Neurosurgical FOCUS - 24(3-4):E25

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March 2008 Volume 24, Number = 3-4

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<= /TD>

Molecular and cell biology of = brain tumor=20 stem cells: lessons from neural progenitor/stem = cells

Zhigang Xie,=20 Ph.D.¹², and Lawrence S. Chin,=20 M.D.¹

¹Departments of = Neurosurgery=20 and = ²Pharmacology and=20 Experimental Therapeutics, Boston University School of = Medicine, Boston, Massachusetts

Abbreviations used in=20 this paper: BMP =3D bone morphogenetic = protein; BTSC=20 =3D brain tumor stem cell; CNS =3D central nervous = system; EGF =3D=20 epidermal growth factor; EGFR =3D EGF receptor; FGF = =3D fibroblast=20 growth factor; MCPH =3D autosomal recessive primary=20 microcephaly; NICD =3D Notch intracellular domain; = NPSC =3D neural=20 progenitor/stem cells; Shh =3D Sonic hedgehog; VEGF = =3D vascular=20 endothelial growth factor.

Address correspondence = to:=20 Zhigang Xie, Ph.D., Department of Neurosurgery, Boston = University School of Medicine, 720 Harrison Avenue, = Suite=20 7600, Boston, Massachusetts 02118. email: zhigang.xie@bmc.org.

DOI: 10.3171/FOC/2008/24/3-4/E24

Figures = and Tables=20

Abstract	IntroductionThe Relationship Between = ...Mechanisms of BTSC = Self-R...Conclusions and Future = Di...References

3D""=20 The results of studies conducted in = the past=20 several years have suggested that malignant brain = tumors may=20 harbor a small fraction of tumor-initiating cells that = are=20 likely to cause tumor recurrence. These cells are = known as=20 brain tumor stem cells (BTSCs) because of their = multilineage=20 potential and their ability to self-renew in vitro and = to=20 recapitulate original tumors in vivo. The = understanding of=20 BTSCs has been greatly advanced by knowledge of neural = progenitor/stem cells (NPSCs), which are multipotent = and=20 self-renewing precursor cells for neurons and glia. In = this=20 article, the authors summarize evidence that genetic = mutations=20 that deregulate asymmetric cell division by affecting = cell=20 polarity, spindle orientation, or cell fate = determinants may=20 result in the conversion of NPSCs to BTSCs. In = addition, they=20 review evidence that BTSCs and normal NPSCs may reside = in=20 similar vascularized microenvironments, where similar=20 evolutionarily conserved signaling pathways control = their=20 proliferation. Finally, they discuss preliminary = evidence that=20 mechanisms of BTSC-associated infiltrativeness may be = similar=20 to those underlying the migration of NPSCs and=20 neurons.

Keywords:=20 infiltration; proliferation; renewal; tumor.

Introduction	AbstractIntroduction = <<The Relationship Between = ...Mechanisms of BTSC = Self-R...Conclusions and Future = Di...References		=

Malignant brain=20 tumors are among the most deadly cancers. Current = treatment=20 strategies, including surgery, radiotherapy, and = chemotherapy,=20 only modestly improve patient survival. The limited = success of=20 these strategies is largely due to a high incidence of = tumor=20 recurrence following treatment. The results of studies = conducted in the past several years suggest that a = rare=20 population of stem cell=96like cells, known as brain = tumor stem=20 cells (BTSCs), may be responsible for the recurrence = of brain=20 tumors. Based on the expression of the plasma membrane = protein=20 CD133 by BTSCs and the ability of BTSCs to self-renew = in=20 neurosphere assays, several groups have been able to = isolate=20 these cells from human brain tumor samples.^{31,35,38,70,86} When=20 orthotopically transplanted into immunodeficient mice, = purified BTSCs gave rise to brain tumors that = histologically=20 resembled original tumors.^31,35,70,86 Thus,=20 targeting BTSCs may be an effective strategy to = prevent brain=20 tumor recurrence.

