Neural Stem Cell Targeting of Glioma is Dependent on PI3K Signaling

¹ Division of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, California, USA
² Department of Hematology/Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
³ Division of Neuroscience, Beckman Research Institute of the City of Hope, Duarte, California, USA
⁴ Division of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, California, USA; Division of Neuroscience, Beckman Research Institute of the City of Hope, Duarte, California, USA
⁵ Brain Disease Research Center, Ajou University School of Medicine, Suwon, Korea; Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, Canada
⁶ Department of Hematology/Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA; Division of Neuroscience, Beckman Research Institute of the City of Hope, Duarte, California, USA

^* To whom correspondence should be addressed. E-mail: cglackin{at}coh.org.

Correspondence may also be addressed to Karen S. Aboody at kaboody@coh.org

	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 shRNA-mediated ablation of c-Met significantly attenuated the response. Furthermore, inhibition of Ras-PI3K signaling impaired the migration of hNSCs towards HGF and other growth factors. Migration towards 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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