Stem cells are undoubtedly critical in normal cellular development as well as tumor biology and better characterization of these cells is likely to have profound influence on the classification schemes of tumors. In this manuscript, we present the generally accepted definitions of key concepts in stem cell biology and review some of the related molecular pathways. In addition, we put forth our position on how progress in this field should be affecting the future classification schemes of central nervous system neoplasia. We strongly believe that the ever increasing knowledge in the field of neural and brain tumor stem cells should be influential in the subsequent attempts to classify brain tumors.
Stem Cells
The concept of a “stem cell” in biology has been in
existence since the 19th century in the works of scientists
like Alexander A Maksimov or Ernst Heinrich Haeckel[1]. These scientists have postulated the existence of stem
cells that give rise to mature cells. Today, the term stem cell
identifies the cells that are capable of replication and possess
a number of unique characteristics. First, all stem cells are
required to be unspecialized cells capable of renewing
through asymmetric cell division even after long periods
of inactivity (self-renewal)[2]. Second, under certain
conditions, stem cells can be induced to differentiate into
numerous types of specialized cells (pluripotency)[2]. In
addition, a stem cell is subject to physiological regulatory
mechanisms of the organism (regulability)[3]. In some
organs, stem cells regularly divide to repair and replace
damaged cells, while in others stem cells only divide under
special conditions. There is much debate on the types
and nature of stem cells, yet most agree that these cells
exist mostly in the embryo and to a much lesser extent in
the adult[4]. The three cardinal features (self-renewal,
pluripotency, regulability) are critical in the identification
of “normal” stem cells in organisms.
Numerous proteins that also exist in mature cells have been postulated as stem cell markers. While the expression of these markers has been considered sufficient for stemness, cells harboring such markers often do not have all three cardinal features of normal stem cells[5]. On the other hand, bona fide stem cells do not seem to harbor some of these markers[6]. As of today, a perfect stem cell marker is elusive and the most reasonable studies utilize a panel of markers to confirm “stemness” of a given cell in addition to demonstration of pluripotency and asymmetric division capacity.
Neural Stem Cells
Neural stem cells (NSCs) are the self-renewing, pluripotent
cells that can give rise to all types of differentiated
neuroepithelial cells. The first putative NSCs were isolated
in 1992 from the subventricular zone of mice brain[7].
Following these studies, NSCs have been isolated from
various areas of the fetal and adult brain of many species[8,9]. The discovery of NSCs during adult life significantly
altered our understanding of brain physiology and
suggested that neurogenesis is possible in the adult and may
confer some plasticity to the CNS[4].
As a source of NSCs, the subventricular zone of the lateral ventricle (SVZ), its cellular composition and architecture have been well studied[10]. These studies suggest that NSCs in SVZ (so called B cells) give rise to more restricted, “transiently amplifying progenitor cells” (so called C cells), which eventually differentiate into neuroblasts (so called A cells) and oligodendrocytes[4]. NSCs have also been identified in other parts of the adult brain. As a caudal extension of the SVZ, the subcallosal zone between the hippocampus and corpus callosum was also found to contain cells that behaved in a stem cell fashion in vitro[11]. Furthermore, subgranular zone of the dentate gyrus (SGZ)[12], the boundary between internal granular layer and white matter of the cerebellum[13], and spinal cord[14] were shown to harbor cells with stem cell properties. In all these sites, either the cells identified as NSCs lack pluripotency or the demonstration of their stem cell properties predicates special conditions.
The historical model for NSC maturation proposed the emergence of distinct neuronal and glial precursors early in the development. This theory was based on the idea that neurogenesis and gliogenesis occurred independent of each other[15]. Others suggested that NSCs in ventricular zone of the embryo give rise to neuronal precursors as well as radial glia[16]. However, recent evidence suggests that NSCs can also be induced to differentiate into mesenchymal cell types[2]. Studies in avian and mammalian species also demonstrated presence of radial glia in adults[17,18].
Some authors argue that most mature cells in the CNS are not directly derived from NSCs, but arise through formation of the transitional cell types known as intermediate precursor cells[19]. Precursor cell defines an immature embryonal cell with limited differentiation potential that will give rise to mature cells along a committed pathway. Most importantly, the precursor cells may not undergo asymmetric mitotic division and are more limited in their potency as opposed to the stem cells.
NSCs can be identified by the neurosphere assay in which the cells of interest form three-dimensional spheroids in serumfree media on a non-adhesive substrate in the presence of βFGF and EGF[7]. Neurospheres include precursor cells and mature cells in addition to a small number of putative stem cells. Thus, neurosphere formation is not specific for NSCs and precursor cells can also form neurospheres in culture. However, precursor cells often lose this ability in repeated passages unlike stem cells that can continuously form neurospheres. NSCs can also be isolated by the neural colony-forming cell assay. This assay allows discrimination between NSCs and precursor cells, but also has significant limitations[20].
There is no doubt that understanding NSC biology and stages of neurogenesis can provide greater insight into CNS tumor biology. Through this insight, we could better identify the cell of origin for each mature cell type and characterize specific markers along the differentiation pathways. The latter will greatly enhance our understanding of CNS tumors and allow us to better classify them based on an improved cell of origin paradigm.
Markers of Neural Stem Cells
One of the first reported NSC markers is nestin, which is an
intermediate filament and had been associated with both
stem cells and precursor cells[21]. Nestin expression has
been correlated with the stemness of a cell and its expression
decreases with concomitant increase in neuronal or glial
differentiation marker expression[22]. Another interesting
marker is CD133 that was initially demonstrated in mouse
brains[23]. CD133 positive cells isolated from the human
brain are capable of neurosphere formation in vitro and
proliferation, migration and differentiation in vivo[24].
