Nerve growth factor receptor (NGFR): A key player in glioblastoma progression

Glioblastoma (GBM) is a highly invasive brain cancer arising from astrocytes, and current treatments are often ineffective, limiting patient five-year survival to <5%, despite maximal safe resection, temozolomide (TMZ) chemotherapy, and radiotherapy. Alterations in receptor tyrosine kinase (RTK) signaling are a hallmark of GBM progression and invasion. Numerous clinical trials have explored commonly altered RTKs, but none have offered a viable target that effectively increases patient outcomes and survival. This review synthesizes available literature on the role of the nerve growth factor receptor (NGFR), particularly the p75 neurotrophin receptor (p75NTR), in GBM progression. p75NTR is a member of the tumor necrosis factor receptor (TNFR) superfamily and is a "death receptor" that lacks intrinsic kinase activity, distinguishing it fundamentally from RTKs such as TrkA, which also serves as a receptor for the nerve growth factor ligand. p75NTR expression is markedly enhanced relative to normal brain tissue, and its signaling is differentially regulated, where p75NTR has roles in supporting tumor invasion, hypoxic adaptation, stemness maintenance, and resistance to conventional TMZ and radiation therapy. p75NTR drives GBM invasion through neurotrophin-dependent mechanisms and through proteolytic cleavage by α- and γ-secretases. Under hypoxic conditions, p75NTR stabilizes HIF-1α and HIF-2α, further promoting angiogenesis, immune evasion, and stem cell phenotypes. By synthesizing available NGFR and GBM data, this review identifies p75NTR as the primary NGFR implicated in GBM progression and positions it as a rationally supported therapeutic target for GBM. This review also identifies key questions warranting further investigation into p75NTR's molecular mechanisms.