Acquisition of new tumor cell properties by MSC-derived exosomes

Abstract

Interaction between multi-functional mesenchymal stroma/stem cells (MSC) and human tumor cells involves the exchange of biological material via extracellular vesicles including exosomes. Protein analysis of MSC-derived exosomes demonstrated the presence of MMP-2 and MSC-specific markers including CD90 and ecto-5'-nucleotidase (CD73). Incubation of tumor cells with these membranous particles revealed a rapid uptake of MSC-released microvesicles whereby breast cancer cells incorporated ~19% and SCCOHT-1 cells representing a rare type of small cell ovarian cancer assimilated ~28% of available exosomes within 24 h. This interaction was accompanied by functional alterations of tumor cell properties during integration of exosomal content from MSC. Indeed, exosome-associated MMP-2 exhibited functional enzyme activity and MCF-7 breast cancer cells with undetectable MMP-2 protein acquired expression of this enzyme and corresponding gelatinase functionality after stimulation with MSC-derived exosomes. Similar effects were observed in SCCOHT-1 cells during culture in the presence of MSC-derived exosomes which enabled new metabolic activities in this tumor cell type. Together, these findings demonstrated that the internalization of MSC-derived exosomes was associated with the acquisition of new tumor cell properties by altering cellular functionalities and providing the capability to re-organize the tumor microenvironment.

Interaction of MSC with tumor cells

“…Whereas exosomes are defined as small homogeneous membrane particles of endocytic origin ranging in size from 40 to 100 nm, microvesicles are directly shed from the plasma membrane into the extracellular environment representing a larger and heterogeneous population with 50 to 1000 nm in diameter [49]. Although both types of microparticles differ in size, origin and releasing mechanism, exosomes and microvesicles contain a large panel of proteins, functional mRNAs and regulatory microRNAs (miRs) which contribute to the cellular interplay between MSC and cancer cells within the tumor microenvironment and thereby altering the functionality of recipient cells [37]. …”

“…Previous results demonstrated that MSC-derived exosomes can modulate the function of tumor cells by induction of MMP-2 and ecto-5’-nucleotidase activity resulting in a more complex tumor microenvironment with higher tumor heterogeneity [37, 50]. Alternatively, MSC-derived exosomes also contain tumor supportive miRs which enhance tumor growth in vivo [51].…”

Mesenchymal Stem Cell-Derived Exosomes: New Opportunity in Cell-Free Therapy

“…Apart from the common surface markers of exosomes (CD9 and CD81), MSC-DEs express several molecules of MSCs, such as CD29, CD44, CD90 and CD73. 51,52 In addition to proteins, exosomes are enriched with a collection of cytokines, certain lipid rafts such as phosphoglycerides, cholesterol, ceramide, fatty-acyl chains as well as mRNAs, miRNAs, non-coding RNAs, tRNAs, rRNAs and rarely DNA. 35 …”

Extracellular vesicles as regulators of tumor fate: crosstalk among cancer stem cells, tumor cells and mesenchymal stem cells

“…As previously discussed, tumor cells can modify the surrounding cells, inducing protumorigenic phenotypes. This bidirectional crosstalk is partly mediated by EVs originating from both the MSCs and tumor cells, as shown by Yang et al (115) (Figure 3). Peinado et al (116) showed that tumor cells can modify bone marrow cells, promoting recruitment and "educating" them toward a pro-vasculogenic and prometastatic phenotype.…”