Figure 2.

The pro-oncogenic and anti-oncogenic effects of the NGF signaling pathway in CSC metabolism and EMT. Schematic model illustrating the opposite pro-oncogenic (left) and anti-oncogenic (right) actions of NGF signaling pathway in the control of CSCs growth and cancer evasion from the host immune system. Pro-oncogenic pathway. CSCs promote tumor growth, perineural invasion, CSCs proliferation and spreading through vessels and nerves by NGF release. In fact, tumor-released NGF attracts cholinergic endings and promotes cancer expansion and neoangiogenesis through neuronal-derived Ach and VEGF. Further, CSCs inhibit the host immune response and facilitate metastatic spreading through IL-10, IL-6, and TGF-β. Excess amount of proNGF stimulates macrophages polarization toward the M2 phenotype, giving rise to TAMs, which are unable to phagocytize cancer cells. Moreover, MDSCs induce Tregs expansion by TGF-β release and contribute to dismount the T-cells mediated immune response. Anti-oncogenic pathway. On the other hand, increasing evidences pinpoint a role for NGF pathway in promoting tumor surveillance by both natural and adaptive immune cells. The NGF-TrkA signaling system induces phagocytic M1 macrophages, thus resolving cancerogenic inflammation. Moreover, NGF receptors allow membrane exposure of activatory NK receptors. The p75-expressing γδ T cells are phagocytic T cells of the so-called “lymphoid stress surveillance” system. NGF-TrkA promotes MHC-I and MHC-II expression by cancer cells and CSCs, and allow recruitment of IL-2 activated T cells in lymph- , promoting the tumor mass eradication. The illustration includes images modified from “freevector.com”, distributed under the Creative Commons Attribution 4.0 license (CC BY 4.0).