Employing mesenchymal stem cells to support tumor-targeted delivery of extracellular vesicle (EV)-encapsulated microRNA-379
O’Brien, K. P. Khan, S. Gilligan, K. E. Zafar, H. Lalor, P. Glynn, C. O’Flatharta, C. Ingoldsby, H. Dockery, P. De Bhulbh, A.
O’Brien, K. P.
Khan, S.
Gilligan, K. E.
Zafar, H.
Lalor, P.
Glynn, C.
O’Flatharta, C.
Ingoldsby, H.
Dockery, P.
De Bhulbh, A.
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Publication Date
2018-01-25
Type
Article
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Citation
O’Brien, K. P., Khan, S., Gilligan, K. E., Zafar, H., Lalor, P., Glynn, C., , O’Flatharta, C., Ingoldsby, H., Dockery, P. De Bhulbh, A., Schweber, J. R., St John, K., Leahy, M., Murphy, J. M., Gallagher, W. M., O’Brien, T., Kerin, M. J., Dwyer, R. M., Dwyer, R. M. (2018). Employing mesenchymal stem cells to support tumor-targeted delivery of extracellular vesicle (EV)-encapsulated microRNA-379. Oncogene, 37(16), 2137-2149. doi: 10.1038/s41388-017-0116-9
Abstract
Adult Mesenchymal Stem Cells (MSCs) have a well-established tumor-homing capacity, highlighting potential as tumor-targeted delivery vehicles. MSCs secrete extracellular vesicle (EV)-encapsulated microRNAs, which play a role in intercellular communication. The aim of this study was to characterize a potential tumor suppressor microRNA, miR-379, and engineer MSCs to secrete EVs enriched with miR-379 for in vivo therapy of breast cancer. miR-379 expression was significantly reduced in lymph node metastases compared to primary tumor tissue from the same patients. A significant reduction in the rate of tumor formation and growth in vivo was observed in T47D breast cancer cells stably expressing miR-379. In more aggressive HER2-amplified HCC-1954 cells, HCC-379 and HCC-NTC tumor growth rate in vivo was similar, but increased tumor necrosis was observed in HCC-379 tumors. In response to elevated miR-379, COX-2 mRNA and protein was also significantly reduced in vitro and in vivo. MSCs were successfully engineered to secrete EVs enriched with miR-379, with the majority found to be of the appropriate size and morphology of exosomal EVs. Administration of MSC-379 or MSC-NTC cells, or EVs derived from either cell population, resulted in no adverse effects in vivo. While MSC-379 cells did not impact tumor growth, systemic administration of cell-free EVs enriched with miR-379 was demonstrated to have a therapeutic effect. The data presented support miR-379 as a potent tumor suppressor in breast cancer, mediated in part through regulation of COX-2. Exploiting the tumor-homing capacity of MSCs while engineering the cells to secrete EVs enriched with miR-379 holds exciting potential as an innovative therapy for metastatic breast cancer.
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Publisher
Springer Nature
Publisher DOI
10.1038/s41388-017-0116-9
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Attribution-NonCommercial-NoDerivs 3.0 Ireland