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This Article Free via Open Access: OA OA Full Text Full Text (PDF) Supplemental Data OA All Versions of this Article: 2007-0887v1 26/6/1575    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Google Scholar Articles by Kendall, S. E. Articles by Glackin, C. A. PubMed PubMed Citation Articles by Kendall, S. E. Articles by Glackin, C. A.

TISSUE-SPECIFIC STEM CELLS

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

Divisions of ^aMolecular Medicine and
^cNeuroscience, Beckman Research Institute and
^bDepartment of Hematology/Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA;
^dBrain Disease Research Center, Ajou University School of Medicine, Suwon, Korea;
^eDivision of Neurology, Department of Medicine, University of British Columbia Hospital, University of British Columbia, Vancouver, Canada

Key Words. Neural stem cells • Glioma • Hepatocyte growth factor • c-Met • Ras-phosphoinositide 3-kinase signaling • Cell migration • Tumor targeting

Correspondence: Carlotta A. Glackin, Ph.D., Division of Molecular Medicine, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, California 91010, USA. Telephone: 626-301-8896; Fax: 626-301-8121; e-mail: cglackin{at}coh.org; or Karen S. Aboody, M.D., Department of Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, California 91010, USA. Telephone: 626-471-7177; Fax: 626-301-8857; e-mail: kaboody{at}coh.org

Received October 22, 2007; accepted for publication February 29, 2008.
First published online in STEM CELLS EXPRESS   March 13, 2008.



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.

Disclosure of potential conflicts of interest is found at the end of this article.