The Relationship Between BTSCs = and=20 NPSCs	AbstractIntroductionThe Relationship Between ...=20 <<References

The rational design of BTSC-based brain tumor = therapies=20 requires a thorough understanding of how BTSCs acquire = and=20 maintain their unusual ability to self-renew and = infiltrate.=20 Our knowledge in this field has been greatly enhanced = by=20 studies of NPSCs, precursor cells that can self-renew = and=20 generate neurons and glia. Different types of NPSCs = exist in=20 the mammalian brain during different developmental=20 stages.^20,33,51 The=20 earliest NPSCs are neuroepithelial cells, which appear = prior=20 to the onset of neurogenesis during embryonic = development.=20 Neuroepithelial cells initially expand via symmetric = cell=20 division and then develop into more lineage-restricted = NPSCs=20 known as radial glia. Radial glia may give rise to = neurons via=20 asymmetric cell division or by generating intermediate = neural=20 progenitors, which then produce 2 daughter neurons via = symmetric cell division. During postnatal stages, = radial glia=20 transform into slowly dividing neurogenic astrocytes = in 2=20 specific brain areas: the subventricular zone of the = lateral=20 ventricle and the subgranular zone of the hippocampal = dentate=20 gyrus. Neurogenic astrocytes undergo asymmetric = division to=20 self-renew and generate transient amplifying cells, = which=20 rapidly divide to produce neuroblasts.

The ability of NPSCs to self-renew and = the=20 persistence of neurogenesis in the adult brain have = led to the=20 hypothesis that NPSCs may give rise to BTSCs through = genetic=20 mutations.^65,76 Several=20 lines of evidence support this hypothesis. First, = NPSCs and=20 BTSCs share molecular markers such as CD133 and = nestin, and=20 gene profiles of various brain tumors recapitulate = that of=20 NPSCs at different developmental stages.^57,75 Next,=20 the proliferation of NPSCs and BTSCs is controlled by = similar=20 molecular pathways (discussed later in this paper). = Third,=20 NPSCs and BTSCs behave similarly in culture, forming=20 neurospheres under growth factor=96supplemented = non-adherent=20 conditions and giving rise to a mixture of neurons,=20 astrocytes, and oligodendrocytes when induced to=20 differentiate.^{31,35,38,70,86} Lastly,=20 analyses of mouse models have revealed that malignant = brain=20 tumors may arise in regions containing NPSCs and that = genetic=20 alterations in NPSCs can induce malignant brain = tumors.^{24,36,62,71,87}=20 Together, the results of these studies suggest that = NPSCs are=20 likely, although not necessarily exclusive, sources of = BTSCs.

Mechanisms of BTSC=20 Self-Renewal	AbstractIntroductionThe Relationship Between = ...Mechanisms of BTSC Self-R...=20 <<References

The investigation of the mechanisms that control = BTSC=20 proliferation has been guided by our knowledge of the=20 molecular and cellular basis of NPSC self-renewal. = Neural=20 progenitor/stem cells exhibit highly polarized cell = morphology=20 and undergo asymmetric or symmetric divisions in = specific=20 microenvironments, where a number of signaling = pathways=20 maintain the balance between self-renewal and = differentiation=20 of the NPSCs.

Asymmetric Division of NPSCs=20

All primary NPSCs, including neuroepithelial cells, = radial=20 glia, and neurogenic astrocytes, exhibit highly = polarized cell=20 morphology. Both neuroepithelial cells and radial glia = span=20 the entire cerebral wall by extending a thin basal = process=20 that contacts the basement membrane and a relatively = thick=20 apical process that contacts the ventricular surface. = The=20 basal process serves as a support for the migration of = newly=20 generated neurons away from the proliferative zone, = whereas=20 the apical process forms intercellular adhesion = structures at=20 the tip to connect neighboring NPSCs.³³ The=20 plasma membrane of the tip of the apical process may = contain=20 cell fate determinants. Whether these cell fate = determinants=20 are segregated into daughter cells symmetrically or=20 asymmetrically depends on the orientation of the = mitotic=20 spindle during mitosis.^12,33=20 Neurogenic astrocytes in the adult brain also exhibit=20 polarized morphology with either an apical process or = a basal=20 process, although they do not span the entire cerebral = wall.²⁰

The establishment of cell polarity is necessary for = unequal=20 distribution of cell fate determinants and, therefore, = proper=20 asymmetric cell division and the specification of = daughter=20 cell fates. For instance, conditional ablation of a = Rho GTPase=20 cdc42 in the embryonic mouse telencephalon resulted in = the=20 retraction of the apical process from the ventricular = surface=20 and the loss of apical Par complex and adherens = junctions in=20 primary NPSCs.¹⁴ This=20 disruption of apical polarity in turn caused increased = production of intermediate neural progenitors from = primary=20 NPSCs.¹⁴

In addition to cell polarity, the = orientation of=20 the mitotic spindle also controls the distribution of = cell=20 fate determinants by governing the cleavage = plane.^12,33,85 The=20 critical role of spindle orientation in cell fate=20 specification during neurogenesis was initially = discovered in=20 the Drosophila nervous system.⁸⁵ Recent=20 studies suggest that spindle orientation also plays a = key role=20 in mammalian neurogenesis. For instance, loss of = Aspm,²⁸=20 Nde1,²⁷ or=20 G signaling⁶⁴ in=20 primary NPSCs of the developing neocortex results in = altered=20 spindle orientation, which may underlie a premature = depletion=20 of primary NPSCs.

