The role of pleiotrophin in glioma invasion of the subventricular zone
- The lateral ventricle subventricular zone (SVZ) is a frequent site of high-grade glioma (HGG) spread, and tumor invasion of the SVZ is a predictor of a worse clinical prognosis. A range of HGG types invade the SVZ stem cell niche, including both adult glioblastoma and pediatric high-grade gliomas such as diffuse intrinsic pontine glioma (DIPG). The cellular and molecular mechanisms mediating this frequent invasion of the SVZ are poorly understood. Here, we demonstrate that neural precursor cell (NPC):glioma cell communication underpins the propensity of glioma to colonize the SVZ. SVZ NPCs secrete chemoattractant signals toward which glioma cells home. Biochemical and proteomic analyses of factors secreted by SVZ NPCs revealed a discrete list of candidate proteins. Necessity and sufficiency testing implicated the neurite outgrowth-promoting factor pleiotrophin, along with three required binding partners (secreted protein acidic and rich in cysteine (SPARC), SPARC-like protein 1, and heat shock protein 90B), as key mediators of this chemoattractant effect. Pleiotrophin protein expression is strongly enriched in the SVZ, and knockdown of pleiotrophin expression starkly reduced glioma invasion of the SVZ in the adult murine brain. Pleiotrophin, in complex with the three binding partners, activated the Rho/Rho kinase pathway in DIPG cells, and inhibition of Rho kinase resulted in decreased DIPG invasion toward SVZ neural precursor cell-secreted factors. These findings demonstrate a pathogenic role for neural precursor cell:glioma interactions and potential therapeutic targets to limit glioma invasion.
|Type of resource
|electronic; electronic resource; remote
|1 online resource.
|Qin, Elizabeth Yi
|Stanford University, Neurosciences Program.
|Statement of responsibility
|Elizabeth Yi Qin.
|Submitted to the Program in Neurosciences.
|Thesis (Ph.D.)--Stanford University, 2018.
- © 2017 by Elizabeth Yi Qin
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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