However, this marker has been found in differentiated as
well as precursor cells in humans, and its utility has been
questioned[5]. A similar protein, CD34 that can reliably
identify hematopoietic stem cells is not as helpful in the
identification of NSCs, and is less specific and less sensitive
than CD133[25]. Musashi-1, an RNA-binding protein,
was also reported as being highly expressed in NCSs, glial
precursors as well as astrocytes and it is down-regulated in
mature neural cells[26].
Many other markers have been suggested but their utility as stem cell marker has been limited[27]. None of the above mentioned markers are specific to stem cells and sorting the cells by these markers may increase the number of stem cells in cultures but do not necessarily isolate them in purity.
The Concept of Brain Tumor Stem Cell
Existence of cells with stem cell properties in tumors was
initially suggested in studies with human acute myeloid
leukemia[28]. Later, cells that share NSC properties were
identified in brain tumors leading to the concept of brain
tumor stem cells (BTSCs)[29]. Despite many publications
on BTSCs, an accurate and consistent description of these
cells has not emerged. Therefore, BTSC is still a concept
without a common definition. One perspective considers
BTSC synonymous with (normal or abnormal) brain
tumor initiating cells that are assumed to give rise to brain
tumors. Others define BTSC as neoplastic cells that have all
the properties of NSC including self-renewal and expression
of stem cell markers. In most instances, pluripotency of
these cells are not well documented.
There is much debate about the cell of origin for BTSCs and whether they are NSCs, precursor cells that have lost cell-cycle regulation or mature cells that have gained stem cell features. Most tumor cells have the ability to proliferate, but it is not clear if this is self-renewal capability akin to stem cells or to precursor cells. Furthermore, there is insufficient evidence that BTSCs actually undergo asymmetric cell division and generate both differentiated and undifferentiated cells.
While putative BTSCs share many features with normal NSCs, they also show significant differences. BTSCs often form neurospheres more efficiently at a faster rate and can be sustained in culture much longer than NSCs[30]. In addition, injection of BTSCs into immunodeficient mice is tumorigenic whereas injection of normal NSCs constantly fail to produce tumors. Tumors caused by BTSCs are locally invasive and can migrate along white matter tracts to distant sites in the host brain[30]. Most importantly, cells differentiating from BTSC exhibit aberrant morphology and dual-fate markers in contrast to cells differentiating from normal NSCs[31]. The expression of NSC markers such as nestin, CD133 or Musashi-1 have been different in BTSC[29,31]. While the expression of stem cell markers in tumors does not imply stem cell character, the absence of these markers does not exclude tumor-initiating properties of the cells in question[32]. All of these challenges raise doubt about the validity of studies that identify BTSCs based on markers that have not been conclusively proven to distinguish stem cells from other cell types.
CNS Tumor Classification and Stem Cells
Primary CNS tumors constitute a diverse group of
neoplasms that range from indolent to highly malignant,
and our understanding of their diversity is best reflected
by the recent WHO classification[33]. This classification
scheme, similar to earlier classifications, is based on the
presumed tumor cell of origin. The cell of origin paradigm
relies on the morphological resemblance of tumor cells to
their normal counterparts in the adult CNS. In tumors
such as medulloblastoma and ependymoblastoma, the cell
of origin is considered to be precursor cells. However, not
all tumors, entities or variants in WHO classification can
be traced to a normal cellular element. This fact is reflected
in tumors such as angiocentric glioma, chordoid glioma or
dysembryoplastic neuroepithelial tumor.
Current WHO classification provides biologically and clinically relevant scheme for the majority of the CNS tumors and gives some insight for the others. Most of the studies that provide critical information regarding the molecular and genetic features of the CNS tumors use the WHO classification[34]. Further refinement of the classification through better Identification of cell of origin and tumorigenic pathways can lead to significant improvements in our understanding of CNS neoplasms. It will be equally beneficial to correctly define brain tumor initiating cells and to identify whether such cells originate from NSCs. Thus, the characterization of precursor cells and NSCs in the CNS and their differentiation pathways becomes crucial in to answer the above questions. A better insight will further allow better and biologically more relevant tumor classification schemes and hopefully better management of patients. One of the helpful ways in this effort is the study of molecular pathways that are common to both NSC biology and CNS tumors.
Common Molecular Pathways in NSC Biology and CNS Tumors
A number of pathways involved in cell proliferation,
differentiation and migration were shown to be critical in the regulation and function of NSCs. Some of these
pathways and their dysregulation were also implicated in
CNS neoplasia. While it is hardly possible to construct a
comprehensive list, some of the critical pathways are briefly
mentioned in this section. As more common pathways
are discovered for both normal and tumor stem cells, we
expect to determine a stronger association between NSC
dysregulation and CNS tumorigenesis.
Epidermal Growth Factor Receptor, Phosphoinosite 3-Kinase
and the Phosphatase and Tensin Homologue
The epidermal growth factor receptor (EGFR) is a
transmembrane glycoprotein with an external ligand
binding domain and a cytoplasmic region that is
homologous to other tyrosine kinases[35]. EGFR family of
proteins is widely expressed in many tissues and mediates
various cellular processes including cell division, adhesion,
differentiation and apoptosis. Ligand binding induces
receptor dimerization and tyrosine kinase activation, which
further initiates various downstream signaling cascades including the phosphoinositide 3-kinase (PI3K) (Figure 1),
mitogen activated protein kinase (MAPK) (Figure 2) and
signal transducer and activator of transcription 3 (STAT3)
pathways.
