Abstract
BackgroundExosomes are membrane nano-vesicles secreted by a multitude of cells that harbor biological constituents such as proteins, lipids, mRNA and microRNA. Exosomes can potentially transfer their cargo to other cells, implicating them in many patho-physiological processes. Mesenchymal stem cells (MSCs), residents of the bone marrow and metastatic niches, potentially interact with cancer cells and/or their derived exosomes. In this study, we investigated whether exosomes derived from adult T-cell leukemia/lymphoma (ATL) cells act as intercellular messengers delivering leukemia-related genes that modulate the properties of human MSCs in favor of leukemia. We hypothesized that the cargo of ATL-derived exosomes is transferred to MSCs and alter their functional behavior to support the establishment of the appropriate microenvironment for leukemia.ResultsWe showed that both ATL cells (C81 and HuT-102) and patient-derived cells released Tax-containing exosomes. The cargo of HuT-102-derived exosomes consisted of miR-21, miR-155 and vascular endothelial growth factor. We demonstrated that HuT-102-derived exosomes not only deliver Tax to recipient MSCs, but also induce NF-κB activation leading to a change in cellular morphology, increase in proliferation and the induction of gene expression of migration and angiogenic markers.ConclusionsThis study demonstrates that ATL-derived exosomes deliver Tax and other leukemia-related genes to MSCs and alter their properties to presumably create a more conducive milieu for leukemia. These findings highlight the contribution of leukemia-derived exosomes in cellular transformation and their potential value as biomarkers and targets in therapeutic strategies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-016-0307-4) contains supplementary material, which is available to authorized users.
Highlights
Exosomes are membrane nano-vesicles secreted by a multitude of cells that harbor biological con‐ stituents such as proteins, lipids, messenger RNA (mRNA) and microRNA
Exosomes derived from adult T-cell leukemia/lymphoma (ATL) cells harbor Tax, miR‐21, miR‐155 and vascular endothelial growth factor (VEGF) The presence of secreted exosomes in the culture supernatants of Human T-cell lymphotropic virus type I (HTLV-I) negative and positive cell lines was assessed by Scanning Electron Microscope (SEM) and by the expression of exosome specific markers
The cargo of leukemia-derived exosomes included Tax which was detected in the exosomes isolated from HTLV-I positive cells and not in those isolated from negative cells, at the RNA and protein levels
Summary
Exosomes are membrane nano-vesicles secreted by a multitude of cells that harbor biological con‐ stituents such as proteins, lipids, mRNA and microRNA. Whereas the role of exosomes derived from solid cancers has been extensively investigated in supporting tumor growth, angiogenesis, metastasis and drug resistance [17, 19], their function in hematological malignancies has not been fully assessed Some studies highlighted their immuno-suppressive functions [20,21,22,23] whereas others reported an enhanced cytotoxic effect of immune cells pre-exposed to leukemiaderived exosomes [20, 24,25,26]. Taverna et al demonstrated that exosomes from chronic myeloid leukemia (CML) cell lines trigger endothelial cell activation and angiogenesis due to IL-8-mediated increase in cell adhesion molecules [27, 28] This angiogenic effect was attributed by other studies to specific exosomal microRNAs (miRNAs) that stimulate endothelial cell migration and tube formation [29, 30]. Exosomes from HTLV-I positive cells were found to contain viral proteins and inflammatory mediators and to protect target cells from apoptosis [36]
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