Cell Autonomous and Cell Non-Autonomous Roles of p75 Neurotrophin Receptor (p75NTR) in Glioblastoma Progression

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2018-04-30
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Abstract
Glioblastoma multiforme (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 cell autonomous and cell non-autonomous roles of p75NTR in GBM progression. Immunohistochemical studies and western blot analyses demonstrated 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. In addition to the cell autonomous roles of p75NTR in regulating GBM progression, this thesis provided novel findings about the cell non-autonomous roles of p75NTR in mediating glioma invasion. We further demonstrated that p75NTR is transferred between glioma cells through extracellular vesicles (EVs) to induce invasive properties in recipient glioma cells. Interestingly, proteolytic processing of p75NTR was detected in EVs and was required for meditating glioma cell invasion by p75NTR-containing EVs, as EVs isolated from glioma cells expressing a cleavage-resistant chimera of p75NTR (p75Fas-S) or from cells treated with a γ-secretase inhibitor failed to induce glioma cell invasion. p75NTR was also found in EVs isolated from sera of mice bearing brain tumors generated by p75NTR-expressing BTICs. These data highlight a previously unknown function of this receptor and suggest it may be a novel therapeutic target in the treatment of this devastating cancer.
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Alshehri, M. (2018). Cell Autonomous and Cell Non-Autonomous Roles of p75 Neurotrophin Receptor (p75NTR) in Glioblastoma Progression (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/31874