Cancer stem cells in nervous system tumorsSheila K Singh1,2, Ian D Clarke1,2, Takuichiro Hide1,2and Peter B Dirks*,1,21The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Canada;2Programin Developmental Biology, Department of Laboratory Medicine and Pathobiology, Division of Neurosurgery, University of Toronto,Toronto, CanadaMost current research on human brain tumors is focusedon the molecular and cellular analysis of the bulk tumormass. However, evidence in leukemia and more recently insolid tumors such as breast cancer suggests that the tumorcell population is heterogeneous with respect to prolifera-tion and differentiation. Recently, several groups havedescribed the existence of a cancer stem cell population inhuman brain tumors of different phenotypes from bothchildren and adults. The finding of brain tumor stem cells(BTSCs) has been made by applying the principles for cellculture and analysis of normal neural stem cells (NSCs) tobrain tumor cell populations and by identification of cellsurface markers that allow for isolation of distinct tumorcell populations that can then be studiedin vitroandinvivo. A population of brain tumor cells can be enriched forBTSCs by cell sorting of dissociated suspensions of tumorcells for the NSC marker CD133. These CD133þcells,which also expressed the NSC marker nestin, but notdifferentiated neural lineage markers, represent a minor-ity fraction of the entire brain tumor cell population, andexclusively generate clonal tumor spheres in suspensioncultureandexhibitincreasedself-renewalcapacity.BTSCs can be induced to differentiatein vitrointo tumorcells that phenotypically resembled the tumor from thepatient. Here, we discuss the evidence for and implicationsof the discovery of a cancer stem cell in human braintumors. The identification of a BTSC provides a powerfultool to investigate the tumorigenic process in the centralnervous system and to develop therapies targeted to theBTSC. Specific genetic and molecular analyses of theBTSC will further our understanding of the mechanismsofbraintumorgrowth,reinforcingparallelsbetweennormal neurogenesis and brain tumorigenesis.Oncogene(2004)23,7267–7273. doi:10.1038/sj.onc.1207946Keywords:brain tumor stem cell; neural stem cell; ﬂowcytometry; CD133IntroductionBrain tumors are typically comprised of morphologi-cally diverse cells that express a variety of neural lineagemarkers. Study of brain tumors by traditional histo-pathology has only yielded a limited amount of knowl-edgeoftheclinicalbehaviorofthetumor.Itisrecognized that tumors with vastly different histologyhave a different prognosis, but often brain tumors thatshare similar morphology and phenotype can have avery different prognosis and response to treatment.