Figure 1: Simplified diagram demonstrating critical elements of the EGFR/PI3K/mTOR pathway. In this diagram, the molecules labeled with the green color are predominantly pro-proliferative or activating molecules, while redcolored molecules identify antiproliferative molecules as well as tumor suppressors and checkpoints. The yellow-colored molecules can be either pro or anti-proliferative depending on the specific cell or circumstance. Red lines indicate inhibitory reactions while dark arrows are activating reactions. EGF(R): epithelial growth factor (receptor); FKBP: FK506 binding protein; 4E-BP1: translation initiating factor 4E binding protein-1; mTOR: mammalian target of rapamycin; PI3K: phosphoinositide 3-kinase; PIP: phosphatidylinositol 4,5- bisphosphate; PIP3: phosphatidylinositol[3,4,5]- trisphosphate; TSC1 and 2: tuberous sclerosis complex proteins 1 and 2; PKB: protein kinase B; GSK3b: glycogen synthase kinase 3 beta; BAD: Bcl-2-associated death promoter; CASP9: caspase 9; Mdm2: murine double minute oncogene 2 protein.
Activated EGFR signaling enhances proliferation and survival, and inhibits differentiation of NSCs[36]. Dysregulation of EGFR signaling is one of the most common genetic alterations in malignant gliomas[37]. EGFR gene overexpression, with or without amplification, occurs in 40-70% of primary glioblastomas and various clinical trials have utilized therapies targeting EGFR[38]. In addition, activating mutations such as EGFRvIII are found in approximately half of the tumors overexpressing EGFR and have been associated with poor prognosis[39].
One of the principal enzymes activated by the EGFRligand interaction is PI3K. Activation of PI3K triggers phosphorylation of phosphatidylinositol-4,5-biphosphate (PIP2) into phosphatidylinositol-3,4,5-triphosphate (PIP3) which in turn phosphorylates protein kinase B (PKB) also known as Akt[40]. Phosphorylated PKB subsequently affects various substrates that regulate cell survival, growth, proliferation and metabolism including Bcl-2/Bcl-XL-associated death promoter (BAD), tuberous sclerosis complex 2 (TSC2), proline-rich AKT substrate 40 (PRAS40), cyclin-dependent kinase 27 and 21, and glycogen synthase kinase-3β (GSK3β)[41]. The diversity of PKB targets leads to significant convergence between the PI3K pathway and others such as Wnt/β-catenin and sonic hegdehog and Myc in many tumors[3,42]. One of the bestconserved functions of PKB is its role to promote cell growth mainly through activation of mTOR (mammalian target of rapamycin) complex 1(mTORC1). PKB phosphorylates the TSC2 within TSC1-TSC2 (Tuberin-Hamartin) complex and blocks their ability to inhibit the formation of mTORraptor complex (mTORC1)[43]. mTORC1 regulates protein synthesis by phosphorylating translation initiation factors and increasing the level of proteins that are needed for cell cycle progression, proliferation, angiogenesis, and survival pathways.
The phosphatase and tensin homologue (PTEN) negatively regulates PI3K/PKB/mTOR signaling pathway by dephosphorylating PIP3 to PIP2[40]. It is the second most commonly mutated tumor suppressor gene only after TP53, and inactivated in various malignancies including brain tumors[44]. PTEN antagonizes tumor proliferation induced by the PI3K/PKB pathway, and PTEN loss is associated with PI3K/PKB pathway activation. Loss of PTEN is quite common in high grade gliomas and the analysis of PTEN either by immunohistochemistry or mutational analysis has found significant use in clinical practice[45].
Mitogen Activated Protein Kinase Pathway
The MAPK pathway is a genetically conserved signaling
cascade that involves a series of protein kinases most of
which are activated by phosphorylation (Figure 2). Binding
of receptor tyrosine kinases by growth factors leads to
downstream phosphorylation of Ras, Raf, Mek and Erk
which regulate transcriptional factors related to the cell
cycle, migration, angiogenesis, and self-renewal of NSCs[46]. Ras activation can be reversed by GTPase-activating
proteins such as Neurofibromin 1 (NF1)[47]. The MAPK
pathway is dysregulated in a wide range of malignant
tumors including high grade gliomas[48]. The importance
of the MAPK pathway in the pathogenesis of pilocytic
astrocytomas was initially suggested by the association of
Neurofibromatosis-1 (NF-1) and optic gliomas. Although
mutations of NF1 gene cannot be shown in sporadic
pilocytic astrocytomas, further studies revealed duplication
of KRAS and BRAF genes leading to fusion proteins[49].
Tropomyosin-Related Kinase and Pan-Neurotrophin
Receptor
The tropomyosin-related kinase (Trk) receptors (TrkA, TrkB
and TrkC) are receptor tyrosine kinases that can be activated
by one or more of neurotrophins including nerve growth
factor (NGF), brain-derived neurotrophic factor (BDNF),
and neurotrophins 3 and 4 (NT3 and NT4)[50]. Activated
receptor provides recruitment of adaptor proteins that will
initiate signaling cascades including Ras/Raf/Erk and PI3K/
PKB. Neurotrophin-mediated activation of Trk receptors
regulates cell proliferation, survival and remodeling.
Expression of TrkA has been linked to positive prognosis
in medulloblastoma[51]. Expression of TrkA and TrkC
was correlated with apoptosis in medulloblastoma[52].
In addition, Trk receptor expression has been suggested in
reactive astrocytes as well as astrocytic tumors, in contrast
to oligodendroglial tumors[53].
All the neurotrophins also bind to the pan-neurotrophin receptor p75NTR which is an unusual member of the Fas tumor necrosis factor (TNF) receptor family[54]. P75NTR regulates affinity and specificity of Trk receptors to neurotrophins so that Trk receptors are more sensitive to low levels of their preferred ligands in the presence of p75NTR[54]. In addition to potential attenuation of Trk signaling by limiting the non-preferred ligand activation, studies have shown that p75NTR has autonomous proapoptotic effects. Recent studies showed that p75NTR is a specific marker of cerebellar external granular layer cells and is expressed in a subset of medulloblastomas[55].
