Exosome and mesenchymal stem cell cross-talk in the tumor microenvironment

Mesenchymal stem cells (MSCs) are a major component of the tumor microenvironment (TME) and play a key role in promoting tumor progression. The tumor uses exosomes to co-opt MSCs and re-program their functional profile from normally trophic to pro-tumorigenic. These tumor-derived small vesicles called "TEX" carry and deliver a cargo rich in proteins and nucleic acids to MSCs. Upon interactions with surface receptors on MSCs and uptake of the exosome cargo by MSCs, molecular, transcriptional and translational changes occur that convert MSCs into producers of factors that are necessary for tumor growth and that also alter functions of non-tumor cells in the TME. The MSCs re-programmed by TEX become avid producers of their own exosomes that carry and deliver mRNA and miRNA species as well as molecular signals not only back to tumor cells, directly enhancing their growth, but also horizontally to fibroblasts, endothelial cells and immune cells in the TME, indirectly enhancing their pro-tumor functions. TEX-driven cross-talk of MSCs with immune cells blocks their anti-tumor activity and/or converts them into suppressor cells. MSCs re-programmed by TEX mediate pro-angiogenic activity and convert stromal cells into cancer-associated fibroblasts (CAFs). Although MSCs have a potential to exert anti-tumor activities, they largely provide service to the tumor using the multidirectional communication system established by exosomes in the TME. Future therapeutic options consider disruption of this complex vicious cycle by either molecular or gene-regulated silencing of pro-tumor effects mediated by MSCs in the TME.