Cross Talk between Cancer and Mesenchymal Stem Cells through Extracellular Vesicles Carrying Nucleic Acids

Extracellular vesicles (EVs) are considered to be a novel complex mechanism of cell communication within the tumor microenvironment. EVs may act as vehicles for transcription factors and nucleic acids inducing epigenetic changes in recipient cells. Since tumor EVs may be present in patient biological fluids, it is important to investigate their function and molecular mechanisms of action. It has been shown that tumor cells release EVs, which are capable of regulating cell apoptosis, proliferation, invasion, and epithelial-mesenchymal transition, as well as to suppress activity of immune cells, to enhance angiogenesis, and to prepare a favorable microenvironment for metastasis. On the other hand, EVs derived from stromal cells, such as mesenchymal stem cells (MSCs), may influence the phenotype of tumor cells through reciprocal cross talk greatly influenced by the transcription factors and nucleic acids they carry. In particular, non-coding RNAs (ncRNAs), including microRNAs and long ncRNAs, have recently been identified as the main candidates for the phenotypic changes induced in the recipient cells by EVs. ncRNAs, which are important regulators of mRNA and protein expression, can function either as tumor suppressors or as oncogenes, depending on their targets.

EV transfer of ncRNA between MSCs and tumor cells

Green, rose, and yellow flows represent the EV-mediated exchange of information between cells. All mentioned RNAs have been detected in both MSC-EVs and T-EVs. Green flow: RNAs that transferred function in both MSC and tumor cells. Rose flow: it depicts bidirectional transfer of tumor-suppressor miRNAs. Whereas the anti-tumoral action of these EV-carried miRNAs is well established, no data are available on their function on MSC (question mark). Yellow flow: it indicates traffic of oncomiRs and oncogenes, that were shown to prime MSCs toward a protumoral phenotype. The action of EVs carrying these RNAs has not been investigated in tumor cells (question mark).