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The Journal of Neuroscience, March 9, 2005, 25(10):2637-2646; doi:10.1523/JNEUROSCI.5118-04.2005

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Neurobiology of Disease
Glioblastoma-Induced Attraction of Endogenous Neural Precursor Cells Is Associated with Improved Survival

Rainer Glass,^1 * Michael Synowitz,^1,3 * Golo Kronenberg,^2,4 Joo-Hee Walzlein,¹ Darko S. Markovic,¹ Li-Ping Wang,¹ Daniela Gast,^2,5 Jürgen Kiwit,³ Gerd Kempermann,^2,5 * and Helmut Kettenmann^1 *

¹Cellular Neuroscience and ²Neural Stem Cell Groups, Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany, ³Department of Neurosurgery, Helios Hospital Berlin, 13125 Berlin, Germany, ⁴Department of Psychiatry, Free University, Charité-Campus Benjamin Franklin, 14050 Berlin, Germany, and ⁵Volkswagen Stiftung Research Group, Department of Experimental Neurology, Charité University Hospital, Humboldt University, 10117 Berlin, Germany

Neural precursor cells contribute to adult neurogenesis and to limited attempts of brain repair after injury. Here we report that in a murine experimental glioblastoma model, endogenous neural precursors migrate from the subventricular zone toward the tumor and surround it. The association of endogenous precursors with syngenic tumor grafts was observed, after injecting red fluorescent protein-labeled G261 cells into the caudate-putamen of transgenic mice, which express green fluorescent protein under a promoter for nestin (nestin-GFP). Fourteen days after inoculation, the nestin-GFP cells surrounded the tumors in several cell layers and expressed markers of early noncommitted and committed precursors. Nestin-GFP cells were further identified by a characteristic membrane current pattern as recorded in acute brain slices. 5-Bromo-2-deoxyuridine labeling and dye tracing experiments revealed that the tumor-associated precursors originated from the subventricular zone. Moreover, in cultured explants from the subventricular zone, the neural precursors showed extensive tropism for glioblastomas. Tumor-induced endogenous precursor cell accumulation decreased with age of the recipient; this correlated with increased tumor size and shorter survival times in aged mice. Coinjection of glioblastoma cells with neural precursors improved the survival time of old mice to a level similar to that in young mice. Coculture experiments showed that neural precursors suppressed the rapid increase in tumor cell number, which is characteristic of glioblastoma, and induced glioblastoma cell apoptosis. Our results indicate that tumor cells attract endogenous precursor cells; the presence of precursor cells is antitumorigenic; and this cellular interaction decreases with aging.

Key words: glioma; neuropathology; tumor; neural precursor; neurogenesis; gliogenesis; stem cells

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Received Sep 3, 2004; revised January 25, 2005; accepted January 25, 2005.

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