title: Generation of cancerous neural stem cells forming glial tumor by oncogenic stimulation.
abstract: Neural stem cells in the brain have been shown to be 'cells of origin' of certain brain cancers, most notably astrocytomas and medulloblastoma. In particular, in a mouse model, the targeting of genetic modifications for astrocytoma-relevant tumor suppressors to neural stem cells causes malignant astrocytoma to arise, thereby suggesting that astrocytoma is derived from neural stem cells. However, it remains to be determined whether this important finding is reproducible in humans. Herein, we generated cancerous neural stem cells by introducing a set of oncogenes to human fetal neural stem cells (hfNSCs). Serial genetic modification with v-myc for immortalization and consequent H-Ras for oncogenic stimulation with viral gene delivery proved sufficient to induce the transformation of hfNSCs. The resultant F3.Ras cells evidenced a variety of the hallmarks of brain cancer stem cells and most importantly were tumorigenic, forming brain cancers consisting of both a large number of differentiated and a very few undifferentiated populations of cells in an in vivo mouse model. On the contrary, oligodendrocytes derived from the v-myc expressing parent neural stem cells were not transformed by H-Ras, which suggests that neural stem cells may be more susceptible to cancerous transformation by a combination of oncogenes. We also determined that v-myc expressing fetal neural stem cells were defective in p53 response upon the introduction of H-Ras; this finding suggests that an insufficient p53-dependent tumor suppressive mechanism would be associated with high oncogenic susceptibility to H-Ras introduction.
authors.affiliation: Department of Life Sciences, Sogang University, Seoul 121-742, Korea.
authors.forename: Ji-Seon
authors.initials: JS
authors.lastname: Lee
authors.forename: Hong Jun
authors.initials: HJ
authors.lastname: Lee
authors.forename: Bo-Hyun
authors.initials: BH
authors.lastname: Moon
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Song
authors.forename: Mi-Ok
authors.initials: MO
authors.lastname: Lee
authors.forename: Sung Han
authors.initials: SH
authors.lastname: Shim
authors.forename: Hyung Seok
authors.initials: HS
authors.lastname: Kim
authors.forename: Min Cheol
authors.initials: MC
authors.lastname: Lee
authors.forename: Jeong Taik
authors.initials: JT
authors.lastname: Kwon
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Fornace
authors.forename: Seung U
authors.initials: SU
authors.lastname: Kim
authors.forename: Hyuk Jin
authors.initials: HJ
authors.lastname: Cha
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D004198:Disease Susceptibility; D053686:Fetal Stem Cells / Q000473:pathology; D016259:Genes, myc; D011905:Genes, ras; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology*; D009857:Oncogenes / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016159:Tumor Suppressor Protein p53