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

The tumor microenvironment comprises a heterogeneous population of tumorigenic and non-tumorigenic cells. Cancer stem cells (CSCs) and mesenchymal stem cells (MSCs) are components of this microenvironment and have been described as key regulators of different aspects of tumor physiology. They act differently on the tumor: CSCs are described as tumor initiators and are associated with tumor growth, drug resistance and metastasis; MSCs can integrate the tumor microenvironment after recruitment and interact with cancer cells to promote tumor modifications. Extracellular vesicles (EVs) have emerged as an important mechanism of cell communication under the physiological and pathological conditions. In cancer, secretion of EVs seems to be one of the main mechanisms by which stem cells interact with other tumor and non-tumor cells. The transfer of bioactive molecules (lipids, proteins and RNAs) compartmentalized into EVs triggers different responses in the target cells, regulating several processes in the tumor as angiogenesis, tumor invasiveness and immune escape. This review focuses on the role of CSCs and MSCs in modulating the tumor microenvironment through secretion of EVs, addressing different aspects of the multidirectional interactions among stem cells, tumor and tumor-associated cells.