Generation of Cancerous Neural Stem Cells Forming

Authors: JiSeon Lee Hong Jun Lee BoHyun Moon SeungHyun Song MiOk Lee Sung Han Shim Hyung Seok Kim Min Cheol Lee Jeong Taik Kwon Albert J Fornace Seung U Kim Hyuk Jin Cha

Publish Date: 2011/07/14

Volume: 8, Issue: 2, Pages: 532-545

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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 astrocytomarelevant 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 vmyc for immortalization and consequent HRas for oncogenic stimulation with viral gene delivery proved sufficient to induce the transformation of hfNSCs The resultant F3Ras 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 vmyc expressing parent neural stem cells were not transformed by HRas which suggests that neural stem cells may be more susceptible to cancerous transformation by a combination of oncogenes We also determined that vmyc expressing fetal neural stem cells were defective in p53 response upon the introduction of HRas this finding suggests that an insufficient p53dependent tumor suppressive mechanism would be associated with high oncogenic susceptibility to HRas introductionThis work was supported by grants from Korea Science and Engineering Foundation KOSEF 20110006835HJC Priority Research Centers Program 2010–0028297 HJC the National RD Program for Tumor Control of the Ministry of Health Welfare and Family Affair Republic of Korea 0820310322650SUK and the Canadian Myelin Research Initiative SUK

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