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A Preclinical Mouse Model of Osteosarcoma to Define the Extracellular Vesicle-mediated Communication Between Tumor and Mesenchymal Stem Cells
Published on: May 6, 2018
Employing mesenchymal stem cells to support tumor-targeted delivery of extracellular vesicle (EV)-encapsulated
K P O'Brien1, S Khan1, K E Gilligan1
1Discipline of Surgery, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, Galway, Ireland.
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.
Insights
Engineered mesenchymal stem cells (MSCs) secrete extracellular vesicles (EVs) carrying miR-379, a tumor suppressor microRNA. These miR-379 enriched EVs show therapeutic potential for metastatic breast cancer by reducing tumor growth and increasing necrosis.
Area of Science:
- Oncology
- Cell Biology
- Biotechnology
Background:
- Adult Mesenchymal Stem Cells (MSCs) possess tumor-homing capabilities, making them suitable for targeted cancer delivery.
- MSCs release extracellular vesicles (EVs) containing microRNAs involved in intercellular communication.
- MicroRNAs, such as miR-379, are implicated in cancer progression and can act as tumor suppressors.
Purpose of the Study:
- To characterize miR-379 as a potential tumor suppressor in breast cancer.
- To engineer MSCs for enhanced secretion of miR-379-enriched EVs for therapeutic applications.
- To evaluate the in vivo efficacy of these engineered EVs in a breast cancer model.
Main Methods:
- Assessed miR-379 expression levels in patient tumor tissues and metastases.
- Stably expressed miR-379 in breast cancer cell lines (T47D, HCC-1954) to evaluate its effect on tumor formation and growth in vivo.
- Engineered MSCs to overexpress miR-379 and secrete miR-379-enriched EVs.
- Characterized the size and morphology of secreted EVs.
- Administered engineered MSCs and their derived EVs to mice bearing breast cancer xenografts to assess therapeutic effects and safety.
Main Results:
- miR-379 expression was significantly lower in lymph node metastases compared to primary tumors.
- Overexpression of miR-379 reduced tumor formation and growth in T47D cells and increased tumor necrosis in HCC-1954 cells.
- Engineered MSCs successfully produced EVs enriched with miR-379, with appropriate exosomal characteristics.
- Systemic administration of cell-free EVs enriched with miR-379 demonstrated a therapeutic effect without causing adverse effects.
- miR-379 was found to regulate COX-2 expression in breast cancer cells.
Conclusions:
- miR-379 functions as a potent tumor suppressor in breast cancer, partly by regulating COX-2.
- MSCs engineered to secrete miR-379-enriched EVs represent a promising cell-free therapeutic strategy for metastatic breast cancer.
- This approach leverages the natural tumor-homing ability of MSCs for targeted delivery of therapeutic microRNAs.
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