The Role of Neurotrophin Signaling in Gliomagenesis: A Focus on the p75 Neurotrophin Receptor (p75 NTR /CD271).

The p75 neurotrophin receptor (p75 ^NTR , a.k.a. CD271), a transmembrane glycoprotein and a member of the tumor necrosis family (TNF) of receptors, was originally identified as a nerve growth factor receptor in the mid-1980s. While p75 ^NTR is recognized to have important roles during neural development, its presence in both neural and nonneural tissues clearly supports the potential to mediate a broad range of functions depending on cellular context. Using an unbiased in vivo selection paradigm for genes underlying the invasive behavior of glioma, a critical characteristic that contributes to poor clinical outcome for glioma patients, we identified p75 ^NTR as a central regulator of glioma invasion. Herein we review the expanding role that p75 ^NTR plays in glioma progression with an emphasis on how p75 ^NTR may contribute to the treatment refractory nature of glioma. Based on the observation that p75 ^NTR is expressed and functional in two critical glioma disease reservoirs, namely, the highly infiltrative cells that evade surgical resection, and the radiation- and chemotherapy-resistant brain tumor-initiating cells (also referred to as brain tumor stem cells), we propose that p75 ^NTR and its myriad of downstream signaling effectors represent rationale therapeutic targets for this devastating disease. Lastly, we provide the provocative hypothesis that, in addition to the well-documented cell autonomous signaling functions, the neurotrophins, and their respective receptors, contribute in a cell nonautonomous manner to drive the complex cellular and molecular composition of the brain tumor microenvironment, an environment that fuels tumorigenesis.
(© 2017 Elsevier Inc. All rights reserved.)