BM mesenchymal stromal cell–derived exosomes facilitate multiple myeloma progression
Aldo M. Roccaro, … , David T. Scadden, Irene M. Ghobrial
Aldo M. Roccaro, … , David T. Scadden, Irene M. Ghobrial
Published March 1, 2013
Citation Information: J Clin Invest. 2013;123(4):1542-1555. https://doi.org/10.1172/JCI66517.
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Research Article Oncology

BM mesenchymal stromal cell–derived exosomes facilitate multiple myeloma progression

Abstract

BM mesenchymal stromal cells (BM-MSCs) support multiple myeloma (MM) cell growth, but little is known about the putative mechanisms by which the BM microenvironment plays an oncogenic role in this disease. Cell-cell communication is mediated by exosomes. In this study, we showed that MM BM-MSCs release exosomes that are transferred to MM cells, thereby resulting in modulation of tumor growth in vivo. Exosomal microRNA (miR) content differed between MM and normal BM-MSCs, with a lower content of the tumor suppressor miR-15a. In addition, MM BM-MSC–derived exosomes had higher levels of oncogenic proteins, cytokines, and adhesion molecules compared with exosomes from the cells of origin. Importantly, whereas MM BM-MSC–derived exosomes promoted MM tumor growth, normal BM-MSC exosomes inhibited the growth of MM cells. In summary, these in vitro and in vivo studies demonstrated that exosome transfer from BM-MSCs to clonal plasma cells represents a previously undescribed and unique mechanism that highlights the contribution of BM-MSCs to MM disease progression.

Authors

Aldo M. Roccaro, Antonio Sacco, Patricia Maiso, Abdel Kareem Azab, Yu-Tzu Tai, Michaela Reagan, Feda Azab, Ludmila M. Flores, Federico Campigotto, Edie Weller, Kenneth C. Anderson, David T. Scadden, Irene M. Ghobrial

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Figure 1

Characterization of BM-MSC–derived exosomes and their ability to be transferred to MM cells.

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Characterization of BM-MSC–derived exosomes and their ability to be tran...
(A) Primary BM-MSCs are able to release exosomes. Exosomes were immunogold labeled with anti-CD63 and anti-CD81. Scale bar: 100 nm. (B) Western blot on MM (n = 3) and normal (n = 2) BM-MSC–derived exosome proteins using anti-CD63 and anti-CD81 antibodies. The normal stromal cell line HS-5 is also shown. Lysates obtained from human CD63– or human CD81–transfected 293T cells served as positive controls. (C) MM.1S cells were cultured in the absence (control) or presence of normal or MM BM-MSC–derived PKH67-labeled exosomes for 30 minutes. Exosomes were uptaken from MM cells, as shown using a confocal microscope (original magnification, ×100). MM cells were stained using DAPI (nuclei) and FITC-conjugated anti-tubulin antibody.