes. We found that exosomes might impair the cytotoxic activity of PBMCs when DCs are present. We found that exosomes had no effect on the growth and apoptosis of SKOV3 cells. However, exosomes may induce apoptosis of precursors, mature DCs and PBMCs. We found that FasL and TRAIL were present in the exosome suspension and addition of an anti-FasL antibody may decrease the percentage of apoptosis of DCs and PBMCs. We conclude that exosomes exist in ascites of 85.4% of patients with ovarian cancer. Moreover, these exosomes may be of multi-origin. Exosomes had no effect on the growth and apoptosis of tumor cells but impaired the cytotoxic activity of PBMCs in the presence of DCs. Exosomes also may induce apoptosis of the precursors of DCs, DCs and PBMCs. FasL and TRAIL on exosomes may partly account for the apoptosis of cells of the immune system.

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“…Latency type II, on the other hand, results in the expression of LMP1, LMP2 and EBNA1 as seen in HL and NPC, whereas in latency type III, all latent proteins/antigens are expressed in the course of acquired immune deficiency syndrome (AIDS)-related lymphomas and lymphoblastoid cell lines (LCLs) [17,18]. Of note, the LMPs-carrying exosomes have been previously shown to be secreted by EBV-infected cells particularly the NPC cells [19][20][21].…”

Section: Exosomal Latent Membrane Proteins (Lmps)mentioning

confidence: 99%

Exosomes as the Promising Biomarker for Epstein-Barr Virus (EBV)-Associated Cancers

Teow¹,

Peh²

2017

Novel Implications of Exosomes in Diagnosis and Treatment of Cancer and Infectious Diseases

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Exosomes are microvesicles with sizes ranging from 50 to 150 nm. These small vesicles are known to morphologically and functionally resemble virus particles from human immunodeficiency virus type I (HIV-I) and human T-lymphotropic virus type I (HTLV-I). The function of exosomes is to mainly mediate cell-to-cell communication by exchanging various macromolecules including proteins, lipids and nucleic acids in diverse cellular processes. Due to its size and structural simplicity, the transfer of pathogenic or virulent cellular factors across the cells mediated by exosomes is more efficient, hence facilitating the dissemination of viral infections and cancer diseases. The pathogenic role of exosomes in various cancers such as lung and breast, and their potentials as biomarkers have been previously studied, yet limited information is known for Epstein-Barr virus (EBV)-associated cancers. In this chapter, we discuss current evidences that support the pathogenic roles of exosomes in EBV-related cancers and their potentials as biomarkers in cancer diagnostics and therapy response. Here, we also highlight the potential challenges in the development of exosome-based biomarkers for clinical application.

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Exosomes released by EBV-infected nasopharyngeal carcinoma cells convey the viral Latent Membrane Protein 1 and the immunomodulatory protein galectin 9

Cited by 237 publications

References 38 publications

Human tumor virus utilizes exosomes for intercellular communication

Human tumor virus utilizes exosomes for intercellular communication

Exosomes in the ascites of ovarian cancer patients: origin and effects on anti-tumor immunity

Exosomes as the Promising Biomarker for Epstein-Barr Virus (EBV)-Associated Cancers

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