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 7

Characterization of exosomal protein content and functional sequelae.

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Characterization of exosomal protein content and functional sequelae. (A...
(A) Scatter plot showing exosomal and cellular protein content of MM and normal BM-MSC–derived samples. (B) MM.1S cells were exposed to exosomes isolated from MM (n = 6) or normal (n = 3) BM-MSCs for 24 hours, and IL-6 concentration was measured on conditioned media using human IL-6 ELISA. Bars indicate SD. (C) MM.1S cells were exposed to exosomes isolated from MM or normal BM-MSCs for 24 hours, and IL-6 concentration was measured in conditioned media in the presence or absence of an IL-6–blocking antibody (0.2 μg/ml) using human IL-6 ELISA. Mouse IgG2B served as isotype control. Bars indicate SD. (D) Western blot on MM (n = 6) and normal (n = 3) BM-MSC–derived exosomes using anti-fibronectin, anti–junction plakoglobin, anti-CCL2, and anti-actin antibodies. (E and F) Adhesion of MM cells to BSA (negative control), poly-d-lysine (positive control), and fibronectin-coated wells, exposed or not to MM (n = 4) or normal (n = 3) BM-MSC–derived exosomes (200 μg/ml; 6 hours). Length of adhesion was 2 hours. All data are mean ± SD of triplicate experiments. Cell-conditioned media absent cells and processed as in all samples tested served as control.