Abstract
Abstract
Human glioblastoam is a heterogeneous tumor composed 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 and have been highlighted as therapeutic targets for patients with malignant glioma. The ability of glioma cells to invade into the surrounding brain parenchyma is a major clinical issue rendering glioblastoma incurable by conventional therapies. In a previous study, we found that the p75 neurotrophin receptor (p75NTR) significantly enhanced invasion and migration of genetically distinct glioma by a cell autonomous mechanism. In addition, p75NTR was frequently observed in a highly invasive population of cells from freshly resected patient specimens. Importantly, p75NTR was found to mediate glioma invasion by neurotrophin-dependent regulated intramembrane proteolysis (RIP). Blocking of p75NTR proteolysis by the generation of cleavage-resistance mutants, or treatment of animals bearing p75NTR-postive intracranial tumors with γ-secretase inhibitors, significantly inhibited glioma invasion and prolonged survival. Using a large panel of patient-derived-BTICs we have investigated the role of p75NTR in the stem-like compartment. Here we investigate the biological effects of p75NTR down-regulation on glioma derived BTICs. Immunocytochemical studies western blot analysis reveal that p75NTR is variably expressed on BTICs and that treatment with γ-secretase inhibitors significantly decreases BTIC invasion in 3D cultures in vitro. Down-regulation of p75NTR using shRNA significantly decreases BTICs invasion, proliferation and self-renewal ability. Moreover, p75NTR was present on as a component of BTIC-derived extracellular vesicles (EVs) that are implicated in tumor cell invasion through a cell non-autonomous mechanism. We found that p75NTR containing EVs promote invasion of non-invasive glioma cells. The composition of p75NTR containing EVs and their roles in glioma invasion are currently been investigated.
Citation Format: Mana Alshehri, Bo Young Ahn, Xiuling Wang, Shiekh Tanveer, Jennifer Chan, Donna L Senger, Stephen M Robbins. Cell autonomous and cell non-autonomous roles of p75 neurotrophin receptor (p75NTR) in glioma invasion. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A32.