BM mesenchymal stromal cell–derived exosomes facilitate multiple myeloma progression
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
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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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.