Article
Endogenous neural precursor cells accumulate at tumors of the human brain and induce cell death of high-grade gliomas
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Published: | May 13, 2014 |
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Objective: Data from mouse models suggest that high-grade gliomas (HG-gliomas) originale from somatic mutant neural stem and precursor cells (NPCs). We found that endogenous NPCs also defend the brain against HG-gliomas. Here, we describe the signal transduction mechanism of NPC-mediated tumor suppression and present data on the tropism of endogenous NPCs to human HG-gliomas.
Method: For our experiments we used transgenic mouse models, human HG-glioma biopsies, molecular biology techniques (microarrays, real-time PCR, mass-spectrometry, array-CGH, fluorescence in situ hybridization), cell-culture (primary NPC- and glioma cultures of human and murine origin), immunohistochemistry and survival studies in orthotopic mouse tumor models.
Results: NPCs migrate from the subventricular zone to HG-gliomas, reduce glioma expansion and prolong survival by releasing a group of fatty acid ethanolamides that have agonistic activity on the vanilloid receptor (transient receptor potential vanilloid subfamily member-1; TRPV1). TRPV1 expression is much higher in HG-gliomas than in tumor-free brain and TRPV1 stimulation triggers tumor cell death. NPC-mediated tumor suppression can be mimicked in the adult brain by the systemic administration of synthetic vanilloids suggesting that TRPV1 agonists hold potential as new HG-astrocytoma therapeutics. Furthermore, we analyzed the tumor-parenchyma interface of neurosurgical resections for the presence of NPCs. We observed that PSA-NCAM-positive NPCs, which are genetically distinct from the the tumor mass, accumulate at the border of high-grade gliomas and display a marker profile consistent with immature migratory neural progenitors.
Conclusions: Overall, our data reveal that NPCs are attracted to high-grade gliomas in humans, that NPCs suppress HG-gliomas in tumor models and that NPC-released anti-tumorigenic factors can be used inpre-clinical HG-glioma therapy.