Neural Stem Cell Targeting of Glioma Is Dependent on Phosphoinositide 3-Kinase Signaling

Stephen E. Kendall^a, Joseph Najbauer^b, Heather F. Johnston^c, Marianne Z. Metz^b, Shan Li^a,c, Marisa Bowers^b, Elizabeth Garcia^b, Seung U. Kim^d,e, Michael E. Barish^c, Karen S. Aboody^b,c, Carlotta A. Glackin^a

ABSTRACT

The utility of neural Stem Cells (NSCs) has extended beyond Regenerative Medicine to targeted Gene delivery, as NSCs possess an inherent tropism to solid tumors, including invasive gliomas. However, for optimal clinical implementation, an understanding of the molecular events that regulate NSC tumor tropism is needed to ensure their safety and to maximize therapeutic efficacy. We show that human NSC lines responded to multiple tumor-derived growth factors and that hepatocyte growth factor (HGF) induced the strongest chemotactic response. Gliomatropism was critically dependent on c-Met signaling, as short hairpin RNA-mediated ablation of c-Met significantly attenuated the response. Furthermore, inhibition of Ras-phosphoinositide 3-kinase (PI3K) signaling impaired the migration of human neural stem cells (hNSCs) toward HGF and other growth factors. Migration toward tumor cells is a highly regulated process, in which multiple growth factor Signals converge on Ras-PI3K, causing direct modification of the cytoskeleton. The signaling pathways that regulate hNSC migration are similar to those that promote unregulated glioma invasion, suggesting shared cellular mechanisms and responses.

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