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Brain tumour stem cells: the undercurrents of = human brain=20 cancer and their relationship to neural stem cells

Peter=20 B Dirks*

Division of Neurosurgery and Program in Developmental = Biology,=20 University of Toronto=20
Hospital for Sick Children, 555 University Avenue, Toronto, = Ontario=20 M5G 1X8, Canada

(peter.dirks{at}sickkids.ca) =

Abstract

Conceptual and technical advances in neural stem cell = biology are=20 being applied to the study of human brain tumours. These studies suggest = that=20 human brain tumours are organized as a hierarchy and are maintained by a = small=20 number of tumour cells that have stem cell properties. Most of the bulk=20 population of human brain tumours comprise cells that have lost the = ability to=20 initiate and maintain tumour growth. Although the cell of origin for = human brain=20 tumours is uncertain, recent evidence points towards the brain's known=20 proliferative zones. The identification of brain tumour stem cells has = important=20 implications for understanding brain tumour biology and these cells may = be=20 critical cellular targets for curative therapy.

Keywords:

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1. Introduction

Brain tumours are a diverse group of neoplasms afflicting = both=20 children and adults and are among the human cancers with the poorest = outcome (DeAngelis=20 2001). There are no known modifiable risk factors identified for = brain=20 tumour prevention. According to National Cancer Institute of Canada = statistics=20 (http://www.ncic.cancer.ca/), = 2500 new=20 cases of brain tumours and 1650 deaths are expected to occur in adults = in 2005,=20 for a death to case ratio (0.67) only exceeded by cancer of the = oesophagus,=20 pancreas, lung and multiple myeloma. In adults, the commonest malignant = brain=20 tumour, the glioblastoma multiforme, has a 2-year survival rate of less = than=20 10%. In children, brain tumours are the second commonest type of cancer = (17% of=20 all childhood cancer) and cause 25% of cancer deaths, just trailing = leukaemia in=20 both the categories. Survivors of brain tumours often have intellectual=20 impairment related to chemotherapy and radiation therapy and even brain = tumours=20 classified as benign can be lethal due to their location in surgically=20 inaccessible areas.

At the core of treatment failure is a poor understanding of = the=20 cellular and molecular mechanisms regulating tumour growth, for example = which=20 cells in the diverse tumour population initiate and maintain brain = tumour=20 growth? What are the molecular mechanisms involved? What is the normal = cell in=20 the brain that is transformed into a brain tumour?

Recently, by applying the principles of stem cell biology to = the study=20 of human brain tumours, new insight has been gained into understanding = the=20 cellular mechanisms that drive the growth of brain tumours. A key = finding is the=20 demonstration that human brain tumours are organized as a cellular and=20 functional hierarchy based on a subpopulation of brain tumour cells that = have=20 stem cell properties. Brain tumour stem cells have potent = tumour-initiating and=20 -maintaining ability, a property not shared by most of the cells in the = tumour.=20 Recent studies also suggest that brain tumours can be considered as = caricatures=20 of normal development, with relatively rare cancer stem cells aberrantly = maturing into more differentiated cancer cells that lose the ability to=20 proliferate. The discovery of brain tumour stem cells has important = implications=20 for brain tumour research and treatment and, together with earlier = findings in=20 human leukaemia and recent findings in human breast cancer, strongly = implicates=20 cancer stem cells as the undercurrent that fuels the growth of many = human=20 cancers. The implication is that if we can understand the mechanisms = regulating=20 the behaviour of cancer stem cells, we can develop new treatments that = target=20 the cellular source of cancer's growth. Much of the insight into brain = tumour=20 stem cells comes directly from neural stem cell (NSC) research. =

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2. Applying neural stem cell biology to brain cancer

Most, if not all, of our normal somatic tissues are organized as a = cellular=20 hierarchy based on stem cells. So why could not human brain tumours, as = aberrant=20 organs, also be organized as such a hierarchy (see figure=20 1)? The discovery of NSCs in the mammalian brain has laid the = foundations=20 for designing experiments to test whether this hierarchy also exists in = human=20 brain tumours.

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Figure 1=20

Stem cell hierarchy in (a) = normal brain and=20 (b) brain tumours. Rare stem cells in the brain are able to = self-renew=20 to maintain themselves and also generate progenitors that proliferate = and then=20 differentiate into mature cells that form the highly organized brain = parenchyma.=20 The hierarchy remains poorly defined in terms of markers that = unequivocally=20 define stem cells from progenitor cells. Brain tumours are also = organized as a=20 hierarchy based on cancer stem cells. Cancer stem cells are dysregulated = in=20 terms of self-renewal and proliferation and they aberrantly = differentiate into=20 cells that form the bulk of the disorganized cancer tissues.

NSCs are defined as rare cells in the brain that are capable of = extensive=20 self-renewal, proliferation and multilineage differentiation (Hall=20 & Watt 1989; Potten=20 & Loeffler 1990; Fuchs=20 & Segre 2000; Weissman=20 2000; Seaberg=20 & van der Kooy 2003). NSCs can be isolated from the embryonic or = adult=20 mammalian brain of mice (Reynolds & Weiss 1992,=20 1996;=20 Lois=20 & Alvarez-Buylla 1993), primates (Gould=20 et al. 1999) and humans (Eriksson=20 et al. 1998; Flax=20 et al. 1998; Fricker=20 et al. 1999; Vescovi=20 et al. 1999a,b;=20 Roy=20 et al. 2000a,b;=20 Sanai=20 et al. 2004). NSCs divide symmetrically for self-renewal = and=20 generate differentiated progeny (neurons, astrocytes, oligodendrocytes) = through=20 asymmetric divisions (figure=20 2; Gage=20 1998; Temple=20 2001). Postnatally, NSCs exist in the subventricular zones (SVZ) = throughout=20 the entire neuraxis persisting through adulthood into old age (Weiss=20 et al. 1996; Tropepe=20 et al. 1997; Gage=20 1998, 2000).=20 Stem cells have also been demonstrated to exist in the adult hippocampus = (Palmer=20 et al. 1997), but there remains some controversy about = whether the=20 hippocampus contains a mixture of lineage-restricted progenitor cells = with=20 limited self-renewal ability as opposed to true self-renewing stem cells = (Seaberg=20 & van der Kooy 2002); these discrepancies may relate to = differences in=20 culture systems and assays used by different groups to characterize the = cells.=20 As we are now armed with a definitive knowledge that a small number of = cells in=20 the brain have stem cell potential, it suggests that these cells could = be the=20 origin of human brain tumours.

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Figure 2=20

Stem cell division: symmetrical and = asymmetrical.=20 Stem cells make cell fate decisions with cell division, choosing to = (a)=20 replenish and expanding themselves symmetrically, or (b) = maintaining=20 themselves asymmetrically by generating one stem cell and one progenitor = cell.=20 These processes involve stem cell self-renewal. (c) Stem cells = can=20 theoretically divide symmetrically to generate two differentiated = progeny, which=20 would lead to stem cell extinction. Symmetry of cell division may be = regulated=20 by intrinsic or extrinsic factors. Currently, the molecular mechanisms=20 regulation of cell fate decisions in brain tumour stem cells is = unexplored, but=20 could have important implications for understanding clonal expansion and = maintenance of tumours.

