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

Abstract

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 proteinlabeled 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.

The brain tumor microenvironment

“…Large numbers of endogenous NPCs, e.g. from the subventricular zone (SVZ) lining the lateral ventricles or from the corpus callosum, migrate toward experimental brain tumors (Assanah et al, 2006(Assanah et al, , 2009Chirasani et al, 2010;Glass et al, 2005;Walzlein et al, 2008). NPCs home in to pathologic brain tissue and possibly also to tumors due to expression of CXCR4 (Kokovay et al, 2010;Xu et al, 2009).…”

Neuronal stem cells in the central nervous system and in human diseases

“…Neural stem cells are known to be able to migrate to the injury and tumor mass. Studies have shown that exogenous murine embryonic neural stem cells or endogenous neural stem cells have capabilities to move toward xenografted tumor in vivo in murine models (Glass et al, 2005;Mapara et al, 2007). Hence, this homing ability of NSC may make these cells available as shuttles to transport therapeutic agents, such as cytokines, peptides, and so on.…”

Novel Treatment Strategies for Malignant Gliomas Using Neural Stem Cells

“…Furthermore, glioblastoma cells attract endogenous precursor cells from the SVZ. 44 These findings could be of high clinical value if translated into human glioma therapy (FIG. 1).…”

“…[43][44][45] Endogenous NSCs are naturally attracted to gliomas 44 and have the ability to migrate into the tumor mass, even contributing to the tumor bulk. When NSCs are coinjected into rodent brain with glioma cells, NSCs rapidly migrate great distances to track and surround glioma tumors.…”

“…Coinjection of unmodified NSCs with glioblastoma cells into the brains of mice results in increased survival and decreased tumor progression, suggesting that NSCs have intrinsic antitumorigenic properties and may release factors that inhibit glioblastoma proliferation. 44,45 It is critical to further understand the molecular nature of this NSC-mediated antitumor effect for the identification of new therapies for glioblastomas.…”