ENDOGENOUS NEURAL PRECURSOR CELLS INDUCE CELL DEATH OF HIGH-GRADE ASTROCYTOMAS AND HAVE A TROPISM TO TUMORS IN THE HUMAN BRAIN

OBJECTIVE: Data from mouse models suggest that high-grade gliomas (HG-gliomas) origin 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. METHODS: 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 tumour 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 systemic administration of the synthetic vanilloids suggesting that TRPV1 agonists hold potential as new HGastrocytoma therapeutics. Furthermore, we analyzed the tumor-parenchyma interface of neurosurgical resections for the presence of NPCs and distinguished these physiological cells from the tumor mass. 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 neuronal progenitor cells. CONCLUSION: Overall, our data reveal a mechanism for NPC attraction CNS tumors and suggest that NPCs accumulate in human high-grade astrocytomas. In mouse models NPCs suppress HG-gliomas and the endogenous anti-tumorigenic factors can be used as pre-clinical HG-glioma therapeutics.