Although NSCs are now known to exist in very restricted = zones of the=20 brain, their precise purification has remained elusive. NSCs cannot yet = be=20 unambiguously identified with markers. Until recently, NSCs were mainly = defined=20 by the expression of nestin, a cytoplasmic intermediate filament protein = (Hockfield=20 & McKay 1985; Lendahl=20 et al. 1990; Gates=20 et al. 1995), but it is clear that nestin identifies neural = progenitors as well as stem cells. In vitro, nestin expression = is lost=20 with differentiation of NSCs into neurons and glia and, in = vivo, is=20 retained postnatally only in proliferative zones, such as the cerebellar = external granule layer (EGL; Hatten=20 & Heintz 1995), and in the SVZ (Morshead=20 et al. 1994). Recently, direct isolation of NSCs from human = foetal=20 brain using flow cytometry for the cell surface marker, CD133 (AC133,=20 prominin1), was reported (Uchida=20 et al. 2000). CD133 was originally shown to be a = haemopoietic stem=20 cell marker (Miraglia=20 et al. 1997; Yin=20 et al. 1997), but it is also expressed in the SVZ of = developing=20 mice and humans, being found on the apical membrane of cells lining the=20 ventricle, with more restricted expression than nestin (Weigmann=20 et al. 1997; Corbeil=20 et al. 2000; Sawamoto=20 et al. 2001). Isolated human foetal brain cells expressing = CD133=20 have marked stem cell activity as determined in clonogenic neurosphere = assays=20 (Uchida=20 et al. 2000). CD133+ human foetal brain cells transplanted = into the=20 mouse differentiate, persist and incorporate seamlessly into the brain = (Tamaki=20 et al. 2002).

Cultured NSCs have also been identified by the = =E2=80=98side population=E2=80=99=20 phenotype using fluorescent activated cell sorting (cells which = differentially=20 exclude Hoeschst 33342 DNA dye; Kim=20 & Morshead 2003) as a relatively large cell that has low = expression of=20 CD24 and peanut agglutinin binding (Rietze=20 et al. 2001) or as cells expressing the Sox2 transcription = factor=20 (Cai=20 et al. 2002; D'Amour=20 & Gage 2003; Graham=20 et al. 2003; Brazel=20 et al. 2005). In vivo, NSCs have also been = identified as=20 radial glial cells, expressing markers BLBP, GLAST and RC2 (Feng=20 et al. 1994; Chanas-Sacre=20 et al. 2000a,b;=20 Malatesta=20 et al. 2000; Hartfuss=20 et al. 2001; Noctor=20 et al. 2001; Parnavelas=20 & Nadarajah 2001).

There is particularly strong evidence in mice and humans = that the=20 in vivo SVZ stem cell is a GFAP+ cell (therefore an astrocyte)=20 identified as a morphological type B SVZ cell by electron microscopy = (Doetsch=20 et al. 1997,=20 1999;=20 Morshead=20 et al. 2003; Sanai=20 et al. 2004). Although the A2B5 antigen and the = PSA=E2=80=93NCAM cell=20 surface protein have been used to isolate neuronal- and glial-restricted = progenitors, respectively (Mujtaba=20 et al. 1999), the hierarchy of stem, progenitor and = differentiated=20 cells remains poorly defined. In particular, GFAP marks a postnatal = putative=20 rare SVZ stem cell as well as a large number of differentiated = astrocytes.=20 However, GFAP may not identify mouse embryonic NSCs (Imura=20 et al. 2003). Identification of more definitive markers = within the=20 normal NSC hierarchy should also be very informative for brain tumour = research.=20

NSCs can be cultured in adherent (Johe=20 et al. 1996; Kalyani=20 et al. 1997) or non-adherent (Reynolds=20 & Weiss 1992) conditions in the presence of serum-free media = with EGF=20 and FGF2. These cells are frequently studied in suspension as = neurospheres owing=20 to ease of clonogenic evaluation (figure=20 3). A neurosphere represents a clonal single cell-derived floating = cluster=20 of proliferating cells (Reynolds & Weiss 1992,=20 1996;=20 Tropepe=20 et al. 1999). A neurosphere contains thousands of cells and = is a=20 mixture of stem and progenitor cells, but only 50=E2=80=93100 of these = cells are stem=20 cells. The number of stem cells in a neurosphere is determined in a = clonogenic=20 assay (limiting dilution analysis), which determines the ability of = singly=20 dissociated primary sphere cells to give rise to secondary spheres that = are=20 capable of differentiating down all three neural lineages (Tropepe=20 et al. 1999). This assay also allows one to quantitate=20 self-renewal, which is defined as distinct from proliferation: = self-renewal=20 involves a cell division that also involves a cell fate decision, = resulting in=20 at least one daughter cell that retains the full stem cell potential of = the=20 parent cell. A multipotent secondary sphere can only form from a stem = cell.=20 Undifferentiated neurospheres can be extensively passaged, but when = plated onto=20 an adherent substrate in serum, they differentiate into the three main = neural=20 lineages (neurons, astrocytes, oligodendrocytes).

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Figure 3=20

Neurosphere assay of NSCs in = vitro. The=20 neurosphere assay is used to study neural precursor cells in culture. = Isolated=20 from embryonic or adult brain, rare cells in serum-free conditions, in = the=20 presence of EGF and FGF, generate floating colonies of cells from single = cells.=20 Neurosphere cells express neural precursor markers, but not = differentiated=20 markers, but can be induced to differentiate into all three major neural = lineages in the presence of serum and with cell adhesion. Neurosphere = cells can=20 be dissociated and replated in EGF and FGF to regenerate spheres. The = replating=20 efficiency of spheres is a measure of the number of stem cells, and the = size of=20 the sphere reflects progenitor proliferative activity. Human brain = tumours can=20 be similarly cultured in neurosphere conditions to understand the stem = cell=20 hierarchy of these neoplasms.

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3. Cancer stem cells in solid tumours

The connection between normal stem cells and cancer (Reya=20 et al. 2001; Pardal=20 et al. 2003) is emerging in many tissues, particularly, = blood (Lapidot=20 et al. 1994; Bonnet=20 & Dick 1997; Passegue=20 et al. 2003), brain (Hemmati=20 et al. 2003; Singh et al. 2003,=20 2004a,b;=20 Galli=20 et al. 2004; Yuan=20 et al. 2004), mammary gland (Al-Hajj=20 et al. 2003; Liu et al. 2003,=20 2004),=20 gut (Gregorieff=20 & Clevers 2005; Pinto=20 & Clevers 2005; Radtke=20 & Clevers 2005; Reya=20 & Clevers 2005) and skin (Brown=20 et al. 1998; Bolotin=20 & Fuchs 2003; Perez-Losada=20 & Balmain 2003; Tumbar=20 et al. 2004), and prospective isolation of cancer stem = cells has=20 been achieved in human leukaemia (Lapidot=20 et al. 1994; Bonnet=20 & Dick 1997), myeloma (Matsui=20 et al. 2004), breast cancer (Al-Hajj=20 et al. 2003) and brain tumours (Singh=20 et al. 2004b). Human melanoma (Fang=20 et al. 2005) and prostate cancer (Collins=20 et al. 2005) also contain subpopulations of cells that = demonstrate=20 clonogenic ability in vitro, but these purified cells are yet = to be=20 demonstrated in a functional in vivo assay. Putative cancer = stem cell=20 populations have also been identified in murine models of prostate = cancer (Xin=20 et al. 2005; Wang=20 et al. 2006) and lung cancer (Kim=20 et al. 2005).

Indeed, that cancer tissues resemble developing tissues is = a=20 long-standing observation, which has suggested a close connection = between stem=20 cells and cancer (McCulloch=20 1983; Pierce=20 & Speers 1988; Huntly=20 & Gilliland 2005). Till=20 and McCulloch (1961) initially demonstrated that the bone marrow = contained=20 single cells that clonally gave rise to myeloerythroid colonies in the = spleen=20 (Till=20 & McCulloch 1961; Becker=20 et al. 1963). Clues that tumour growth may be driven by = tumour stem=20 cells were demonstrated by in vitro analysis of haemopoietic = neoplasms=20 and metastatic tumours, where only a minority of the cells plated formed = clonogenic colonies (Bergsagel=20 & Valeriote 1968; Hamburger=20 & Salmon 1977), but, particularly, when the self-renewal of = cells in the=20 primary colony was tested in secondary replating assays (Buick=20 et al. 1979). These studies suggested that the = morphologically=20 heterogeneous cancer tissues exist in a functional hierarchy with = respect to=20 proliferation and tumour initiation.

