Figure 1.

Schematic representation of both stages of the process of metastases formation with tropism to the brain: the tumor microenvironment (TME) and the pre-metastatic niche (PMN)/metastases establishment in the brain. In the TME, tumor derived exosomes (TDEs) are responsible for many critical phenomena, such as epithelial–mesenchymal transition (EMT) and angiogenesis, which supports tumor growth, invasion, survival, and metastases formation. In this stage, the exosomes can also induce endothelial barrier permeation, facilitating the passage of cancer cells to the blood flow. In the brain, exosomes from cancer cells induce many alterations that contribute to PMN establishment, such as blood–brain barrier (BBB) permeation, metabolism and immune response modulation and vascular co-option induction, which supports the brain parenchyma invasion by arriving circulating tumor cells, metastases formation and cancer cells survival. Brain metastases are also supported by the crosstalk between cancer cells and cells from the BBB, such as astrocytes. For their critical role in metastases formation, exosomes can be considered as a promising new target for metastatic cancer therapy, using inhibitors of exosomes’ biogenesis. Alternatively, these extracellular vesicles have been investigated as biomarkers for metastatic cancer diagnosis and prognosis, as vehicles in drug delivery systems (DDS) and as cell-free therapeutic tools in anti-tumor vaccination.