Brain Tumor Stem Cells: Deregulation of = Asymmetric Division?=20

A tight control of asymmetric division ensures that = the=20 balance between self-renewal and differentiation is = maintained=20 in NPSCs. Since BTSCs are characterized by = uncontrolled=20 proliferation or self-renewal, one possibility is that = NPSCs=20 harboring mutations that impair asymmetric division = may become=20 BTSCs and thus promote tumorigenesis. In support of = this=20 possibility, genetic studies of Drosophila CNS=20 neurogenesis have revealed that mutations that affect = cell=20 polarity, spindle orientation, or cell fate = determinants may=20 induce NPSC overproliferation and brain tumors. For = instance,=20 overexpression of a membrane-targeted atypical protein = kinase=20 C, a highly conserved protein that controls the = polarity of=20 many different types of cells, induced neoplastic = overgrowth=20 of neuroblasts,⁴⁵ which=20 are NPSCs in the Drosophila CNS. = Correspondingly, loss=20 of atypical protein kinase C caused reduced neuroblast = proliferation.⁶³ Loss of=20 lethal giant larvae (lgl)⁴⁵ or=20 polo,⁷⁸ which=20 are important for polarized distribution of cell fate=20 determinants,^54,56,78 also led=20 to neoplastic overgrowth of neuroblasts. In addition = to=20 deregulation of cell polarity, the mispositioning of a = mitotic=20 spindle resulting from loss of a NuMA homolog,=20 mud;^11,59 a=20 centrosomal protein, cnn;⁴⁴ or a=20 kinase, aurora,^44,79 has also=20 been linked to excess neuroblast self-renewal and = brain tumor=20 formation. Finally, mutations in genes encoding cell = fate=20 determinants such as brain tumor (brat) and = prospero=20 (pros) caused increased self-renewal of = neuroblasts and=20 brain tumor formation.^6,8,15,46

Much less is known about how asymmetric division = may=20 contribute to brain tumorigenesis in mammals. = Nonetheless,=20 several lines of evidence suggest that the underlying=20 mechanisms may be at least partially conserved between = Drosophila and mammals. First, in mice lacking = the=20 polarity gene Lgl1, the homolog of = Drosophila=20 lgl, cortical neuroepithelial cells exhibited = increased=20 self-renewal and formed rosette-like structures = similar to=20 those found in human primitive neuroectodermal = tumors.⁴⁰ Second,=20 mammalian polo-like kinase 1 (Plk1), a homolog of=20 Drosophila polo, has been implicated in various = human=20 cancers including gliomas,⁷⁴ the most=20 common type of primary brain tumors. Third, mammalian = Aurora A=20 kinase, a homolog of Drosophila aurora, is also = a key=20 regulator of the mitotic spindle.⁴ = While the=20 function of Aurora A kinase in NPSC self-renewal and = brain=20 tumorigenesis remains to be determined, the expression = of=20 Aurora A kinase has been found to be elevated in = several types=20 of human cancers.⁴ = Fourth,=20 one of the causative genes for human MCPH, = CDK5RAP2, is=20 a homolog of Drosophila cnn and also encodes a=20 centrosomal protein.¹⁰ Since=20 MCPH is a brain development disorder characterized by = reduced=20 size of both the brain and the NPSC pool,²² it is=20 likely that, similar to the product of cnn, the = protein=20 product of CDK5RAP2 also regulates NPSC = self-renewal=20 via mitotic spindle=96dependent mechanisms. Lastly, = studies of=20 another causative gene for MCPH, ASPM,⁹ = have=20 provided a more direct link between asymmetric = division and=20 brain tumorigenesis in mammals. In the developing = mouse brain,=20 the Aspm protein has been shown to promote NPSC = self-renewal=20 by maintaining the mitotic spindle in an orientation = that=20 favors symmetric division.²⁸ In a=20 gene profiling analysis of glioblastomas, the most = common and=20 malignant human primary brain tumors, ASPM was=20 identified as an overexpressed gene.³⁷=20 Furthermore, RNA interference=96mediated silencing of=20 ASPM inhibited the proliferation of cultured=20 glioblastoma cells.³⁷ Thus,=20 the Aspm protein may support the expansion of both = NPSCs and=20 brain tumor cells by inhibiting asymmetric = division.

