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 2

Normal and MM BM-MSC–derived exosomes differentially affect MM cell proliferation in vitro and in vivo.

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Normal and MM BM-MSC–derived exosomes differentially affect MM cell prol...
(A and B) MM cell lines MM.1S (A) and RPMI.8226 (B) (30,000 cells/well; RPMI medium plus 10% exosome-depleted FBS) were cultured in the absence or presence of MM (n = 4), MGUS (n = 2), smoldering MM (S-MM; n = 2), or normal (n = 4) BM-MSC–derived exosomes (200 μg/ml; 48 hours). Loaded exosomes are expressed as μg of protein-containing exosomes. Cell proliferation was assessed using [3H]-thymidine uptake. Cell-conditioned media absent cells and processed as in all samples tested served as control. Average of 3 independent experiments is shown. P values were generated using ANOVA. MM and normal BM-MSC–derived exosomes showed a differential impact on MM cell growth in vitro. (C) TEBs were loaded with GFP+Luc+ MM.1S cells alone or with primary MM or normal BM-MSC–derived exosomes (3 × 106 cells/TEB; 1 μg exosomes) and implanted subcutaneously in SCID mice. Exosomes (1 μg) were also injected in situ every 4 days until the end of the studies. Tumor growth was determined by measuring bioluminescence imaging (BLI) intensity at baseline (t0) and days 7 (t1), 10 (t2), and 14 (t3) (n = 5 per group). MM and normal BM-MSC–derived exosomes showed a differential impact on MM cell growth in vivo.