## 4 The Release of miRNAs and Chaperones through EVs as Molecular Signaling and Source of Biomarkers  
Intercellular communication between tumor cells and their neighboring structures, including other cells, is vital for cancer growth and progression, and EVs are key elements in this crosstalk. However, the mechanisms involved are still poorly understood, which stands in the way of progress in cancer treatment. The involvement of brain tumor-derived EVs in the modulation of the tumor microenvironment has been suggested by studies that revealed in those vesicles functionally active molecules that can play a role in cancer progression. \begin{table}
\begin{tabular}{c c c} \hline \hline
**Chaperone/Hsp** & **Role in Gliomas** & **Ref.** \\ \hline Hsp27 & Promotes tumor growth, and cancer-cell proliferation and motility & [209; 210; 211; 212; 213; 214] \\ Hsp47 & Promotes tumor growth, invasiveness, and angiogenesis & [215; 216; 217] \\ Hsp60 & Promotes tumor progression by enhancing cancer-cell proliferation, preventing apoptosis, and inhibiting the antitumor immune response & [218; 219; 220] \\ Hsp70 & Promotes cancer cell proliferation, migration, and invasion, and protects cancer & [227; 228; 229; 230] \\  & cells from apoptosis and anticancer drugs & [231; 232; 233; 234] \\ Hsp90 & Promotes cancer-cell motility, tumor invasiveness, and drug resistance & [231; 232; 233; 235] \\ CCT6 & Promotes GBM cell invasion and has a negative association with patient survival 1 & [241] \\ \hline \hline \end{tabular}  
* GBM, glioblastoma multiforme.  
\end{table} 
Table 3: Reported roles of Hsp27, Hsp47, Hsp60, Hsp70, and Hsp90 in gliomas. The release of Hsps inside vesicles has been reported for different brain tumor cell lines [242]. Moreover, it has been found that Hsp27, Hsp70, and Hsp90 can also be present on the surface of brain tumor-derived EVs [243; 244], which indicate their potential as tumor biomarkers [245; 246]. However, although molecular chaperones have been described as key players in brain tumor biology, in the current literature there are still very few data about the possible role of extracellular Hsps in these tumors. On the contrary, the role of miRNAs carried by EVs released by brain tumor cells is currently under active investigation and debate. MicroRNAs in EVs are abundant by comparison with other cargo molecules [247] and their expression patterns reflect their source, thus providing information about their cells of origin [248]. For instance, gliomas secrete EVs that transport receptors and signaling molecules for oncogenes [16; 249; 250]. The EV-mediated transfer of miRNAs appears to be a way for the tumor to communicate with distinct sets of surrounding antitumor cells, including neurons and glial and vascular cells, which are thus reprogrammed to modify the tumor microenvironment to make it suitable to tumor growth and dissemination [251]. For example, it has been shown that glioma-derived EV saltered synaptic activity in neurons, contributing to tumor growth [251]. In addition, several studies have pinpointed the specific role of certain vesicular miRNAs on target cells, which in essence consisted in mediating the aggressive properties of gliomas [178; 179; 180; 252]. The microRNAs miR-451 and miR-21 are present at very high levels in the EVs produced by primary GBM cells, and are uptaken by microglia, which is followed by a phenotype change of the recipient cell accompanied by upregulation of cytokines, chemokines, and matrix metalloproteinases (MMP), all of which promote growth and invasion of GBM cells while lessening of the immune response [168]. MiR-21 transferred by GBM-EVs to microglia regulates the expression of the Btg2 gene, involved in the control of cellular proliferation and differentiation [169]. The dysregulation of c-Myc and Btg2 attests that the GBM-EVs have a functional activity on neighboring target cells.