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Employing mesenchymal stem cells to support tumor-targeted delivery of extracellular vesicle (EV)-encapsulated microRNA-379

Oncogene volume 37, pages 2137–2149 (2018)Cite this article

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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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Acknowledgements

The authors are grateful to Catherine Curran, Emer Hennessy, Natasha Solovyova, and Dr. Georgina Shaw for technical support provided.

Funding

KPO’B and SK: Irish Cancer Society BREAST-PREDICT collaborative cancer research center CCRGAL13; KEG: Irish Research Council (IRC) Postgraduate Scholarship GOIPG/2016/978; HZ: IRC Enterprise Partnership Scheme Postdoctoral Research Fellowship EPSPD/2016/20. JRS and KSJ: Wellcome Trust biomedical vacation scholarship; ADB: Health Research Board summer scholarship SS-2015-1365. This research was also supported by Science Foundation Ireland grants 09/SRC/B1794 and 12/RI/2338, funding from the European Union’s 7th Framework Programme under grant agreement no. HEALTH-2007-B-223298 (PurStem), and the charity Breast Cancer Research.

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Authors and Affiliations

  1. Discipline of Surgery, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, Galway, Ireland

    K. P. O’Brien, S. Khan, K. E. Gilligan, C. Glynn, A. De Bhulbh, J. R. Schweber, K. St John, M. J. Kerin & R. M. Dwyer

  2. Cardiovascular Research Centre Galway, School of Medicine, National University of Ireland Galway, Galway, Ireland

    H. Zafar

  3. Discipline of Anatomy, School of Medicine, National University of Ireland Galway, Galway, Ireland

    P. Lalor & P. Dockery

  4. Regenerative Medicine Institute (REMEDI), CURAM, National University of Ireland Galway, Galway, Ireland

    C. O’Flatharta, J. M. Murphy & T. O’Brien

  5. Division of Anatomic Pathology, University Hospital Galway, Galway, Ireland

    H. Ingoldsby

  6. Tissue Optics and Microcirculation Imaging Group, School of Physics, National University of Ireland Galway, Galway, Ireland

    M. Leahy

  7. Cancer Biology and Therapeutics Laboratory, UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland

    W. M. Gallagher

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  1. K. P. O’Brien
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O’Brien, K.P., Khan, S., Gilligan, K.E. et al. Employing mesenchymal stem cells to support tumor-targeted delivery of extracellular vesicle (EV)-encapsulated microRNA-379. Oncogene 37, 2137–2149 (2018). https://doi.org/10.1038/s41388-017-0116-9

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