While these findings are consistent = with the=20 possibility that NPSCs with dysregulated asymmetric = division=20 may become BTSCs, solid evidence is lacking. To = further test=20 this possibility, it will be necessary to analyze = asymmetric=20 division directly on BTSCs and to determine whether = genetic=20 manipulations that target asymmetric division will be=20 sufficient to convert mammalian NPSCs to = BTSCs.

A Vascular Niche for NPSCs and = BTSCs=20

The microenvironment plays a critical role in how = NPSCs=20 divide. In the adult mammalian brain, NPSCs (that is,=20 neurogenic astrocytes) reside in niches enriched with=20 capillaries.²⁰ In the=20 embryonic mammalian brain, NPSCs are also closely = associated=20 with the vasculature.^7,77 Neural=20 progenitor/stem cells and blood vessels may = communicate=20 bidirectionally. On one hand, NPSCs may induce = endothelial=20 cells to form vascular tubes by secreting VEGF and=20 brain-derived neurotrophic factor.⁴⁸ On the=20 other hand, endothelial cells may support the = self-renewal of=20 NPSCs by secreting trophic factors such as VEGF and = pigment=20 epithelium-derived factor.^43,61,67

A recent study using 3D reconstruction = of=20 immuno-stained brain tumors revealed that, similar to = NPSCs,=20 BTSCs also establish close relationships with blood=20 vessels.¹³ Both in=20 culture and when transplanted into the mouse brain, = the=20 self-renewal of BTSCs was enhanced by the presence of=20 endothelial cells.¹³=20 Furthermore, depletion of the tumor vasculature = eradicated=20 BTSCs and inhibited the growth of tumor xenografts in = the=20 mouse brain.¹³ These=20 data suggest that BTSCs reside in a vascular niche = where=20 endothelium-derived trophic factors support BTSC = self-renewal.=20 Within this vascular niche, BTSCs may also promote=20 angiogenesis by secreting VEGF.^2,55=20 Therefore, the excessive vascularization typical of = malignant=20 brain tumors may result from positive feedback between = BTSCs=20 and blood vessels.

Control of BTSC Proliferation by = Developmental=20 Signaling Pathways=20

In addition to being governed by = vasculature-related=20 trophic factors, the proliferation of BTSCs is also = governed=20 by other signaling pathways within the niche, such as = BMPs,=20 Notch, and Shh.^18,72 These=20 pathways are known to play key roles in several = aspects of=20 neural development, including the self-renewal and=20 differentiation of NPSCs.

Bone morphogenetic proteins belong to the = transforming=20 growth factor=96β superfamily of secreted = ligands.⁶⁶ By=20 binding to cell-surface receptors (BMP receptors), = BMPs=20 activate transcription factors (SMADs), which then = translocate=20 into the nucleus to regulate gene expression. = Originally=20 identified as bone-inducing factors, BMPs were later = found to=20 also have important functions in neurogenesis. = Interestingly,=20 the role of BMPs in neurogenesis is complicated and = may even=20 appear paradoxical.¹⁶ Under=20 certain conditions BMPs may specify the dorsal = identity of the=20 neural tube and promote the proliferation of NPSCs, = whereas=20 under other conditions BMPs may induce apoptosis, = mitotic=20 arrest, and differentiation of NPSCs. The results of a = recent=20 study using mice transplanted with human glioblastoma = cells=20 suggest that the activation of BMP signaling may = inhibit the=20 proliferation and promote the differentiation of = BTSCs,=20 thereby reducing the ability of BTSCs to initiate=20 tumors.⁵⁸ Analysis=20 of a medulloblastoma xenograft model suggests that = BMPs may=20 also inhibit brain tumorigenesis by inducing = apoptosis;³⁴ however,=20 it is unclear whether BTSCs undergo apoptosis in this=20 model.