Wnt Signaling Pathway
The Wnt signaling pathway is composed of a complex set
of proteins that lead to activation of nuclear transcription
factors and regulation of cell fate. The so-called “canonical
Wnt signaling pathway” describes the series of events that
occur when Wnt proteins bind to their transmembrane
receptors (Frizzled) and activate the cytoplasmic signaling
proteins (Dishevelled, Dsh) (Figure 3A). Activated Dsh
disrupts the complex of Axin, adenoma poliposis coli
protein (APC), GSK3β and β-catenin. This complex
targets β-catenin degradation and its disruption causes
accumulation of β-catenin that leads to transcription of
genes related to cell cycle entry/proliferation and survival
such as Cyclin D1 and cMYC[56].
WNT signaling induces proliferation of progenitor cells as well as neural differentiation[57]. Recent studies demonstrate β-catenin accumulation in gliomas and medulloblastomas via mutations of β-catenin, APC or Axin1[58,59]. In addition, medulloblastomas showing nuclear β- catenin positivity were reported to have better prognosis compared to β-catenin negative medulloblastomas[60].
Sonic Hedgehog Signal Transduction Pathway
Hedgehog signal transduction pathway is a ubiquitous
signaling cascade that is common to many species (Figure 3B). Three secreted hedgehog ligands have been identified
in mammals and sonic hedgehog homolog (Shh) is the best
studied ligand. Shh binds its receptor patched (Ptch) leading
to disinhibition of the transmembrane proto-oncogene,
Smoothened (Smo). Smo initiates a signaling cascade
that activates transcription factors such as Gli proteins[61]. Activated Gli proteins promote the transcription of
numerous genes including cell cycle regulators (Cyclin
D1, Cyclin E, cMYC and nMYC), growth factors and their
receptors[62].
The Shh pathway is essential for the normal development of human cortex[63], granular cell precursors in the cerebellum[64] and formation and regulation of adult neural stem cells in the SVZ[65]. SHH gene mutations are associated with a number of developmental anomalies and Shh pathway dysregulation has been found in some gliomas and medulloblastomas[34].
BMI Polycomb Ring Finger Oncogene
B-cell specific Moloney murine leukemia virus integration
site 1 (BMI-1) is a member of Polycomb group (PcG)
gene family of chromatin modifiers and transcriptional
repressors. These molecules are necessary for efficient
self-renewal of adult hematopoietic stem cells and NSCs.
BMI-1 promotes cell proliferation and stem cell renewal by
inhibiting the transcription of the cyclin-dependent kinase
inhibitors, p16INK4A and p19ARF that are responsible for RB1
and TP53 gene activation, respectively[66].
BMI-1 has a very broad tissue distribution and its deficiency results in severe neurological, skeletal and hematopoietic defects[67]. BMI-1 is also thought to function as an inhibitor of senescence by inhibiting p53 protein. BMI- 1 over-expression has been related to glial neoplasms[68]. Furthermore, BMI-1 overexpression was reported in medulloblastomas as an alternative mechanism for Shh pathway activation[69].
Notch Signaling Pathway
The Notch signaling pathway (NSP) is highly conserved
throughout the species and is critical for cell differentiation
during embryogenesis and adult life. The Notch gene
encodes a heterodimeric transmembrane receptor in the plasma membrane and NSP is initiated upon cell to cell
interaction. Activation of the receptor leads to cleavage
of the intracellular domain by presenilin-γ-secretase
complex and the cytoplasmic region is transferred to the
nucleus. Notch then binds to the transcriptional regulator
complex resulting in displacement of co-repressors and
recruitment of co-activators that regulate cell-cycle entry
and progression.
Notch is involved in lateral inhibition, which ensures that distinct cell types are produced in correct numbers from a pluripotent cell population[70]. NSP is required for the maintenance of the NSC pool and regulation of cell differentiation and attenuation of notch signaling induces differentiation of neuronal and glial cells[71]. NSP dysregulation is found in numerous developmental defects as well as in gliomas, embryonal tumors and meningiomas[72,73].
Bone Morphogenic Proteins
Bone morphogenic proteins (BMPs) are members of the
transforming growth factor-β (TGF-β) superfamily that
interact with specific cell surface receptors through a class of
proteins (SMADs). Approximately 20 BMP family members
have been identified to date and each one has a distinct role
in the development and maintenance of different tissues[74]. BMPs interact with signaling pathways such as Notch,
Wnt and MAPK[75,76]. BMPs promote self-renewal and
maintenance of NSCs, and are critical for the regulation of
cell fate[76]. BMP signaling was shown to be dysregulated
in tumors such as glioblastoma and medulloblastoma[77,78]. In these tumors, BMPs were found to induce apoptosis,
reduce proliferation and trigger differentiation.
Myc Transcription Factor
Although Myc does not represent a pathway, members
of the Myc family of basic helix-loop-helix transcription
factors are downstream targets of the several of the above
mentioned pathways. Particularly cMyc and nMyc have
critical roles in the control of cell-cycle progression and cell
immortality. They regulate the NSC proliferation, cell fate
determination of proliferating progenitor cells, and inhibit
neural differentiation[3].
Myc protein expression has been reported in up to 64% of medulloblastomas and cMYC or nMYC amplification has been identified in 10-15% of medulloblastomas[79]. MYC gene expression or amplification is also associated with a poor prognosis[80]. MYC gene upregulation can act in combination with other pathways in the pathogenesis of medulloblastoma[81].
SUMMARY
Despite the increasing number of studies involving NSCs,
there is still a need to provide uniform definitions of
concepts and reliable markers that can identify stem cells.
