title: Neural stem cell targeting of glioma is dependent on phosphoinositide 3-kinase signaling.
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. Disclosure of potential conflicts of interest is found at the end of this article.
authors.affiliation: Division of Molecular Medicine, Beckman Research Institute, City of Hope, 1500 East Duarte Road, Duarte, California 91010, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Kendall
authors.forename: Joseph
authors.initials: J
authors.lastname: Najbauer
authors.forename: Heather F
authors.initials: HF
authors.lastname: Johnston
authors.forename: Marianne Z
authors.initials: MZ
authors.lastname: Metz
authors.forename: Shan
authors.initials: S
authors.lastname: Li
authors.forename: Marisa
authors.initials: M
authors.lastname: Bowers
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garcia
authors.forename: Seung U
authors.initials: SU
authors.lastname: Kim
authors.forename: Michael E
authors.initials: ME
authors.lastname: Barish
authors.forename: Karen S
authors.initials: KS
authors.lastname: Aboody
authors.forename: Carlotta A
authors.initials: CA
authors.lastname: Glackin
mesh_terms: D001932:Brain Neoplasms / Q000201:enzymology / Q000473:pathology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D002633:Chemotaxis; D005910:Glioma / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D007668:Kidney; D009474:Neurons / Q000201:enzymology / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000502:physiology*; D013234:Stem Cells / Q000201:enzymology / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D020830:rac1 GTP-Binding Protein