P17.87 * ENDOGENOUS NEURAL PRECURSOR CELLS ACCUMULATE AT METASTATIC BRAIN TUMORS AND TROPISM OF PRECURSOR CELLS IS INDUCED BY TUMOR-RELEASED VEGF-A

Abstract

OBJECTIVE: Data from transgenic mouse models show that neuronal progenitor cells (NPCs) can migrate towards experimental brain tumors and modulate the course of pathology. However, the pathways attracting NPCs to CNS neoplasms were unknown and it was unexplored if NPCs migrate towards metastatic brain tumors in humans. METHODS: We analyzed the tumor-parenchyma interface of neurosurgical resections for the presence of (NPCs) and distinguished these physiological cells from the tumor mass ( by fluorescence in situ hybridization, FISH). Also, we performed experiments with transgenic mouse models, cell-culture (primary NPC- and glioma cultures of human and murine origin), cell migration assays and immunohistochemistry. RESULTS: We observed that PSA-NCAM-positive NPCs accumulate at CNS metastases. These metastatic tumors are distinguished from neural cells by defined sets of markers. Transplanting murine glioma cells embedded in a cell impermeable hollow fiber capsule into the brains of nestin-gfp reporter mice shows that diffusible factors are sufficient to induce a neurogenic reaction. In vitro, vascular endothelial growth factor (VEGF) secreted from glioma cells increases the migratory and proliferative behavior of adult human brain derived neural stem and progenitor cells via stimulation of VEGF receptor-2 (VEGFR-2). In vivo, inhibiting VEGFR-2 signaling with a function-blocking antibody leads to a reduction in NPC migration in response to tumors. CONCLUSION: Overall, our data reveal a mechanism for NPC attraction to CNS tumors and suggest that NPCs accumulate in human high-grade astrocytomas.