Mesenchymal Stem-Cell-Derived Exosomes as Novel Drug Carriers in Anti-Cancer Treatment: A Myth or Reality?

Abstract

Although cancer therapy has significantly advanced in recent decades, patients and healthcare professionals are still quite concerned about adverse effects due to the non-targeted nature of currently used chemotherapeutics. Results obtained in a large number of recently published experimental studies indicated that mesenchymal stem-cell-derived exosomes (MSC-Exos), due to their biocompatibility, ability to cross biological barriers, and inherent targeting capabilities, could be used as a promising drug-delivery system for anti-cancer therapies. Their lipid bilayer protects cargo of anti-cancer drugs, making them excellent candidates for the delivery of therapeutic agents. MSC-Exos could be engineered to express ligands specific for tumor cells and, therefore, could selectively deliver anti-cancer agents directly in malignant cells, minimizing side effects associated with chemotherapeutic-dependent injury of healthy cells. MSC-Exos can carry multiple therapeutic agents, including anti-cancer drugs, micro RNAs, and small bioactive molecules, which can concurrently target multiple signaling pathways, preventing tumor growth and progression and overcoming resistance of tumor cells to many standard chemotherapeutics. Accordingly, in this review article, we summarized current knowledge and future perspectives about the therapeutic potential of MSCs-Exos in anti-cancer treatment, opening new avenues for the targeted therapy of malignant diseases.

Keywords: anti-cancer agents; exosomes; mesenchymal stem cells; micro RNAs; target therapy.

Figure 1

Molecular mechanisms responsible for the beneficial effects of MSC-Exos-mediated delivery of anti-cancer agents. Due to their nano-size dimension, biocompatibility, ability to cross biological barriers, and capacity to deliver their cargo directly into target cells, MSC-Exos have been used as carriers of many anti-cancer drugs and bioactive molecules. MSC-Exos were able to selectively deliver several chemotherapeutics (doxorubicin, paclitaxel, vincristine sulfate, atorvastatin, norcantharidin) in tumor cells, minimizing side effects associated with chemotherapeutic-driven injury of tumor-surrounding healthy cells. Additionally, MSC-Exos managed to increase accumulation of these anti-cancer drugs in tumor tissues and to enhance their toxicity against malignant cells. In tumor cells, MSC-Exos modulated PI3K/Akt and MAPK signaling pathways and induced programmed cell death by increasing synthesis of pro-apoptotic proteins (Bax and caspase-3) and by suppressing synthesis of anti-apoptotic Bcl-2 protein. By delivering reovirus directly in acute myeloid cells, MSC-Exos enhanced viral-induced oncolytic effects against these malignant cells. Additionally, reovirus-infected tumor cells were easily recognized by dendritic cells which presented viral antigens to cytotoxic T cells, inducing activation of T-cell-driven immune response against tumor cells. Additionally, MSC-Exos were used for targeted delivery of anti-cancer micro RNAs (miRNAs) in tumor tissues. By delivering miR-26a into hepatocellular carcinoma cells, MSC-Exos suppressed CDK6 and E2F3-dependent proliferation and invasiveness of tumor cells and inhibited rapid growth and progression of liver cancer in experimental animals. MSC-Exos were used to transfer miR-138-5p in bladder cancer cells, inhibiting the expression of oncogenic YY1 factor. MiR-29b-carrying MSC-Exos managed to significantly reduce total number of peritoneal metastases in gastric-cancer-bearing animals. By delivering anti-Mir221 in colon cancer cells, MSC-Exos increased the expression of tumor-suppressor genes (PTEN and p57KIP2), induced programmed cell death of malignant cells and attenuated growth and progression of colon cancer in experimental animals.