Emerging Roles of Mesenchymal Stem/Stromal-Cell-Derived Extracellular Vesicles in Cancer Therapy

Abstract

Despite the tremendous efforts of many researchers and clinicians, cancer remains the second leading cause of mortality worldwide. Mesenchymal stem/stromal cells (MSCs) are multipotent cells residing in numerous human tissues and presenting unique biological properties, such as low immunogenicity, powerful immunomodulatory and immunosuppressive capabilities, and, in particular, homing abilities. Therapeutic functions of MSCs are mediated mostly by the paracrine effect of released functional molecules and other variable components, and among them the MSC-derived extracellular vesicles (MSC-EVs) seem to be one of the central mediators of the therapeutic functions of MSCs. MSC-EVs are membrane structures secreted by the MSCs, rich in specific proteins, lipids, and nucleic acids. Amongst these, microRNAs have achieved the most attention currently. Unmodified MSC-EVs can promote or inhibit tumor growth, while modified MSC-EVs are involved in the suppression of cancer progression via the delivery of therapeutic molecules, including miRNAs, specific siRNAs, or suicide RNAs, as well as chemotherapeutic drugs. Here, we present an overview of the characteristics of the MSCs-EVs and describe the current methods for their isolation and analysis, the content of their cargo, and modalities for the modification of MSC-EVs in order for them to be used as drug delivery vehicles. Finally, we describe different roles of MSC-EVs in the tumor microenvironment and summarize current advances of MCS-EVs in cancer research and therapy. MSC-EVs are expected to be a novel and promising cell-free therapeutic drug delivery vehicle for the treatment of cancer.

Keywords: cancer therapy; cell-free therapy; drug delivery vehicle; extracellular vesicles; mesenchymal cells.

Figure 1

Schematic representation of the biogenesis and cargo of MSC–EVs. Extracellular vesicles (EVs) are a heterogenous group of lipid bilayer membrane organelles of different size (~30–3000 nm). Their subpopulations are derived via distinct pathways. Exosomes which are formed by inward budding of the endolysosomal membrane create early endosomes (EEs) during the maturation of multivesicular endosomes (MVEs) and are released by exocytosis upon fusion of MVEs with cell surface. Microvesicles are formed by shedding out from the cell plasma membrane. MSC-EV cargo comprises luminal-cargo-containing proteins, nucleic acids, peptides, amino acids, and lipid derivates surrounded by a lipid bilayer membrane. MSC-EVs contain transmembrane proteins, lipid-anchored membrane proteins, surface proteins, including MSC-specific proteins (e.g., CD73), soluble proteins, transport proteins (tubulin, actin, and actin-binding molecules), tetraspanins (CD9, CD63, CD81, and CD82), cell adhesion proteins, integrins, ESCRT proteins, enzymes, heat-shock proteins, and various types of RNAs and DNAs6. Created by BioRender.com.

Figure 2

Bioengineering of MSC-EVs and applications of bioengineered MSC-EVs in cancer therapy. Engineered MSC-EVs enhance tumor targeting specificity through targeted drug delivery, increased drug sensitivity of cancer cells, and enhanced efficiency of targeted therapy. Bioengineered MSC-EVs exhibit a higher therapeutic potential, which facilitates the inhibition of cancer progression.6There are two main categories of MSC-EV engineering, cargo engineering and surface engineering, including two main loading strategies: pre-loading and post-loading. Surface modifications are referring to specific targeting of MSC-EVs. Created by BioRender.com.

Figure 3

Schematic representation of distinct roles of native MSC-EVs in tumor microenvironment. Mesenchymal stem/stromal cells (MSCs) are present in multiple human tissues, including bone marrow, adipose tissue, amniotic fluid, dental pulp, umbilical cord blood, Wharton´s jelly, etc. Natural MSC-EVs manifest dual role in promoting and inhibiting multiple stages of tumorigenesis. They can mediate tumor proliferation, angiogenesis, apoptosis, tumor invasion (EMT), resistance to drugs, radio- and chemotherapy, and immunosuppression. On the other hand, natural MSC-EVs can exhibit therapeutic effects of modulating immune response, promoting apoptosis of cancer cells, inhibiting EMT and tumor invasion, and enhancing drug sensitivity. Created by BioRender.com.