Notch signaling is an evolutionarily conserved = pathway that=20 mediates the interaction between neighboring = cells.⁴⁹ The core=20 components of this pathway include the ligands delta = and=20 serrate; the receptor Notch; a γ-secretase = complex that=20 cleaves the receptor Notch to produce NICD; = NICD-associated=20 nuclear effectors Su(H) and MAM; and Notch target = genes, such=20 as HES, HES-related, and BLBP. Notch = signaling=20 has pleiotropic functions in neural development, such = as=20 maintaining NPSC proliferation, inducing glial fate, = and=20 promoting neurite elaboration.⁴⁹ The=20 activation of the Notch pathway has been linked to = many human=20 cancers,⁶⁹=20 including malignant brain tumors.^23,39,57,60 Two=20 recent studies suggest that the role of Notch = signaling in=20 brain tumorigenesis may involve BTSCs. In the first = study,=20 Shih and Holland⁶⁸ showed=20 that Notch signaling enhanced the expression of = nestin, a=20 marker for BTSCs, in glioblastoma tissues. = Furthermore, when=20 combined with K-ras, activation of Notch in = nestin-expressing=20 cells induced progenitor-like brain lesions. In the = second=20 study, Fan et al.²⁶ blocked=20 Notch signaling in medulloblastoma cells by using a = specific=20 inhibitor of γ-secretase, which is required for = the cleavage=20 of Notch receptor to the activated form NICD. This = inhibitor=20 effectively ablated the BTSC population, possibly by = inducing=20 apoptosis, and markedly impaired medulloblastoma = growth both=20 in vitro and in a xenograft mouse model. Together, = these 2=20 studies suggest that Notch signaling may promote brain = tumorigenesis by stimulating the proliferation and = blocking=20 the apoptosis of BTSCs.

Sonic hedgehog is a secreted protein that belongs = to the=20 hedgehog family, members of which are best known as = morphogens=20 important for the development of Drosophila and = vertebrates.³⁰ Sonic=20 hedgehog signaling is initiated by the binding of Shh = to a=20 12-pass membrane receptor =93patched=94 (PTC1). This = binding=20 relieves the repression of a 7-pass = G-protein=96coupled receptor=20 =93Smoothened=94 (SMO) by PTC1. The activation of SMO = leads to a=20 series of signaling cascades that result in nuclear=20 translocation of GLI transcription factors, which then = regulate the expression of target genes. Sonic = hedgehog=20 signaling plays multifaceted roles during CNS = development,=20 including ventral patterning, oligodendrocyte = specification,=20 the proliferation and survival of NPSCs, and axon=20 guidance.³⁰ Genetic=20 analyses of human brain tumor tissues and mouse models = have=20 revealed that increased activity of the Shh pathway is = involved in the development of both medulloblastoma = and=20 glioblastoma.¹⁸ The=20 contribution of Shh to brain tumorigenesis may be at = least=20 partially through BTSCs. In human glioma samples, = BTSCs may=20 exhibit elevated Shh activity.^3,19,25=20 Importantly, pharmacological inhibition or RNA=20 interference=96mediated silencing of Shh signaling = decreased the=20 self-renewal of BTSCs derived from these tumor samples = and=20 impaired the ability of these BTSCs to initiate tumors = in a=20 xenograft mouse model.^3,19 Thus,=20 Shh signaling may promote brain tumorigenesis by = maintaining=20 the capacity of BTSCs to self-renew.

The proliferation of BTSCs is likely = to also be=20 controlled by other signaling pathways, such as those=20 involving Wnt, EGF, and FGF. A conserved pathway = important for=20 the development of various systems, Wnt signaling has = been=20 shown to promote NPSC proliferation and has been = linked to=20 multiple cancers, including brain tumors.^17,18=20 Increased EGF signaling resulting from = gain-of-function=20 mutations of its receptor EGFR or loss-of-function = mutations=20 of its downstream regulator PTEN is typical of primary = glioblastomas.⁵³ The FGFs=20 promote NPSC proliferation⁵⁰ and have=20 also been implicated in brain tumorigenesis.^29,82,83 Both EGF=20 and FGF2 are key supplements used for maintaining = BTSCs in=20 neurosphere culture assays.⁴⁷=20 Nevertheless, there is no direct evidence that Wnt, = EGF, or=20 FGF signaling regulates BTSC self-renewal in = vivo.