On the other hand, the immediate benefit of identifying
BTSCs is not quite clear and there is still much to be learned
about them. The similarities and differences between
normal NSCs and BTSCs may help us understand the
mechanisms of CNS tumorigenesis. In this effort, the first
critical step appears to be the recognition of regulatory steps
in formation, maintenance and proliferation of NSCs and
mature cells of the CNS. Common molecular pathways to
both normal and neoplastic cells may provide us an insight
about what goes wrong, and what can be done to prevent
or reverse it. Through this insight, we could develop a more
advanced model of “cell of origin” for each CNS tumor
type and hopefully provide better prognostic markers and
targets for future therapies.
The current WHO classification of the tumors of the CNS has been very successful in providing a reproducible and clinically relevant scheme to accurately classify the majority of the tumors. There is no doubt that the 2007 classification scheme is a “living document” that is prone to modifications. Emerging knowledge about the NSC biology and BTSCs will present the opportunity to develop complementary data to improve this classification system in the near future. We believe that the next modification of the WHO scheme can be achieved through identification of pathways from NSCs to the mature cells of the CNS, and the mechanisms involved in their dysregulation.
1) Haeckel E: The Evolution of Man Vol:1: Human Embryology or
Ontogeny. London, Watts&Co, 1912
2) Vescovi AL, Galli R, Gritti A: The neural stem cells and their
transdifferentiation capacity. Biomed Pharmacother 2001,
55:201-205 [ Özet ]
3) Kenney AM, Widlund HR, Rowitch DH: Hedgehog and PI-
3 kinase signaling converge on Nmyc1 to promote cell cycle
progression in cerebellar neuronal precursors. Development
2004,131:217-228 [ Özet ]
4) Alvarez-Buylla A, García-Verdugo JM, Tramontin AD: A unified
hypothesis on the lineage of neural stem cells. Nat Rev Neurosci
2001, 2:287-293 [ Özet ]
5) Florek M, Haase M, Marzesco AM, Freund D, Ehninger G,
Huttner WB, Corbeil D: Prominin-1/CD133, a neural and
hematopoietic stem cell marker, is expressed in adult human
differentiated cells and certain types of kidney cancer. Cell Tissue
Res 2005, 319:15-26 [ Özet ]
6) Sun Y, Kong W, Falk A, Hu J, Zhou L, Pollard S, Smith A: CD133
(Prominin) negative human neural stem cells are clonogenic and
tripotent. PLoS One 2009, 4:5498 [ Özet ]
7) Reynolds BA, Weiss S: Generation of neurons and astrocytes
from isolated cells of the adult mammalian central nervous
system. Science 1992, 255:1707-1710 [ Özet ]
8) Doetsch F, Caillé I, Lim DA, García-Verdugo JM, Alvarez-
Buylla A: Subventricular zone astrocytes are neural stem cells in
the adult mammalian brain. Cell 1999, 97:703-716 [ Özet ]
9) Sanai N, Tramontin AD, Quiñones-Hinojosa A, Barbaro NM,
Gupta N, Kunwar S, Lawton MT, McDermott MW, Parsa AT,
Manuel-García Verdugo J, Berger MS, Alvarez-Buylla A: Unique
astrocyte ribbon in adult human brain contains neural stem cells
but lacks chain migration. Nature 2004, 427:740-744 [ Özet ]
10) Doetsch F, García-Verdugo JM, Alvarez-Buylla A: Cellular
composition and three-dimensional organization of the
subventricular germinal zone in the adult mammalian brain. J
Neurosci 1997, 17:5046-5061 [ Özet ]
11) Seri B, Herrera DG, Gritti A, Ferron S, Collado L, Vescovi
A, Garcia-Verdugo JM, Alvarez-Buylla A: Composition and
organization of the SCZ: a large germinal layer containing
neural stem cells in the adult mammalian brain. Cereb Cortex
2006,16:103-111 [ Özet ]
12) Gage FH, Kempermann G, Palmer TD, Peterson DA, Ray
J: Multipotent progenitor cells in the adult dentate gyrus. J
Neurobiol 1998, 36:249-266 [ Özet ]
13) Lee A, Kessler JD, Read TA, Kaiser C, Corbeil D, Huttner WB,
Johnson JE, Wechsler-Reya RJ: Isolation of neural stem cells
from the postnatal cerebellum. Nat Neurosci 2005, 8:723-729 [ Özet ]
14) Dromard C, Guillon H, Rigau V, Ripoll C, Sabourin JC, Perrin
FE, Scamps F, Bozza S, Sabatier P, Lonjon N, Duffau H, Vachiery-
Lahaye F, Prieto M, Tran Van Ba C, Deleyrolle L, Boularan A,
Langley K, Gaviria M, Privat A, Hugnot JP, Bauchet L: Adult
human spinal cord harbors neural precursor cells that generate
neurons and glial cells in vitro. J Neurosci Res 2008, 86:1916-
1926 [ Özet ]
15) Luskin MB, Pearlman AL, Sanes JR: Cell lineage in the cerebral
cortex of the mouse studied in vivo and in vitro with a recombinant
retrovirus. Neuron 1988, 1:635-647 [ Özet ]
16) Galileo DS, Gray GE, Owens GC, Majors J, Sanes JR: Neurons
and glia arise from a common progenitor in chicken optic tectum:
demonstration with two retroviruses and cell type-specific
antibodies. Proc Natl Acad Sci U S A 1990, 87:458-462 [ Özet ]
17) Alvarez-Buylla A, Theelen M, Nottebohm F: Proliferation “hot
spots” in adult avian ventricular zone reveal radial cell division.