The definitive demonstration of cancer stem cells in human = neoplasia=20 was first made in 1994 in leukaemia (Lapidot=20 et al. 1994). Injection of a small subpopulation of acute=20 myelogenous leukaemia cells, identified by a cell surface phenotype also = found=20 in normal haemopoietic stem cells, caused a leukaemia in immunodeficient = mice=20 (Lapidot=20 et al. 1994; Bonnet=20 & Dick 1997). Importantly, the cellular heterogeneity of the = resulting=20 leukaemia matched that of the patient's leukaemia. The principle of = cancer stem=20 cells was then extended to solid tumours, first in breast cancer and = then in=20 brain tumours. In breast cancer, a rare fraction of CD44+ and = CD24lo/=E2=88=92=20 expressing human breast cancer cells uniquely caused tumours when small = numbers=20 of cells were engrafted into the mammary fat pads of non-obese diabetic = severe=20 combined immunodeficient (NOD/SCID) mice (Al-Hajj=20 et al. 2003).

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4. Identification of brain tumour stem cells

If NSCs can be isolated from the brain by culturing serum = free in=20 epidermal growth factor (EGF)/fibroblast growth factor (FGF), could this = culture=20 system also identify stem cells in brain tumours? Several groups = studying human=20 brain tumours identified small numbers of cells with clonogenic = potential based=20 on the neurosphere assay (Ignatova=20 et al. 2002; Hemmati=20 et al. 2003; Singh et al. 2003,=20 2004b;=20 Galli=20 et al. 2004; Yuan=20 et al. 2004; Huhn=20 et al. 2005). In culture, these brain tumour cells form=20 self-renewing neurosphere-like colonies, and they have an ability to=20 differentiate into one or more neural lineages. In neurosphere = conditions, brain=20 tumour cells express nestin and CD133. Brain tumours grown as spheres = also=20 express molecular markers associated with neural precursors, such as = Sox2, Bmi1=20 (Hemmati=20 et al. 2003), Notch, Emx2, Pax6 (Galli=20 et al. 2004) and Jagged1 (Ignatova=20 et al. 2002). Following differentiation, they express = markers of=20 mature neurons, astrocytes and oligodendrocytes. Often, multiple = differentiated=20 lineages are found in individual patient tumours, but there is a strong = bias to=20 differentiate into a cell type that is predominant in the patient's = tumour, so,=20 for example, nestin+ astrocytoma cells grown as spheres in EGF and FGF=20 differentiate into GFAP+ astrocytes after plating in serum. However,=20 glioblastomas can differentiate into GFAP+ astrocytes and = =CE=B1-III-tubulin+ neurons=20 (Ignatova=20 et al. 2002; Galli=20 et al. 2004; Singh=20 et al. 2004b; Yuan=20 et al. 2004), suggesting that they are derived from a cell = that has=20 multilineage differentiation capacity, a stem cell, as opposed to the=20 traditional thinking that these tumours were derived from = dedifferentiated=20 normal astrocytes. Brain tumour cells grown in neurosphere conditions = have now=20 been very recently shown to more faithfully recapitulate the phenotype = and=20 genotype of primary patient tumours compared with serum-derived lines = from the=20 same patient tumours (Lee=20 et al. 2006).

The sphere-forming population was then found to reside in = the=20 fraction of primary brain tumour cells that express the NSC/precursor = cell=20 surface marker CD133 (Uchida=20 et al. 2000; Singh et al. 2003,=20 2004b).=20 CD133+ cells represent a subpopulation of cells in brain tumours with a=20 frequency of as low as 1% or less in low-grade tumours to as high as 30% = in=20 highly aggressive glioblastomas, with a relatively close correlation = with=20 clonogenic frequency based on a primary neurosphere-forming assay. = However,=20 within one pathological type of brain tumour, such as glioblastoma, the=20 frequency of expression of this marker could be extremely variable, from = 5 to=20 30% in different patients' tumours. It is uncertain at this time whether = the=20 CD133 fraction in a tumour has any prognostic significance.

CD133+ brain tumour cells, isolated by magnetic bead = sorting, had=20 proliferative and self-renewal ability in vitro, and they = expressed=20 neural precursor markers, such as nestin, but not differentiated = markers, such=20 as =CE=B2-III-tubulin, GFAP and O4. These CD133+ brain tumour cells = could be induced=20 to differentiate to express mature neural cell lineage markers, = highlighting,=20 in vitro, how tumours resemble caricatures of normal = development, with=20 differentiated tumour cells deriving from undifferentiated tumour cells. =

The definitive demonstration of a cancer stem cell requires an in = vivo demonstration that the candidate-purified cancer stem cell is = capable=20 of re-initiating and maintaining growth of a tumour that resembles the = patient's=20 original tumour. Injection of 100=E2=80=931000 uncultured malignant = brain tumour cells,=20 purified by magnetic bead sorting for CD133, could initiate formation of = a=20 serially transplantable tumour in the brains of NOD/SCID mice that was a = phenocopy of the patient's original tumour (figure=20 4), whereas injection of 105 CD133=E2=80=93 cells engrafted, but did = not cause brain=20 tumours (Singh=20 et al. 2004b). Tumour xenografts diffusely = infiltrated=20 into the brain, which is a hallmark of malignant brain tumours. Purified = populations of CD133+ cells injected into the brains of NOD/SCID mice = induced=20 tumours that were heterogeneous and had a minority of cells that = expressed=20 CD133, suggesting differentiation in vivo. Importantly, as = well,=20 sphere-forming glioblastoma cells have been shown to initiate tumours = following=20 transplantation into immunodeficient mice (Galli=20 et al. 2004; Yuan=20 et al. 2004).

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Figure 4=20

Intracranial xenograft of CD133+ human = glioblastoma=20 cells. (a) Low-power micrograph of a NOD=E2=80=93SCID mouse = brain with a human=20 glioblastoma tumour that arose following transplantation of CD133+ = cells.=20 (b) This tumour has typical histologic features of the = patient's=20 original glioblastoma.

More recently, human ependymomas, which are much less = aggressive, but=20 still malignant, brain tumours, were also demonstrated to contain a = subfraction=20 of CD133+ cells that could initiate tumour formation in mice, a property = not=20 seen in the CD133- ependymoma cells (Taylor=20 et al. 2005). Moreover, human ependymoma cells had gene = expression=20 profiles that resembled that of normal radial glial cells (putative = NSCs)=20 isolated from the same relative rostral=E2=80=93caudal position in the = neuraxis as where=20 the tumour was found. These latter results suggest that human = ependymomas arise=20 from regionally distinct populations of radial glial cells.

These findings demonstrate that brain tumours of different = types are=20 heterogeneous not only morphologically, but also functionally, for=20 tumour-initiating ability. The brain tumour stem cells have distinct = biological=20 properties from the bulk of the tumour cells, establishing them as novel = targets=20 for treatment. Although cancer-initiating ability resides in the CD133 = fraction,=20 not every CD133+ cell initiates the formation of a sphere in = vitro,=20 demonstrating that not every CD133+ cell has stem cell properties in = vitro. The =E2=80=98true=E2=80=99 cancer stem cell fraction will = require further=20 purification. The differentiation ability of tumour sphere cells or = CD133+ cells=20 suggests that some aspects of a normal developmental programme is = maintained in=20 these neoplastic cells and that differentiation therapy is a potential = option=20 for brain tumour treatment.

