**5. BDNF and Brain Cancer: An Unexpected Role. An Oncogene or a Tumor Suppressor?**

The role of BDNF and its cognate receptor TrkB in cancer, including brain cancer, has been recognized for a long time [254]. In many types of cancers, BDNF and/or TrkB have been found expressed or in some cases over-expressed [255]. This is not surprising since growth factors, including neurotrophic factors, and their tyrosine kinase receptors have long been involved in tumors with different cell-dependent mechanisms, fostering proliferation, enhancing anti-apoptotic signaling, and making cells unresponsive to anti-proliferative stimuli [256]. The direct oncogenic activity of TrkB might also be due to the crosstalk with EGF receptors that together with its ligand is well-known to promote cell transformation. BDNF administration not only does phosphorylate TrkB but also EGFR [257]. In line with these observations, it has been recently shown that BDNF produced by glioblastoma (GBM) differentiated cells acts on GBM stem cells, fostering their growth through paracrine signaling [258].

However, recently another study showed that exposing mice to an enriched environment is able to decrease the growth of intracranial glioma, decreasing proliferation and invasion, and improving overall survival. Such an effect is achieved by means of both indirect and direct mechanisms. The former acts via natural killer cells of the innate immune system, whereas the latter utilizes BDNF stimulation of its truncated receptor TrkB.T1 on glioma cancer cells. BDNF binding the TrkB.T1 receptor signals to the Rho protein dissociation inhibitor (RhoGDI), the latter detaches from TrkB.T1 and binds to the small G protein RhoA, leading to its inhibition. The authors found that an enriched environment causes the synthesis of IL-15 and BDNF. When mice bearing the glioma and not housed in enriched environments were infused with BDNF, they reduced tumor size and macrophage infiltration. Thus, showing that at least in part, BDNF accounts for the oncolytic effect elicited by the enriched environment [259]. In a more recent study, the same group delved deeper into the mechanisms, finding that enriched environment changes glioma-associated myeloid cells. BDNF plays a central role by stimulating the production of IL-15 in microglia, which in turn stimulates the natural killer cells to produce IFN-γ. Natural killer cells were responsible for the switch to an oncolytic environment [260] (Figure 3).

Taken together, a scenario emerges where BDNF, acting on different cells is able to reorganize the brain microenvironment in such a way that it becomes resilient to neurodegeneration or oncolytic for tumors. In this regard, although supported by much more preliminary data, it seems that also other compounds might share these properties [261,262].