Neuron 1990, 5:101-109 [ Özet ]
18) Tramontin AD, García-Verdugo JM, Lim DA, Alvarez-Buylla
A: Postnatal development of radial glia and the ventricular zone
(VZ): a continuum of the neural stem cell compartment. Cereb
Cortex 2003, 13:580-587 [ Özet ]
19) Kriegstein A, Alvarez-Buylla A: The glial nature of embryonic
and adult neural stem cells. Annu Rev Neurosci 2009, 32:
149-184 [ Özet ]
20) Louis SA, Rietze RL, Deleyrolle L, Wagey RE, Thomas TE, Eaves
AC, Reynolds BA: Enumeration of neural stem and progenitor
cells in the neural colony-forming cell assay. Stem Cells 2008,
26:988-996 [ Özet ]
21) Lendahl U, Zimmerman LB, McKay RD: CNS stem cells express
a new class of intermediate filament protein. Cell 1990, 60:
585-595 [ Özet ]
22) Dahlstrand J, Lardelli M, Lendahl U: Nestin mRNA expression
correlates with the central nervous system progenitor cell state in
many, but not all, regions of developing central nervous system.
Brain Res Dev Brain Res 1995, 84:109-129 [ Özet ]
23) Weigmann A, Corbeil D, Hellwig A, Huttner WB: Prominin,
a novel microvilli-specific polytopic membrane protein of the
apical surface of epithelial cells, is targeted to plasmalemmal
protrusions of non-epithelial cells. Proc Natl Acad Sci U S A 1997,
94:12425-12430 24) Uchida N, Buck DW, He D, Reitsma MJ, Masek M, Phan TV,
Tsukamoto AS, Gage FH, Weissman IL: Direct isolation of
human central nervous system stem cells. Proc Natl Acad Sci USA
2000, 97:14720-14725 [ Özet ]
25) Lanza F, Healy L, Sutherland DR: Structural and functional
features of the CD34 antigen: an update. J Biol Regul Homeost
Agents 2001, 15:1-13 [ Özet ]
26) Sakakibara S, Imai T, Hamaguchi K, Okabe M, Aruga J,
Nakajima K, Yasutomi D, Nagata T, Kurihara Y, Uesugi S,
Miyata T, Ogawa M, Mikoshiba K, Okano H: Mouse-Musashi-1,
a neural RNA-binding protein highly enriched in the mammalian
CNS stem cell. Dev Biol 1996, 176:230-242 [ Özet ]
27) Pruszak J, Sonntag KC, Aung MH, Sanchez-Pernaute R, Isacson
O: Markers and methods for cell sorting of human embryonic
stem cell-derived neural cell populations. Stem Cells 2007,
25:2257-2268 [ Özet ]
28) Bonnet D, Dick JE: Human acute myeloid leukemia is organized
as a hierarchy that originates from a primitive hematopoietic cell.
Nat Med 1997, 3:730-737 [ Özet ]
29) Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire
J, Dirks PB: Identification of a cancer stem cell in human brain
tumors. Cancer Res 2003, 63:5821-5828 [ Özet ]
30) Varghese M, Olstorn H, Sandberg C, Vik-Mo EO, Noordhuis P,
Nistér M, Berg-Johnsen J, Moe MC, Langmoen IA: A comparison
between stem cells from the adult human brain and from brain
tumors. Neurosurgery 2008, 63:1022-1033 [ Özet ]
31) Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M,
Geschwind DH, Bronner-Fraser M, Kornblum HI: Cancerous
stem cells can arise from pediatric brain tumors. Proc Natl Acad
Sci U S A 2003, 100:15178-15183 [ Özet ]
32) Wang J, Sakariassen PØ, Tsinkalovsky O, Immervoll H, Bøe
SO, Svendsen A, Prestegarden L, Røsland G, Thorsen F, Stuhr
L, Molven A, Bjerkvig R, Enger PØ: CD133 negative glioma cells
form tumors in nude rats and give rise to CD133 positive cells. Int
J Cancer 2008, 122:761-768 [ Özet ]
33) Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger
PC, Jouvet A, Scheithauer BW, Kleihues P: The 2007 WHO
classification of tumours of the central nervous system. Acta
Neuropathol 2007, 114:97-109 [ Özet ]
34) Pomeroy SL, Tamayo P, Gaasenbeek M, Sturla LM, Angelo M,
McLaughlin ME, Kim JY, Goumnerova LC, Black PM, Lau C,
Allen JC, Zagzag D, Olson JM, Curran T, Wetmore C, Biegel
JA, Poggio T, Mukherjee S, Rifkin R, Califano A, Stolovitzky
G, Louis DN, Mesirov JP, Lander ES, Golub TR: Prediction of
central nervous system embryonal tumour outcome based on
gene expression. Nature 2002, 415:436-442 [ Özet ]
35) Wells A: EGF receptor. Int J Biochem Cell Biol 1999, 31:637-643 [ Özet ]
36) Ayuso-Sacido A, Moliterno JA, Kratovac S, Kapoor GS,
O'Rourke DM, Holland EC, García-Verdugo JM, Roy NS,
Boockvar JA: Activated EGFR signaling increases proliferation,
survival, and migration and blocks neuronal differentiation in
post-natal neural stem cells. J Neurooncol 2010, 97:323-337 [ Özet ]
37) Mizoguchi M, Betensky RA, Batchelor TT, Bernay DC, Louis DN,
Nutt CL: Activation of STAT3, MAPK, and AKT in malignant
astrocytic gliomas: correlation with EGFR status, tumor grade,