Brain Tumor Invasion and BTSCs=20

Malignant tumors are characterized by both = uncontrolled=20 proliferation and the ability to infiltrate. While = much has=20 been learned about the molecular and cellular basis of = BTSC=20 proliferation since the discovery of BTSCs several = years ago,=20 mechanisms underlying BTSC-associated infiltrativeness = remain=20 poorly understood. Previous studies using non-BTSC = brain tumor=20 cells have identified many cell migration pathways = that=20 regulate cell=96cell adhesion, cell=96ECM adhesion, or = cell=20 motility.⁵² While=20 these pathways are probably important to brain tumor = invasion,=20 it is also necessary to perform studies using purified = BTSCs,=20 which may give rise to tumors with enhanced ability to = infiltrate.^{31,35,47,70,86}

In xenograft mouse models, brain tumor = cells=20 derived from purified BTSCs migrate from the ventral = forebrain=20 toward the olfactory bulb and along axon tracts to the = dorsal=20 cortex,^31,47=20 recapitulating the paths of neuroblasts derived from=20 neurogenic astrocytes in the adult SVZ and = interneurons=20 derived from NPSCs in the embryonic ventral = forebrain.¹ = This=20 observation suggests that similar mechanisms may = underlie the=20 migration of BTSCs (or their progeny) and the = migration of=20 NPSCs and neurons. Consistent with this, preliminary = evidence=20 suggests that genes important for neuronal migration, = such as=20 Slit2 and Lis1, may also be involved in = the=20 migration of medulloblastoma or glioma cells.^73,80 In=20 addition, transforming acid coiled-coil proteins = (TACCs),=20 which promote nuclear migration in embryonic = NPSCs,⁸¹ have=20 been implicated in many human cancers, including=20 glioma.^21,32,41,42 Finally,=20 the ability of transplanted NPSCs to track down brain = tumor=20 cells that have migrated away from the tumor bulk in = the=20 rodent brain⁸⁴ suggests=20 that NPSCs and BTSCs (or their progeny) may migrate = through=20 the same extracellular environment.

Conclusions and Future=20 Directions	AbstractIntroductionThe Relationship Between = ...Mechanisms of BTSC = Self-R...Conclusions and Future Di...=20 <<References

Since the identification of BTSCs several years = ago, these=20 cells have become promising targets for treating brain = tumors.=20 The study of BTSCs has benefited tremendously from our = knowledge of NPSCs, which may give rise to BTSCs = through=20 genetic mutations that deregulate asymmetric cell = division (Fig. 1).=20 Brain tumor stem cells and NPSCs reside in similar=20 microenvironments enriched in capillaries, respond to = similar=20 signaling pathways, and give rise to daughter cells = that=20 migrate along similar paths (Table = 1).

View=20 larger version = (37K)

Fig. 1. A = tentative=20 model for the origin of BTSCs from NPSCs. = The=20 NPSCs exhibit polarized distribution of = cell fate=20 determinants, which are segregated = unequally into=20 the 2 daughter cells during asymmetric = division. A=20 tight control of the polarized = distribution of the=20 cell fate determinants and the orientation = of the=20 mitotic spindle ensures that a balance = between=20 asymmetric division and symmetric division = is=20 maintained. This balance is shifted toward = symmetric division in NPSCs harboring = genetic=20 mutations that disrupt cell polarity, = alter=20 spindle orientation, or inactivate cell = fate=20 determinants important for non=96stem-cell = specification. The increased symmetric = division=20 results in uncontrolled self-renewal, a = hallmark=20 of BTSCs.

TABLE 1 = Comparison of=20 NPSCs and=20 = BTSCs

<= /CENTER>

While great progress has been made in = the field=20 of molecular and cell biology of BTSCs, many questions = remain=20 unanswered. First, although the findings of a number = of=20 studies are consistent with the possibility that = deregulation=20 of asymmetric division may convert NPSCs to BTSCs, = convincing=20 evidence is lacking. Next, how can we distinguish = BTSCs from=20 normal NPSCs in BTSC-based brain tumor therapies? = Since=20 similar molecular pathways may govern the = proliferation of=20 BTSCs and normal NPSCs, targeting these pathways may = not only=20 inhibit brain tumorigenesis, but also impair = endogenous=20 neurogenesis, which plays important physiological = functions.=20 Third, molecular mechanisms underlying the migration = of BTSCs=20 and their progeny remain largely unknown. Lastly, in = most of=20 the studies of BTSCs, investigators have assumed that = these=20 cells express a cell surface marker CD133 and grow=20 nonadherently in vitro. A recent study suggests, = however, that=20 a subset of BTSCs derived from glioblastomas grow = adherently=20 and may not express CD133.⁵ = The=20 significance of this subtype of BTSCs in brain = tumorigenesis=20 needs to be further clarified.

References	AbstractIntroductionThe Relationship Between = ...Mechanisms of BTSC = Self-R...Conclusions and Future = Di...References = <<

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