title: Inhibition of neuronal nitric oxide synthase activity promotes migration of human-induced pluripotent stem cell-derived neural stem cells toward cancer cells.
abstract: The breakthrough in derivation of human-induced pluripotent stem cells (hiPSCs) provides an approach that may help overcome ethical and allergenic challenges posed in numerous medical applications involving human cells, including neural stem/progenitor cells (NSCs). Considering the great potential of NSCs in targeted cancer gene therapy, we investigated in this study the tumor tropism of hiPSC-derived NSCs and attempted to enhance the tropism by manipulation of biological activities of proteins that are involved in regulating the migration of NSCs toward cancer cells. We first demonstrated that hiPSC-NSCs displayed tropism for both glioblastoma cells and breast cancer cells in vitro and in vivo. We then compared gene expression profiles between migratory and non-migratory hiPSC-NSCs toward these cancer cells and observed that the gene encoding neuronal nitric oxide synthase (nNOS) was down-regulated in migratory hiPSC-NSCs. Using nNOS inhibitors and nNOS siRNAs, we demonstrated that this protein is a relevant regulator in controlling migration of hiPSC-NSCs toward cancer cells, and that inhibition of its activity or down-regulation of its expression can sensitize poorly migratory NSCs and be used to improve their tumor tropism. These findings suggest a novel application of nNOS inhibitors in neural stem cell-mediated cancer therapy.
authors: Department of Biological Sciences, National University of Singapore, Singapore, Singapore.
authors: Can
authors: C
authors: Chen
authors: Yi
authors: Y
authors: Wang
authors: Sally S L
authors: SS
authors: Goh
authors: Jing
authors: J
authors: Yang
authors: Dang Hoang
authors: DH
authors: Lam
authors: Yukti
authors: Y
authors: Choudhury
authors: Felix Chang
authors: FC
authors: Tay
authors: Shouhui
authors: S
authors: Du
authors: Wee Kiat
authors: WK
authors: Tan
authors: Yovita Ida
authors: YI
authors: Purwanti
authors: Weimin
authors: W
authors: Fan
authors: Shu
authors: S
authors: Wang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: D052248:Nitric Oxide Synthase Type I
keywords: Boyden chamber assay; Neural stem cells; microarray analysis; neuronal nitric oxide synthase; tumor tropism