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5. Cells of origin for brain cancer

Although there is accumulating evidence that tumours = contain=20 subpopulations of cells with potent cancer-initiating ability not shared = by the=20 bulk population, the cell of origin for the cancer stem cells of brain = tumours=20 has not yet been determined. The term =E2=80=98cancer stem cell=E2=80=99 = does not mean that=20 these tumour cells are derived from normal cells. It is not yet clear = whether=20 cancer-initiating events occur in NSCs, progenitors or differentiated = cells (Passegue=20 et al. 2003). However, NSCs are attractive candidates for = the cells=20 of origin of brain tumour stem cells, because these cells are long lived = and=20 theoretically have primed self-renewal ability, perhaps allowing an = oncogene to=20 more easily initiate uncontrolled proliferation. If we can understand = the cell=20 of origin for brain tumours, we will be better equipped to understand = how the=20 molecular alterations lead to cancer, and how we can target those = alterations=20 for treatment, or prevent them from occurring. The cell that is = transformed may=20 have important bearings on the behaviour of the neoplasm and therefore = may also=20 affect the patient prognosis.

Neuropathological observations of brain tumours have long = suggested=20 that they may be stem cell or progenitor cell derived. Brain tumours = often=20 comprise morphologically heterogeneous cells, with varying numbers of=20 less-differentiated cells which can be identified by the neural = precursor marker=20 nestin (Dahlstrand=20 et al. 1992; Tohyama=20 et al. 1992) as well as cells expressing differentiated = neural=20 lineage markers (Burger=20 et al. 1991), suggesting that the transformed cell has=20 multipotentiality.

The potential for NSC transformation has been further = considered=20 based on the observations of brain tumours occurring in the brain's = putative=20 stem cell or proliferative zones. Clinically, human brain tumours are = also known=20 to frequently arise deep in the brain near the SVZ. Indeed, the SVZ was=20 suspected many years ago to contain embryonal rests that were thought to = give=20 rise to brain tumours, particularly those tumours occurring in the brain = adjacent to the walls of the ventricular system (Globus=20 & Kuhlenbeck 1944). This idea was then further considered after = the=20 identification of mitotically active cells in the subependymal regions = of adult=20 rodents and primates in the 1960s (Smart=20 1961; Altman=20 1963; Lewis=20 1968), and now especially since the brain SVZ has been defined as = the normal=20 NSC niche (Doetsch et al. 1997,=20 1999).=20

In the 1970s, periventricular tumours were demonstrated to = occur in=20 the SVZ region after intraventricular inoculation with avian sarcoma = viruses,=20 with a much higher rate of tumours occurring in neonatal rats versus = adult rats=20 (Copeland=20 et al. 1975; Copeland=20 & Bigner 1977; Vick=20 et al. 1977). The incidence of brain tumours of a variety = of types=20 in mice inoculated with a pellet of carcinogen was much greater if the = pellet=20 was placed in the SVZ region versus the peripheral cortex (Hopewell=20 & Wright 1969). In addition, there is an extensive older = literature that=20 demonstrates that a single dose of the alkylating agent ethylnitrosurea = (ENU) to=20 pregnant rats selectively induces periventricular brain tumours of a = variety of=20 phenotypes in the offspring (Druckrey=20 et al. 1966; Koestner=20 et al. 1971; Koestner=20 1990; Mennel=20 et al. 2004). Animals are more vulnerable with prenatal = exposure to=20 ENU (when there is more neural precursor activity) and the preneoplastic = lesions=20 that occur are identified in the SVZ (Schiffer=20 et al. 1978; Pilkington=20 & Lantos 1979). In mice, ENU-induced brain tumorigenesis occurs = only in=20 the context of p53 homozygous deletion and, in these animals,=20 preneoplastic/early neoplastic lesions are also identified in the SVZ = (Oda=20 et al. 1997; Leonard=20 et al. 2001; Wilhelmsson=20 et al. 2003). p53=E2=88=92/=E2=88=92 Mice have increased = proliferative activity in=20 the SVZ and more neurospheres can be isolated from this region, = suggesting an=20 expansion of the NSC pool, which may make it more susceptible to = neoplastic=20 transformation (Gil-Perotin=20 et al. 2006; Meletis=20 et al. 2006).

Furthermore, in a combined mutant mouse model deficient in = p53 with=20 Lox=E2=80=93Cre engineered conditional allele of NF1 in a GFAP+ = (astrocyte) compartment,=20 100% of mice developed glioblastoma (Zhu=20 et al. 2005). Interestingly, before full-blown tumours = arise,=20 preneoplastic/early neoplastic changes are seen in the SVZ, suggesting = that=20 cells targeted for transformation came from a GFAP+ stem cell in the SVZ = stem=20 cell compartment. The preneoplastic proliferative expansion of the = granule cell=20 precursors in the EGL of the cerebellum demonstrated in Patched1 mutant = mice=20 also suggests that medulloblastomas that arise in these mice come from = this=20 cerebellar precursor compartment (Oliver=20 et al. 2005). However, recently, cerebellar stem cells = purified=20 based on cell sorting for CD133/prominin1 have been demonstrated, = suggesting=20 that these cells are also possible cells of origin for medulloblastomas = (Lee=20 et al. 2005). Could medulloblastomas have two different = cells of=20 origin? It could be speculated that brain tumours of different = phenotypes,=20 occurring in different locations and patients of different ages, may = have=20 different cells of origin. All the genetic models of brain tumours = currently=20 test for tumour initiation in young animals. Perhaps it is not = surprising that,=20 in these models, the more abundant neural precursor populations at young = ages=20 are most probably initiated into cancer, as opposed to differentiated = brain=20 cells. Currently, a mouse model has not been developed that tests for = brain=20 tumour initiation in adult animals.

Interestingly, in murine models of skin carcinogenesis, the = tumour=20 phenotype arising from H-Ras overexpression depended on the cell = compartment in=20 which the oncogene was expressed (Brown=20 et al. 1998; Perez-Losada=20 & Balmain 2003). Benign tumours resulted from H-Ras = overexpression in=20 suprabasal (differentiated) layers of the skin, but invasive carcinomas = resulted=20 if H-Ras was expressed in the hair follicle bulge region, the location = of=20 putative skin stem cells. Along these lines, perhaps there are different = cells=20 of origins for different types of brain tumours, more benign tumours = arising=20 from restricted progenitors or differentiated cells and aggressive = malignant=20 tumours from stem cells or early progenitors. Do deep aggressive brain = tumours=20 arise from SVZ stem cells? Do superficially less-aggressive tumours = arise from=20 regionally located but lineage-restricted progenitor cells? Or, does a=20 transformed SVZ stem cell migrate away from the ventricle into the = cortex to=20 cause a malignant tumour more peripherally? These questions currently = remain=20 unanswered.

Alternatively, the tumour phenotype may depend less on the = cell type=20 initiated and more on the molecular mechanism of tumour initiation. The = oncogene=20 would activate a signalling pathway that specifies differentiation down = one=20 lineage, but blockage down another. Regardless of cell of origin, the = cancer=20 stem cell hypothesis suggests that, once the tumour is initiated, the = tumour is=20 maintained by a subpopulation of cancer stem cells. The molecular events = allow=20 the original cell to acquire stem cell properties, particularly that of=20 self-renewal. The cancer stem cells then initiate and maintain the = tumour=20 growth. Importantly, multilineage differentiation capacity should not be = considered an essential property of a cancer stem cell. Although cancer = stem=20 cells probably will often show multilineage differentiation (as this is = a=20 hallmark of cancer tissues), differentiation will not occur in normal=20 proportions or may be restricted to one lineage. A cancer stem cell = regenerates=20 the heterogeneous tumour mass matching that from which it was derived. = The=20 differentiation ability of the cancer stem cell may change with the = accumulation=20 of genetic changes with tumour progression.