and survival. J Neuropathol Exp Neurol 2006, 65:1181-1188 [ Özet ]
38) Huang PH, Xu AM, White FM: Oncogenic EGFR signaling
networks in glioma. Sci Signal 2009, 2:6 [ Özet ]
39) Heimberger AB, Hlatky R, Suki D, Yang D, Weinberg J, Gilbert
M, Sawaya R, Aldape K: Prognostic effect of epidermal growth
factor receptor and EGFRvII in glioblastoma multiforme
patients. Clin Cancer Res 2005, 11:1462-1466 [ Özet ]
40) Cantley LC: The phosphoinositide 3-kinase pathway. Science
2002, 296:1655-1657 [ Özet ]
41) Manning BD, Cantley LC: AKT/PKB signaling: navigating
downstream. Cell 2007, 129:1261-1274 [ Özet ]
42) Baryawno N, Sveinbjörnsson B, Eksborg S, Chen CS, Kogner
P, Johnsen JI: Small-molecule inhibitors of phosphatidylinositol
3-kinase/Akt signaling inhibit Wnt/beta-catenin pathway crosstalk
and suppress medulloblastoma growth. Cancer Res 2010, 70:
266-276 [ Özet ]
43) Napolioni V, Moavero R, Curatolo P: Recent advances in
neurobiology of tuberous sclerosis complex. Brain Dev 2009,
31:104-113 [ Özet ]
44) Endersby R, Baker SJ: PTEN signaling in brain: neuropathology
and tumorigenesis. Oncogene 2008, 27:5416-5430 [ Özet ]
45) Umesh S, Tandon A, Santosh V, Anandh B, Sampath
S, Chandramouli BA, Sastry Kolluri VR: Clinical and
immunohistochemical prognostic factors in adult glioblastoma
patients. Clin Neuropathol 2009, 28:362-372 [ Özet ]
46) Yamamoto T, Ebisuya M, Ashida F, Okamoto K, Yonehara
S, Nishida E: Continuous ERK activation downregulates
antiproliferative genes throughout G1 phase to allow cell-cycle
progression. Curr Biol 2006, 16:1171-1182 [ Özet ]
47) Lau N, Feldkamp MM, Roncari L, Loehr AH, Shannon P,
Gutmann DH, Guha A: Loss of neurofibromin is associated
with activation of RA S/MAPK and PI3-K/AKT signaling in a
neurofibromatosis 1 astrocytoma. J Neuropathol Exp Neurol
2000, 59:759-767 [ Özet ]
48) Zohrabian VM, Forzani B, Chau Z, Murali R, Jhanwar-Uniyal
M: Rho/RO CK and MAPK signaling pathways are involved in
glioblastoma cell migration and proliferation. Anticancer Res
2009, 29:119-123 [ Özet ]
49) Bar EE, Lin A, Tihan T, Burger PC, Eberhart CG: Frequent gains
at chromosome 7q34 involving BRA F in pilocytic astrocytoma. J
Neuropathol Exp Neurol 2008, 67:878-887 [ Özet ]
50) Huang EJ, Reichardt LF: Trk receptors: roles in neuronal signal
transduction. Annu Rev Biochem 2003, 72:609-642 [ Özet ]
51) Segal RA, Goumnerova LC, Kwon YK, Stiles CD, Pomeroy
SL:Expression of the neurotrophin receptor TrkC is linked to a
favorable outcome in medulloblastoma. Proc Natl Acad Sci U S A
1994, 91:12867-12871 [ Özet ]
52) Eberhart CG, Kaufman WE, Tihan T, Burger PC: Apoptosis,
neuronal maturation, and neurotrophin expression within
medulloblastoma nodules. J Neuropathol Exp Neurol 2001,
60:462-469 [ Özet ]
53) Wadhwa S, Nag TC, Jindal A, Kushwaha R, Mahapatra AK,
Sarkar C: Expression of the neurotrophin receptors Trk A and
Trk B in adult human astrocytoma and glioblastoma. J Biosci
2003, 28:181-188 [ Özet ]
54) Roux PP, Barker PA: Neurotrophin signaling through the p75
neurotrophin receptor. Prog Neurobiol 2002, 67:203-233 [ Özet ]
55) Barnes M, Eberhart CG, Collins R, Tihan T: Expression of
p75NTR in fetal brain and medulloblastomas: evidence of
a precursor cell marker and its persistence in neoplasia. J
Neurooncol 2009, 92:193-201 [ Özet ]
56) Ille F, Sommer L: Wnt signaling: multiple functions in neural
development. Cell Mol Life Sci 2005, 62:1100-1108 [ Özet ]
57) Yu JM, Kim JH, Song GS, Jung JS: Increase in proliferation and
differentiation of neural progenitor cells isolated from postnatal
and adult mice brain by Wnt-3a and Wnt-5a. Mol Cell Biochem
2006, 288:17-28 [ Özet ]
58) Eberhart CG, Tihan T, Burger PC: Nuclear localization and
mutation of beta-catenin in medulloblastomas. J Neuropathol
Exp Neurol 2000, 59:333-337 [ Özet ]
59) Huang H, Mahler-Araujo BM, Sankila A, Chimelli L,
Yonekawa Y, Kleihues P, Ohgaki H: APC mutations in sporadic
medulloblastomas. Am J Pathol 2000, 156:433-437 [ Özet ]
60) Ellison DW, Onilude OE, Lindsey JC, Lusher ME, Weston
CL, Taylor RE, Pearson AD, Clifford SC: beta-Catenin status
predicts a favorable outcome in childhood medulloblastoma: the
United Kingdom Children's Cancer Study Group Brain Tumour
Committee. J Clin Oncol 2005, 23:7951-7957 [ Özet ]
61) Kinzler KW, Vogelstein B: The GLI gene encodes a nuclear
protein which binds specific sequences in the human genome.
