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Generation of Cancerous Neural Stem Cells Forming Glial Tumor by Oncogenic Stimulation

Identifieur interne : 000753 ( Pmc/Curation ); précédent : 000752; suivant : 000754

Generation of Cancerous Neural Stem Cells Forming Glial Tumor by Oncogenic Stimulation

Auteurs : Ji-Seon Lee ; Hong Jun Lee ; Bo-Hyun Moon ; Seung-Hyun Song ; Mi-Ok Lee ; Sung Han Shim ; Hyung Seok Kim ; Min Cheol Lee ; Jeong Taik Kwon ; Albert J. Fornace ; Seung U. Kim ; Hyuk Jin Cha

Source :

RBID : PMC:4043123

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.


Url:
DOI: 10.1007/s12015-011-9280-4
PubMed: 21755312
PubMed Central: 4043123

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<p id="P1">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.</p>
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<surname>Lee</surname>
<given-names>Ji-Seon</given-names>
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<aff id="A1">Department of Life Sciences, Sogang University, Seoul 121–742, Korea</aff>
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<surname>Lee</surname>
<given-names>Hong Jun</given-names>
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<aff id="A2">Medical Research Institute, Chung-Ang University College of Medicine, Seoul, Korea. Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, BC V6T 2B5, Canada</aff>
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<given-names>Bo-Hyun</given-names>
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<aff id="A3">Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC, USA</aff>
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<surname>Song</surname>
<given-names>Seung-Hyun</given-names>
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<aff id="A4">Department of Biomedical Sciences, CHA University, Seoul, Korea</aff>
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<name>
<surname>Lee</surname>
<given-names>Mi-Ok</given-names>
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<aff id="A5">Department of Biomedical Sciences, CHA University, Seoul, Korea</aff>
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<surname>Shim</surname>
<given-names>Sung Han</given-names>
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<aff id="A6">Department of Biomedical Sciences, CHA University, Seoul, Korea</aff>
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<surname>Kim</surname>
<given-names>Hyung Seok</given-names>
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<aff id="A7">Department of Forensic Medicine, Chonnam National University Medical School, Gwangju, Korea</aff>
<email>sukim@interchange.ubc.ca</email>
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<surname>Lee</surname>
<given-names>Min Cheol</given-names>
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<aff id="A8">Department of Pathology, Chonnam National University Medical School, Gwangju, Korea</aff>
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<given-names>Jeong Taik</given-names>
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<aff id="A12">Department of Life Sciences, Sogang University, Seoul 121–742, Korea</aff>
<email>hjcha@sogang.ac.kr</email>
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<fn id="FN1" fn-type="equal">
<p>Ji-Seon Lee and Hong Jun Lee contributed equally to this work.</p>
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<pub-date pub-type="nihms-submitted">
<day>15</day>
<month>5</month>
<year>2014</year>
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<copyright-statement>© Springer Science+Business Media, LLC 2011</copyright-statement>
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<abstract>
<p id="P1">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.</p>
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