Overexpression of human brain tumour-derived oncogenes has = also been=20 tested in different brain cell compartments in vivo in the = neonatal=20 mouse through retroviral transduction. In these models, brain cells = expressing=20 neural precursor markers have been suggested to be more receptive to = oncogenic=20 transformation than differentiated brain cells (Holland et al. = 1998,=20 2000).=20 Expression of oncogenic EGFR (EGFRvIII), or combinations of K-Ras and = Akt more=20 potently induced glioblastoma in a nestin+ cell compartment compared = with a=20 GFAP+ compartment in the newborn mouse brain, with higher frequencies in = the=20 context of p16Ink4a/p19Arf cell cycle regulatory deficiency. Other = studies=20 manipulating cultured differentiated astrocytes versus cultured = neurosphere=20 precursors with oncogenes have suggested that a differentiated mouse = neural cell=20 is equally permissive to transformation if it has a key genetic = alteration=20 (p16Ink4a/p19Arf deficiency) (Bachoo=20 et al. 2002). This alteration may facilitate = dedifferentiation to a=20 stem cell-like phenotype (Bachoo=20 et al. 2002; Passegue=20 et al. 2003).

The cell of origin question, as probed in these studies, is = hampered=20 by limited definition of the normal NSC hierarchy, especially by a = paucity of=20 promoters that can specify gene expression in distinct compartments of = the stem=20 cell hierarchy and by a paucity of cell surface markers that can = distinguish=20 stem cells from multipotent or lineage-restricted progenitors. Nestin, = CD133 and=20 Sox2 identify NSCs and progenitors, and no definite lineage-restricted=20 progenitor cells have been identified. As well, GFAP marks a rare NSC = population=20 as well as an abundance of differentiated astrocytes, complicating=20 interpretation of some of these studies.

Previous=20 Section Next=20 Section

6. Developmental signalling in brain tumour stem cell function

A hypothesis that cancer growth is driven by cancer stem = cells=20 suggests that there should be mechanistic similarities between = self-renewal of=20 normal stem cells and that of cancer stem cells. Cancer could be = considered a=20 disease of unregulated self-renewal where mutations in normal stem cell=20 self-renewal pathways give rise to abnormal proliferation and cancer = growth.=20

Recent studies have now revealed a number of molecular = mechanisms=20 regulating stem cell self-renewal and proliferation. There is particular = interest in the Notch (Hitoshi=20 et al. 2002; Calvi=20 et al. 2003; Chojnacki=20 et al. 2003; Maillard=20 et al. 2003; Radtke=20 & Raj 2003), Sonic hedgehog (Shh; Rowitch=20 et al. 1999; Dahmane=20 & Ruiz-i-Altaba 1999; Wechsler-Reya=20 & Scott 1999; Dahmane=20 et al. 2001; Lai=20 et al. 2003; Machold=20 et al. 2003; Watkins=20 et al. 2003; Palma=20 & Ruiz i Altaba 2004) and Wingless (Chenn & Walsh 2002,=20 2003;=20 Megason=20 & McMahon 2002; Reya=20 et al. 2003; Willert=20 et al. 2003; Kuhnert=20 et al. 2004) pathways as these have been shown to play a=20 particularly important role in normal stem cell self-renewal as well as = in=20 cancer growth when these pathways are dysregulated. As well, homeobox=20 transcription factors, such as HoxB4 (Sauvageau=20 et al. 1995; Antonchuk=20 et al. 2001), the PTEN phosphatase protein (Groszer=20 et al. 2001) and the polycomb group of transcriptional = repressors=20 (Bmi-1; Lessard=20 & Sauvageau 2003; Molofsky=20 et al. 2003; Park=20 et al. 2003; Raaphorst=20 2003), have been implicated in normal and cancer stem cell = self-renewal. In=20 particular, Bmi1 seems to be a target of Shh signalling and is expressed = in=20 human medulloblastomas (Leung=20 et al. 2004), and Bmi1 deficiency in adult mice results in=20 reduction of neurosphere formation (Bruggeman=20 et al. 2005; Molofsky=20 et al. 2005).

A role for Notch in human brain tumours is emerging, with = finding=20 Notch receptor and ligand transcripts in cultures of gliomas (Ignatova=20 et al. 2002) or protein expression in primary glial tumours = (Purow=20 et al. 2005), and also in medulloblastomas where Notch1 or = 2=20 transcripts have been shown to be increased in patient specimens (Fan=20 et al. 2004; Hallahan=20 et al. 2004). Overexpression of Notch2-IC increases = proliferation=20 of medulloblastoma cell lines (Fan=20 et al. 2004) and medulloblastoma cell line growth has been = shown to=20 be suppressed by =CE=B3-secretase inhibitor or a soluble Dll-1 = treatments (Hallahan=20 et al. 2004). RNA interference-mediated downregulation of = Notch=20 receptors and ligands inhibits glioma cell line proliferation and = induces=20 apoptosis. Interestingly, overexpression of an activated Shh co-receptor = smoothened in the cerebellum causes activation of Notch pathway in the = resulting=20 tumours, suggesting crosstalk between these pathways (Hallahan=20 et al. 2004).

The role for Shh signalling in human medulloblastomas has = been=20 clearly established (Ruiz=20 i Altaba et al. 2002; Pasca=20 di Magliano & Hebrok 2003), with the finding of mutations in = multiple=20 Shh pathway members, Ptc1 (Pietsch=20 et al. 1997; Raffel=20 et al. 1997; Wolter=20 et al. 1997), Smo (Reifenberger=20 et al. 1998; Lam=20 1999) and SuFu (Taylor=20 et al. 2002), in these neoplasms, and through the = occurrence of=20 medulloblastomas in Ptc1+/=E2=88=92mice (Goodrich=20 et al. 1997). Interestingly, human brain tumour cell lines = with a=20 variety of phenotypes (not only medulloblastoma) express all three Gli = genes,=20 the transcriptional effectors of Shh signalling; and brain tumour cell = lines of=20 different phenotypes are inhibited by the Shh pathway inhibitor = cyclopamine (Dahmane=20 et al. 2001; Ruiz=20 i Altaba et al. 2002). Interestingly, Gli1 was initially = found to=20 be amplified in a glioblastoma line, although this phenomenon has not = been seen=20 in primary glioblastomas (Kinzler=20 et al. 1987). Recent findings that the Shh pathway remains = active=20 in adult tissues (particularly in the brain; Lai=20 et al. 2003; Machold=20 et al. 2003) and plays a role in specific adult cancers (GI = tract,=20 pancreas, skin; Pasca=20 di Magliano & Hebrok 2003) suggest that Shh could play a role in = tumours=20 of the brain other than childhood medulloblastomas.

As brain tumours seem to be organized as stem cell = hierarchies,=20 further studies of these pathways in the context of purified brain = tumour stem=20 cells will likely bring further understanding to brain tumours. =

Previous=20 Section Next=20 Section

7. The stem cell niche: implications for brain tumours

An important emerging concept over the past several years = in stem=20 cell biology is the concept of the stem cell niche. This concept has = been=20 extensively discussed in a number of excellent reviews and has been best = characterized in the gonads of Drosophila (Spradling=20 et al. 2001; Alvarez-Buylla=20 & Lim 2004; Fuchs=20 et al. 2004). In mammalian systems, the niche has been best = characterized in the haemopoietic system (Calvi=20 et al. 2003) and the skin (Tumbar=20 et al. 2004). The stem cell niche is defined as the local=20 microenvironment of stem cells that functions to indefinitely maintain = stem cell=20 self-renewal and multipotency. The niche can consist of extracellular = matrix=20 components or adjacent tissue non-stem cells. Within a given tissue, = there may=20 be several different types of niches for stem cells and the niche may be = different at different developmental stages. For the postnatal nervous = system,=20 the niche of neural precursors is beginning to be defined in the = hippocampal=20 region and the forebrain SVZ, and differentiated neural cells or blood = vessel=20 cells have been implicated as niche elements. Further, in-depth = understanding of=20 molecular mechanisms between niche elements and NSCs should be = forthcoming soon.=20

In brain tumours, a concept of niche as a supportive = environment for=20 the self-renewal of brain tumour stem cells may also be extremely = important for=20 understanding brain tumour growth. One important consideration and = uncertainty=20 is that we really do not know how the niche functions and whether it = supports=20 stem cell self-renewal or constrains self-renewal. In addition, so far = there is=20 little, if any, published data that define niche elements within tumours = and,=20 presently, we are left with many interesting questions. Does the tumour=20 vasculature provide signals to brain tumour stem cells that enhance = their=20 self-renewal? Does the bulk population of tumour cells support brain = tumour stem=20 cell self-renewal and differentiation? Do brain tumour stem cells become = independent of a niche leading to uncontrolled proliferation, or does = the niche=20 expand with tumour leading to further tumour enlargement? Answers to = these=20 questions should provide some fascinating insight into tumour stem cell=20 behaviour.

