The Role of Neurotrophin Signaling in Gliomagenesis: A Focus on the p75 Neurotrophin Receptor (p75NTR/CD271)

Vitam Horm. 2017;104:367-404. doi: 10.1016/bs.vh.2016.11.001. Epub 2017 Jan 4.

Abstract

The p75 neurotrophin receptor (p75NTR, 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 p75NTR 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 p75NTR as a central regulator of glioma invasion. Herein we review the expanding role that p75NTR plays in glioma progression with an emphasis on how p75NTR may contribute to the treatment refractory nature of glioma. Based on the observation that p75NTR 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 p75NTR 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.

Keywords: Brain tumor; CD271; Cancer stem cells; Glioblastoma; Glioma invasion; Nerve growth factor; Neurotrophin; p75(NTR).

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use
  • Carcinogenesis / metabolism*
  • Carcinogenesis / pathology
  • Drug Resistance, Neoplasm
  • Glioma / drug therapy
  • Glioma / immunology
  • Glioma / metabolism*
  • Glioma / pathology
  • Humans
  • Macrophages / cytology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Macrophages / pathology
  • Microglia / cytology
  • Microglia / immunology
  • Microglia / metabolism
  • Microglia / pathology
  • Models, Neurological*
  • Neoplasm Invasiveness
  • Neoplasm Proteins / agonists
  • Neoplasm Proteins / metabolism
  • Neoplastic Stem Cells / immunology
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Nerve Growth Factors / metabolism*
  • Nerve Tissue Proteins / agonists*
  • Nerve Tissue Proteins / metabolism
  • Neural Stem Cells / cytology
  • Neural Stem Cells / immunology
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / pathology
  • Receptors, Nerve Growth Factor / agonists*
  • Receptors, Nerve Growth Factor / metabolism
  • Signal Transduction* / drug effects
  • Tumor Microenvironment / drug effects

Substances

  • Antineoplastic Agents
  • NGFR protein, human
  • Neoplasm Proteins
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Receptors, Nerve Growth Factor

Grant support