Abstract
Multiple myeloma (MM) is a hematological malignancy caused by a microenviromentally aided persistence of plasma cells in the bone marrow. Monoclonal plasma cells often secrete high amounts of immunoglobulin free light chains (FLCs) that could induce tissue damage. Recently, we showed that FLCs are internalized in endothelial and myocardial cell lines and secreted in extracellular vesicles (EVs). MM serum derived EVs presented phenotypic differences if compared with monoclonal gammopathy of undetermined significance (MGUS) serum derived EVs suggesting their involvement in MM pathogenesis or progression. To investigate the effect of circulating EVs on endothelial and myocardial cells, we purified MM and MGUS serum derived EVs with differential ultracentrifugation protocols and tested their biological activity. We found that MM and MGUS EVs induced different proliferation and internalization rates in endothelial and myocardial cells, thus we tried to find specific targets in MM EVs docking and processing. Pre-treatment of EVs with anti-FLCs antibodies or heparin blocked the MM EVs uptake, highlighting that FLCs and glycosaminoglycans are involved. Indeed, only MM EVs exposure induced a strong nuclear factor kappa B nuclear translocation that was completely abolished after anti-FLCs antibodies and heparin pre-treatment. The protein tyrosine kinase c-src is present on MM circulating EVs and redistributes to the cell plasma membrane after MM EVs exposure. The anti-FLCs antibodies and heparin pre-treatments were able to block the intracellular re-distribution of the c-src kinase and the subsequent c-src kinase containing EVs production. Our results open new insights in EVs cellular biology and in MM therapeutic and diagnostic approaches.
Highlights
Extracellular vesicles (EVs) are emerging as pleiotropic actors in intercellular signaling
We observed a significant increase in EVs production in MM patients, and monoclonal immunoglobulin free light chains (FLCs) were rerouted in the extracellular space via EVs
In the present study, we found that the intracellular uptake of serum MM EVs is enhanced in comparison to monoclonal gammopathy of undetermined significance (MGUS) EVs
Summary
Extracellular vesicles (EVs) are emerging as pleiotropic actors in intercellular signaling. The discovery of exosome (a specific subpopulation of EVs) mediated transfer of specific mRNAs and miRNAs [1] opened the door for EVs research in cancer biogenesis and progression. EVs carry a broad number of cargos such as molecules that take part in determining cell identity, signaling pathways, and deregulation in many cancer forms. Growing evidences show that tumors constitutively shed exosomes with immunosuppressive effects regulating tumor growth, invasion, angiogenesis, and metastasis [2]. It has been published that normal and MM bone marrow–mesenchymal stem cells (BM–MSC)-derived exosomes differentially affect MM cell homing and growth in vivo. A novel mechanism by which BM–MSCs play an oncogenic role in MM is the epigenetic transfer of exosomal miRNA to the tumor clone [3]
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