Previous=20 Section Next=20 Section

8. Summary

Recent studies demonstrate a close link between = developmental=20 biology, stem cells and cancer. Not every cancer cell is functionally = equal.=20 Brain tumours are heterogeneous in part because they exist as a stem = cell=20 hierarchy, relatively fewer stem cells driving the growth of the tumour, = through=20 their own self-renewal and the generation of the bulk tumour population. = The=20 brain tumour stem cells express neural precursor markers, suggesting = that they=20 may be derived from normal neural precursors and are capable of = differentiation,=20 although aberrant. The fact that any differentiation is possible = suggests that=20 brain tumour cells retain some aspects of a functional developmental = programme,=20 demanding further research into understanding the role of developmental=20 signalling pathways in brain tumours.

Although there is evidence that is pointing more clearly towards the = origin=20 of brain tumours from brain proliferative compartments, we still do not = know the=20 cell of origin for brain tumours, and these may vary from one tumour = type to=20 another or may be different in tumours occurring at different patient = ages. One=20 could argue that once the tumour exists, its cell of origin is not = relevant,=20 what is relevant is the cancer stem cell and the directing therapy to = this cell=20 to effect a cure. The cancer stem cell hypothesis suggests that the = cancer stem=20 cell must be eliminated to cure cancer, but it is likely that different=20 components of the tumour hierarchy will need to be targeted. This = hypothesis=20 suggests that our current therapies spare cancer stem cells leading to = tumour=20 regrowth and clinical recurrence (figure=20 5). One key factor for treatment may be the cell cycle status of the = stem=20 cells, as most currently available treatments target cells that are = rapidly=20 cycling. Although normal stem cells, and leukaemic stem cells, have been = shown=20 to be quiescent, the cell cycle status of solid cancer stem cells has = not yet=20 been well characterized. If the brain tumour stem cell is relatively = quiescent,=20 these cells will probably require distinct therapy from tumour = progenitors that=20 are rapidly proliferating.

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Figure 5=20

Cancer stem cells cause tumour regrowth = after=20 apparently successful therapy. The cancer stem cell hypothesis predicts = that=20 cancer stem cells are refractory to conventional therapies and will = regrow the=20 tumour. Top, MRIs of a left-hemisphere glioblastoma is shown at = (a)=20 initial patient presentation, (b) following multimodality = treatment and=20 then (c) at recurrence. It is hypothesized that treatment = eliminated=20 bulk tumour but spared cancer stem cells (below in red). These cancer = stem cells=20 regrew the heterogeneous tumour leading to clinical recurrence.

These are early days for characterizing stem cells in solid = tumours,=20 and these cells must be more highly purified. The next challenge is to=20 understand what regulates tumour stem cell behaviour and to determine = the genes=20 expressed in cancer stem cells to identify novel targets. Hopefully, = these=20 studies will lead to badly needed breakthroughs for brain tumours in = children=20 and adults.

Previous=20 Section Next=20 Section

Acknowledgments

Dr. Dirks' research is supported by the National Cancer = Institute of=20 Canada, Canadian Institutes of Health Research, Canada's Stem Cell = Network,=20 Genome Canada, the Hospital for Sick Children Research Institute, = Hospital for=20 Sick Children Foundation and BrainChild organization.

Previous=20 Section Next=20 Section

Footnotes

One contribution of 14 to a Theme Issue =E2=80=98Stem = cells and brain=20 repair=E2=80=99.
=C2=A9 2007 = The Royal=20 Society

Previous=20 Section

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Abstract
1.=20 Introduction
2.=20 Applying neural stem cell biology to brain cancer
3.=20 Cancer stem cells in solid tumours
4.=20 Identification of brain tumour stem cells
5.=20 Cells of origin for brain cancer
6.=20 Developmental signalling in brain tumour stem cell function
7.=20 The stem cell niche: implications for brain tumours
8.=20 Summary
Acknowledgments
Footnotes
References

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Online ISSN: 1471-2970 | Co= pyright =C2=A9=20 The Royal Society 2009

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undefined) && overrideConfig && = (overrideConfig.length > 0)) {=0A= config =3D overrideConfig;=0A= }=0A= }=0A= }=0A= var origTitle =3D $(this).attr("title");=0A= var newTitle =3D '';=0A= if ((origTitle =3D=3D undefined) || (!origTitle)) {=0A= origTitle =3D '';=0A= }=0A= else {=0A= newTitle =3D origTitle + ' ';=0A= }=0A= newTitle +=3D '[opens in a new window]';=0A= $(this).attr("target", targetName).attr("title", newTitle);=0A= if (config !=3D null) {=0A= $(this).click(function() {=0A= window.open(this.href, targetName, config);=0A= return false;=0A= });=0A= }=0A= }=0A= );=0A= =0A= /* attach onFocus handlers to quick-search fields, to clear the=0A= field when it receives focus IF it contains the default=0A= value (such as "Search the site") */=0A= updateFormInput("#header-qs-search-label", "#header-qs-input", '', '');=0A= =0A= /* handle collapsing content-box areas, with user prefs */=0A= setupCollapsibles();=0A= =0A= /* handle "most" boxes */=0A= handleMostBoxes();=0A= });=0A= =0A= =0A= function setupCollapsibles() {=0A= // sites can override this if they want to target different elements=0A= prepCollapsibles("div.content-box div.collapsible");=0A= }=0A= =0A= /* handle collapsing content-box areas, with optional user prefs */=0A= function prepCollapsibles(parentJQueryEl, setPrefs) {=0A= if (typeof(setPrefs) =3D=3D "undefined") {=0A= setPrefs =3D true;=0A= }=0A= var expandStr, contractStr;=0A= if (gSiteOptions =3D=3D undefined) {=0A= expandStr =3D '+';=0A= contractStr =3D '-';=0A= }=0A= else {=0A= if (gSiteOptions.cbExpandString !=3D undefined) {=0A= expandStr =3D gSiteOptions.cbExpandString;=0A= }=0A= else if (gSiteOptions.expandString !=3D undefined) {=0A= expandStr =3D gSiteOptions.expandString;=0A= }=0A= else { expandStr =3D '+'; }=0A= if (gSiteOptions.cbContractString !=3D undefined) {=0A= contractStr =3D gSiteOptions.cbContractString;=0A= }=0A= else if (gSiteOptions.contractString !=3D undefined) {=0A= contractStr =3D gSiteOptions.contractString;=0A= }=0A= else { contractStr =3D '-'; }=0A= }=0A= $(parentJQueryEl).each(=0A= function(i) {=0A= var $this =3D $(this);=0A= var id =3D $this.attr("id");=0A= if (id !=3D null) {=0A= var $labelElement, $label;=0A= for (var i =3D 0; i < gSiteOptions.collapsibleLabels.length; i++) {=0A= $labelElement =3D gSiteOptions.collapsibleLabels[i];=0A= $label =3D $this.find($labelElement);=0A= if ($label.length) {=0A= // get first one=0A= if ($label.length > 1) {=0A= $label =3D $label.eq(0);=0A= }=0A= break;=0A= }=0A= }=0A= =0A= // if there's already a toggle leave this as is=0A= var alreadyHasToggle =3D ($label.length && = $label.find("a.collapse-toggle").length);=0A= if ($label.length) {=0A= if (!(alreadyHasToggle)) {=0A= var labelText =3D $label.html();=0A= $label.empty().append('' + contractStr + = ' ' + labelText + '');=0A= }=0A= }=0A= =0A= var isOpen =3D true;=0A= if (setPrefs) {=0A= var statePref =3D getPrefValue(id + "-state");=0A= if (statePref && ((statePref =3D=3D 'open') || (statePref =3D=3D = 'closed'))) {=0A= if (statePref =3D=3D 'closed') {=0A= isOpen =3D false;=0A= }=0A= }=0A= else {=0A= // no pref, or unknown value=0A= if ($this.hasClass('default-closed')) {=0A= isOpen =3D false;=0A= }=0A= }=0A= }=0A= var childListType;=0A= if ($this.children("ol").length) {=0A= childListType =3D "ol";=0A= }=0A= else {=0A= childListType =3D "ul";=0A= }=0A= if (!isOpen && !(alreadyHasToggle)) {=0A= toggleCollapse($this, childListType, ($labelElement + " a = span.view-more"), expandStr, contractStr);=0A= }=0A= $this.find("a.collapse-toggle").click(=0A= function(e) {=0A= // need to find first parent that is in either state...=0A= // $(this).parents(".collapsible, .collapsed").each(=0A= $(this).parents().each(=0A= function(i) {=0A= if ($(this).hasClass('collapsible') || = $(this).hasClass('collapsed')) {=0A= var isCollapsed =3D $this.hasClass('collapsed');=0A= if (setPrefs) {=0A= var prefName =3D id + "-state";=0A= if (isCollapsed) {=0A= setPref(prefName, "open");=0A= }=0A= else {=0A= setPref(prefName, "closed");=0A= }=0A= }=0A= toggleCollapse($(this), childListType, ($labelElement + " a = span.view-more"), expandStr, contractStr);=0A= fixColHeights(-1);=0A= return false;=0A= }=0A= }=0A= );=0A= e.preventDefault();=0A= }=0A= );=0A= }=0A= }=0A= );=0A= }=0A= =0A= function handleMostBoxes() {=0A= var hadMostBoxes =3D false;=0A= $("div.most-links-box").each(=0A= function(i) {=0A= var $this =3D $(this);=0A= modClass($this, '', 'js-marker');=0A= hadMostBoxes =3D true;=0A= // 1) get the

