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

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.

Fat Therapeutics: The Clinical Capacity of Adipose-Derived Stem Cells and Exosomes for Human Disease and Tissue Regeneration

“…Similar results were shown in a breast cancer study (O'Brien et al, 2018) employing ADSC-EVs enriched with miR-379, a tumor suppressor miRNA whose expression is down-regulated in breast cancer (Khan et al, 2013). It was found that the miR-379-enriched ADSC-EVs significantly inhibited tumor growth without adverse effects in mice over the 6 weeks of monitoring (O'Brien et al, 2018). These findings suggested a potential application of genetically engineered ADSCs to promote secretion of EVs encapsulated in tumor suppressor miRNAs may be a promising, novel strategy to treat cancer.…”

“…Lou et al demonstrated that miR-122 transfected ADSC-secreted EVs were rich in miR-122, and that uptake of these EVs by cultured HCC cells lead to increased chemosensitivity to chemotherapeutic agents and significant reduction in tumor growth in vivo (Lou et al, 2015). Similar results were shown in a breast cancer study (O'Brien et al, 2018) employing ADSC-EVs enriched with miR-379, a tumor suppressor miRNA whose expression is down-regulated in breast cancer (Khan et al, 2013). It was found that the miR-379-enriched ADSC-EVs significantly inhibited tumor growth without adverse effects in mice over the 6 weeks of monitoring (O'Brien et al, 2018).…”

Prodrug suicide gene therapy for cancer targeted intracellular by mesenchymal stem cell exosomes

“…Therefore, we do not think that exosomal miRNAs could be associated with therapeutic effect by the modulation of target gene expression in tumor cells. This does not exclude the possibility of the active involvement of exosomal miRNAs in the gene regulation in recipient tumor cells . A number of studies in the field of regenerative medicine have shown that nanoparticles produced by MSCs exert their therapeutic effects in several diseases.…”

Extracellular vesicles, news about their role in immune cells: physiology, pathology and diseases

“…Improvements developed recently are focused on the treatment of single or various cancers. The systemic administration of such EVs has demonstrated therapeutic effects in cancer and its metastases [69]. Consider now three other examples specific for single cancers.…”

“…Another approach, already promising for in-vivo therapy of breast cancer, is based on the engineering of MSC cells competent for the release of EVs enriched in the microRNA, miR-379. The systemic administration of such EVs has demonstrated therapeutic effects in cancer and its metastases [69].…”