Mol Cell Biol 1990, 10:634-642 [ Özet ]
62) Vokes SA, Ji H, McCuine S, Tenzen T, Giles S, Zhong S,
Longabaugh WJ, Davidson EH, Wong WH, McMahon AP:
Genomic characterization of Gli-activator targets in sonic
hedgehog-mediated neural patterning. Development 2007,
134:1977-1989 [ Özet ]
63) Ruiz i Altaba A, Palma V, Dahmane N: Hedgehog-Gli signalling
and the growth of the brain. Nat Rev Neurosci 2002, 3:24-33 [ Özet ]
64) Kenney AM, Cole MD, Rowitch DH: Nmyc upregulation by
sonic hedgehog signaling promotes proliferation in developing
cerebellar granule neuron precursors. Development 2003, 130:
15-28 [ Özet ]
65) Palma V, Lim DA, Dahmane N, Sánchez P, Brionne TC, Herzberg
CD, Gitton Y, Carleton A, Alvarez-Buylla A, Ruiz i Altaba A:
Sonic hedgehog controls stem cell behavior in the postnatal and
adult brain. Development 2005, 132:335-344 [ Özet ]
66) Jacobs JJ, Kieboom K, Marino S, DePinho RA, van Lohuizen
M: The oncogene and Polycomb-group gene bmi-1 regulates cell
proliferation and senescence through the ink4a locus. Nature
1999, 397:164-168 [ Özet ]
67) van der Lugt NM, Domen J, Linders K, van Roon M, Robanus-
Maandag E, te Riele H, van der Valk M, Deschamps J, Sofroniew
M, van Lohuizen M, et al: Posterior transformation, neurological
abnormalities, and severe hematopoietic defects in mice with a
targeted deletion of the bmi-1 proto-oncogene. Genes Dev 1994,
8:757-769 [ Özet ]
68) Häyry V, Tynninen O, Haapasalo HK, Wölfer J, Paulus W,
Hasselblatt M, Sariola H, Paetau A, Sarna S, Niemelä M,
Wartiovaara K, Nupponen NN: Stem cell protein BMI-1 is an
independent marker for poor prognosis in oligodendroglial
tumours. Neuropathol Appl Neurobiol 2008, 34:555-563 [ Özet ]
69) Leung C, Lingbeek M, Shakhova O, Liu J, Tanger E, Saremaslani
P, Van Lohuizen M, Marino S: Bmi1 is essential for cerebellar
development and is overexpressed in human medulloblastomas.
Nature 2004, 428:337-341 [ Özet ]
70) Beatus P, Lendahl U: Notch and neurogenesis. J Neurosci Res
1998, 54:125-136 [ Özet ]
71) Hitoshi S, Alexson T, Tropepe V, Donoviel D, Elia AJ, Nye JS,
Conlon RA, Mak TW, Bernstein A, van der Kooy D: Notch
pathway molecules are essential for the maintenance, but not
the generation, of mammalian neural stem cells. Genes Dev
2002,16:846-858 [ Özet ]
72) Cuevas IC, Slocum AL, Jun P, Costello JF, Bollen AW, Riggins
GJ, McDermott MW, Lal A: Meningioma transcript profiles
reveal deregulated Notch signaling pathway. Cancer Res 2005, 65:
5070-5075 [ Özet ]
73) Shih AH, Holland EC: Notch signaling enhances nestin expression
in gliomas. Neoplasia 2006, 8:1072-1082 [ Özet ]
74) Chen D, Zhao M, Mundy GR: Bone morphogenetic proteins.
Growth Factors 2004, 22:233-241 [ Özet ]
75) Kasai M, Satoh K, Akiyama T: Wnt signaling regulates the
sequential onset of neurogenesis and gliogenesis via induction of
BMPs. Genes Cells 2005, 10:777-783 [ Özet ]
76) Colak D, Mori T, Brill MS, Pfeifer A, Falk S, Deng C, Monteiro
R, Mummery C, Sommer L, Götz M: Adult neurogenesis requires
Smad4-mediated bone morphogenic protein signaling in stem
cells. J Neurosci 2008, 28:434-446 [ Özet ]
77) Lee J, Son MJ, Woolard K, Donin NM, Li A, Cheng CH, Kotliarova
S, Kotliarov Y, Walling J, Ahn S, Kim M, Totonchy M, Cusack T,
Ene C, Ma H, Su Q, Zenklusen JC, Zhang W, Maric D, Fine HA:
Epigenetic-mediated dysfunction of the bone morphogenetic
protein pathway inhibits differentiation of glioblastoma-initiating
cells. Cancer Cell 2008, 13:69-80 [ Özet ]
78) Zhao H, Ayrault O, Zindy F, Kim JH, Roussel MF: Posttranscriptional
down-regulation of Atoh1/Math1 by bone
morphogenic proteins suppresses medulloblastoma development.
Genes Dev 2008, 22:722-727 [ Özet ]
79) Gilhuis HJ, Anderl KL, Boerman RH, Jeuken JM, James CD,
Raffel C, Scheithauer BW, Jenkins RB: Comparative genomic
hybridization of medulloblastomas and clinical relevance: eleven
new cases and a review of the literature. Clin Neurol Neurosurg
2000, 102:203-209 [ Özet ]
80) Eberhart CG, Kratz J, Wang Y, Summers K, Stearns D, Cohen
K, Dang CV, Burger PC: Histopathological and molecular
prognostic markers in medulloblastoma: c-myc, N-myc, TrkC,
and anaplasia. J Neuropathol Exp Neurol 2004, 63:441-449 [ Özet ]
81) Rao G, Pedone CA, Coffin CM, Holland EC, Fults DW: c-Myc
enhances sonic hedgehog-induced medulloblastoma formation
from nestin-expressing neural progenitors in mice. Neoplasia
2003, 5:198-204 [ Özet ]
){kind=link}
){kind=link}
){kind=link}