child:=0A= var hasSelected =3D false;=0A= var mostHdrList =3D null;=0A= if ($mostlist.length) {=0A= var hasItems =3D false;=0A= var hdrList =3D '
';=0A= var $mostli =3D $mostlist.children("li");=0A= if ($mostli.length) {=0A= hasItems =3D true;=0A= $mostli.each(=0A= function(i) {=0A= var $hdr =3D $(this).children("h4").html();=0A= if ($(this).hasClass("most-cur-sel")) {=0A= hasSelected =3D true;=0A= hdrList +=3D '
' + $hdr = + '
';=0A= }=0A= else {=0A= hdrList +=3D '
' + $hdr + '
';=0A= }=0A= }=0A= );=0A= }=0A= hdrList +=3D '
';=0A= if (hasItems) {=0A= var header =3D $this.find("div.most-header h3");=0A= if (header.length) {=0A= header.after(hdrList);=0A= }=0A= }=0A= mostHdrList =3D $this.find("div.most-header ul");=0A= }=0A= // 3) if none of the items are selected, make the first one be=0A= if (((mostHdrList !=3D null) && mostHdrList.length) && = (!hasSelected)) {=0A= modClass(mostHdrList.find("li:first"), "most-cur-sel", "");=0A= modClass($this.children("ul").children("li:first"), "most-cur-sel", = "");=0A= }=0A= // 4) bind a handler to each heading li a to toggle = class=3D"most-cur-sel" for =0A= // that item and its corresponding item in the list below=0A= if (((mostHdrList !=3D null) && mostHdrList.length)) {=0A= mostHdrList.find("li a").click(=0A= function(e) {=0A= var curA =3D $(this);=0A= toggleMostSelection(e, $this, curA.text());=0A= }=0A= );=0A= }=0A= }=0A= );=0A= if (hadMostBoxes) {=0A= fixColHeights(-1);=0A= }=0A= }=0A= =0A= function toggleMostSelection(e, mostItemDiv, groupName) {=0A= if (mostItemDiv.length) {=0A= var hdrItems =3D mostItemDiv.find("div.most-header ul li");=0A= if (hdrItems.length) {=0A= hdrItems.each(=0A= function() {=0A= var hdrName =3D $(this).text();=0A= var isChoice =3D (hdrName =3D=3D groupName);=0A= if (isChoice) {=0A= modClass($(this), 'most-cur-sel', '');=0A= }=0A= else {=0A= modClass($(this), '', 'most-cur-sel');=0A= }=0A= }=0A= );=0A= }=0A= var listItems =3D mostItemDiv.children("ul").find("li");=0A= if (listItems.length) {=0A= listItems.each(=0A= function() {=0A= var itemName =3D $(this).children("h4").text();=0A= var isChoice =3D (itemName =3D=3D groupName);=0A= if (isChoice) {=0A= modClass($(this), 'most-cur-sel', '');=0A= }=0A= else {=0A= modClass($(this), '', 'most-cur-sel');=0A= }=0A= }=0A= );=0A= }=0A= }=0A= fixColHeights(-1);=0A= e.preventDefault();=0A= }=0A= =0A= function toggleCollapse(collapsibleEl, hideTagExpr, modTextTagExpr, = expandStr, contractStr) {=0A= if (typeof(expandStr) =3D=3D "undefined") {=0A= expandStr =3D getSiteOption('expandString','+');=0A= }=0A= if (typeof(contractStr) =3D=3D "undefined") {=0A= contractStr =3D getSiteOption('contractString','-');=0A= }=0A= =0A= var $this =3D collapsibleEl;=0A= if ($this.hasClass('collapsed')) {=0A= modClass($this, 'collapsible', 'collapsed');=0A= }=0A= else if ($this.hasClass('collapsible')) {=0A= modClass($this, 'collapsed', 'collapsible');=0A= }=0A= var $toToggle =3D $this.find(hideTagExpr);=0A= if ($toToggle.length) {=0A= $toToggle.toggle();=0A= }=0A= var $rewrite =3D $this.find(modTextTagExpr);=0A= if ($rewrite.length) {=0A= $rewrite.each(=0A= function(i, e) {=0A= var txt =3D $(e).text();=0A= if (txt =3D=3D expandStr) {=0A= $(e).empty().append(contractStr);=0A= }=0A= else if (txt =3D=3D contractStr) {=0A= $(e).empty().append(expandStr);=0A= }=0A= }=0A= );=0A= }=0A= }=0A= =0A= function setupDockBlock(col, dockId, dockClass, contentRules) {=0A= if ((col =3D=3D 2) || (col =3D=3D 3)) {=0A= var navOrigHeight =3D ((col =3D=3D 2) ? gColOrigHeights.col2 : = gColOrigHeights.col3);=0A= var gColNum =3D col;=0A= var gNav =3D ((col =3D=3D 2) ? gCol2 : gCol3);=0A= var gNavHeight =3D ((gNav.length) ? navOrigHeight : 0);=0A= var gNavTopOffset =3D (gNavHeight > 0 ? gNav.offset().top : 0);=0A= var gScrollPos =3D 0;=0A= var gNavDocked =3D false;=0A= /* this won't work in IE 6, so skip it /=0A= / article navigation docking block /=0A= $(window).scroll(function () {=0A= if (gNavHeight > 0 && !isIE6) {=0A= var offsets =3D getPageOffset();=0A= var origHeight =3D ((gColNum =3D=3D 2) ? gColOrigHeights.col2 : = gColOrigHeights.col3);=0A= var navBottom =3D (gNavTopOffset + origHeight) - offsets.y;=0A= if (gScrollPos !=3D offsets.y) {=0A= gScrollPos =3D offsets.y;=0A= if ((navBottom <=3D 0) && !gNavDocked) {=0A= / dock the nav /=0A= gNavDocked =3D true;=0A= addDockBlock(col, dockId, dockClass, contentRules);=0A= }=0A= else if (gNavDocked && (navBottom > 0)) {=0A= / undock the nav /=0A= gNavDocked =3D false;=0A= removeDockBlock(col, dockId);=0A= }=0A= }=0A= }=0A= });=0A= }=0A= }=0A= function addDockBlock(col, dockId, dockClass, contentRules) {=0A= // get direct children li elements only=0A= var colId =3D ("col-" + col);=0A= var newDiv =3D ' 1) {=0A= for (var i =3D 0; i < (contentRules.length - 1); i =3D i + 2) {=0A= var addTo =3D processDockingRule(contentRules[i]);=0A= var add =3D processDockingRule(contentRules[i + 1]);=0A= var addTarget, addVal;=0A= if (addTo.ruleType =3D=3D 'empty') {=0A= addTarget =3D newDivJQuery;=0A= }=0A= else if (addTo.ruleType =3D=3D 'jQuery') {=0A= addTarget =3D $(addTo.rule);=0A= }=0A= if (add.ruleType =3D 'jQuery') {=0A= var addJQEl =3D $(add.rule);=0A= if (addJQEl.length) {=0A= addVal =3D addJQEl.clone();=0A= }=0A= else {=0A= addVal =3D '';=0A= }=0A= }=0A= else if (add.ruleType =3D 'html') {=0A= addVal =3D add.rule;=0A= }=0A= if (addTarget.length && !