However, intercellular trafficking mechanism that determines whether miRNAs are secreted or retained in their originating cells requires further investigation [36]. While secretory miRNAs have been hypothesized to be involved

in mediating cell-cell communication, it remains unclear whether all extracellular miRNAs are associated with exosomes. Different opinions exist regarding this issue. Using a mammalian cell culture model, Wang et al. [37] showed that a significant fraction of extracellular miRNAs resided outside of vesicles and acted in exosome-independent manner. A number of RNA-binding proteins, most importantly nucleophosmin 1 (NPM1), which were released into the cell culture medium together with miRNAs may play a role in protecting miRNAs 17-AAG solubility dmso from degradation. Another study by Turchinovich et al. [38] found that most miRNAs in plasma and cell culture media completely passed through 0.22 μm filters but remained in the supernatant after NU7441 ultracentrifugation at 110000 × g, indicating a non-vesicular origin

of extracellular miRNAs. In addition to revealing that extracellular miRNAs were predominantly free of exosomes or microvesicles, they demonstrated an association between miRNAs and the argonaute protein Ago2, an RNA-induced silencing complex-related protein. They hypothesized that circulating miRNAs were mostly by-products of dead/dying cells that remain stably complexed to Ago2 in the extracellular environment. However, some miRNA/Ago2 complexes may be actively released from cells and act in a PF-6463922 datasheet paracrine manner. Furthermore, the authors of this study do not reject the possibility that some miRNAs may be associated with exosomes. A third possibility exists. A large proportion

of circulating miRNAs are likely derived from blood cells and other organs it is therefore SB-3CT possible that cancer-associated miRNAs in the circulation may originate from immunocytes in the tumor microenvironment or from some other response mediated by the affected organ or system. Tumor cells secrete a variety of miRNAs that act on immunocytes to modulate immune responses and create either an immunostimulatory or an immunotolerant tumor environment. Conversely, immunocytes may secrete cancer-associated miRNAs, thereby promoting or inhibiting proliferation, invasion and apoptosis. As an example, there is an inverse correlation between miR-17-92 expression and transforming growth factor-β receptor II (TGFBR2) transcript levels in CD 34+ hematopoietic stem cells [39]. Furthermore, TGFBR2 is a verified target of miR-17-92 in solid cancers [40]. It is therefore hypothesized that miR-17-92, expressed in T cells, down-regulates TGFBR2 expression, thereby making T cells more resistant to the immunosuppressive effects of TGF-β, which is often expressed at high levels in glioma [41].