p75 neurotrophin receptor (p75NTR) is key regulator of self-renewal, proliferation and differentiation of brain tumour initiating cell

Glioblastoma multiform (GBM) is the most common and aggressive brain tumor that is inevitably a fatal disease. GBM is a heterogeneous tumor consisting of tumor cells and a small population known as brain tumor initiating cells (BTICs) or glioblastoma stem-like cells. BTICs appear to drive tumor progression, underlie therapeutic resistance to current treatment and tumor relapse and have been highlighted as important therapeutic targets. The ability of glioma cells to invade into the surrounding brain parenchyma is a major clinical issue rendering glioblastoma incurable by conventional therapies. Using a large panel of GBM cells including genetically different patient-derived-BTICs we have investigated the roles of p75NTR in regulating GBM progression.  Immunohistochemical studies and western blot analysis revealed that p75NTR is variably expressed on BTICs. Loss-of-function and gain-of-function studies of p75NTR revealed that p75NTR is involved in regulating self-renewal, proliferation, cell cycle progression, symmetry and asymmetry cell divisions, apoptosis, differentiation and invasion of genetically different patient-derived BTICs. Furthermore, Loss-of-function of p75NTR in these BTICs inhibited their tumorigenic behaviors in vivo and extended the survival time of mice bearing brain tumors generated by p75NTR knockdown BTICs compared to their control counterparts. These findings provide new evidence for involvement of p75NTR in regulating GBM progression and suggest p75NTR is a therapeutic target for the treatment of this devastating cancer.

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