(addVal =3D=3D '')) {=0A= addTarget.append(addVal);=0A= }=0A= else {=0A= }=0A= }=0A= }=0A= var newDockJQrule =3D "#" + colId + " #" + dockId;=0A= var newDock =3D $(newDockJQrule);=0A= if (newDock.length) {=0A= prepCollapsibles(newDockJQrule + " div.collapsible, " + newDockJQrule = + " div.collapsed", false);=0A= newDock.fadeIn(250);=0A= }=0A= }=0A= =0A= function processDockingRule(rule) {=0A= var retObj =3D new Object();=0A= retObj.empty =3D (((rule !=3D undefined) && (!(rule =3D=3D ''))) ? = false : true);=0A= if (rule =3D=3D '') {=0A= retObj.ruleType =3D 'empty';=0A= }=0A= else if (/^\$$.+$$/.test(rule)) {=0A= retObj.ruleType =3D 'jQuery';=0A= retObj.rule =3D rule.replace(/^\$$(.+)$$/,"$1");=0A= }=0A= else {=0A= retObj.ruleType =3D 'html';=0A= retObj.rule =3D rule;=0A= }=0A= return retObj;=0A= }=0A= =0A= function removeDockBlock(col, dockId) {=0A= var dockedNav =3D $("div#" + dockId);=0A= if(dockedNav.length) {=0A= dockedNav.fadeOut(250, function() { dockedNav.remove(); });=0A= }=0A= }=0A= =0A= =0A= function updateFormInput(labelMatchString, inputMatchString, = defaultColorString, textColorString) {=0A= if ((defaultColorString =3D=3D null) || (defaultColorString =3D=3D '')) = {=0A= defaultColorString =3D "#A0A0A0";=0A= }=0A= if ((textColorString =3D=3D null) || (textColorString =3D=3D '')) {=0A= textColorString =3D "black";=0A= }=0A= var label =3D $(labelMatchString);=0A= var input =3D $(inputMatchString);=0A= if (input.length) {=0A= if ((label.length) && (input.val() =3D=3D '')) {=0A= input.val(label.text()).css("color",defaultColorString);=0A= }=0A= input.focus(=0A= function(e) {=0A= if ((label.length) && ($(this).val() =3D=3D label.text())) {=0A= $(this).val('').css("color",textColorString);=0A= }=0A= }=0A= );=0A= input.blur(=0A= function(e) {=0A= if ((label.length) && ($(this).val() =3D=3D '')) {=0A= $(this).val(label.text()).css("color",defaultColorString);=0A= }=0A= }=0A= );=0A= }=0A= var parentForm =3D label.parents("form").eq(0);=0A= if (parentForm.length) {=0A= parentForm.submit(=0A= function() {=0A= if ((label.length) && (input.length) && (input.val() =3D=3D = label.text())) {=0A= input.val('');=0A= }=0A= return true;=0A= }=0A= );=0A= }=0A= }=0A= =0A= function checkUnloadedImgs(lookupRule) {=0A= if (lookupRule =3D=3D null) {=0A= lookupRule =3D "img";=0A= }=0A= var imageNum =3D -1;=0A= var images =3D $(lookupRule);=0A= if (images.length) {=0A= imageNum =3D 0;=0A= images.each(=0A= function() {=0A= //if ($(this).height() =3D=3D 0) {=0A= if (this.offsetHeight =3D=3D 0) {=0A= imageNum++;=0A= }=0A= }=0A= );=0A= }=0A= return imageNum;=0A= }=0A= =0A= function fixHeightForImages(iter, numImagesToLoad, lookupRule) {=0A= if (lookupRule =3D=3D null) {=0A= lookupRule =3D "img";=0A= }=0A= if (numImagesToLoad > 0) {=0A= var lastNumImagesToLoad =3D numImagesToLoad;=0A= var newNumImagesToLoad =3D checkUnloadedImgs(lookupRule);=0A= if (newNumImagesToLoad < lastNumImagesToLoad) {=0A= fixColHeights(1);=0A= if ((newNumImagesToLoad > 0) && (iter < 10)) {=0A= setTimeout("fixHeightForImages(" + (iter+1) + "," + = newNumImagesToLoad + ",'" + lookupRule + "')", 1000);=0A= }=0A= }=0A= }=0A= }=0A= function getColInfo(colJQEl) {=0A= var colInfo =3D { valid: false, height: 0, bottom: 0, lastElBottom: 0, = extra: 0, fix: false };=0A= if (colJQEl.length) {=0A= var c =3D colJQEl.children();=0A= if (c.length) {=0A= colInfo.height =3D getObjHeight(colJQEl);=0A= colInfo.bottom =3D colJQEl.offset().top + colInfo.height;=0A= var last =3D c.eq(c.length - 1);=0A= colInfo.lastElBottom =3D last.offset().top + getObjHeight(last);=0A= colInfo.extra =3D colInfo.bottom - colInfo.lastElBottom;=0A= colInfo.valid =3D true;=0A= }=0A= }=0A= return colInfo;=0A= }=0A= function checkColHeights() {=0A= var colToFix =3D 0;=0A= if (gIsMultiCol && ((gColOrigHeights.main + gColOrigHeights.col2 + = gColOrigHeights.col3) > 0)) {=0A= var colMainInfo =3D getColInfo(gColMain);=0A= var col2Info =3D getColInfo(gCol2);=0A= var col3Info =3D getColInfo(gCol3);=0A= if (colMainInfo.valid && (gColLows.main =3D=3D 0)) { gColLows.main =3D = colMainInfo.lastElBottom; }=0A= if (col2Info.valid && (gColLows.col2 =3D=3D 0)) { gColLows.col2 =3D = col2Info.lastElBottom; }=0A= if (col3Info.valid && (gColLows.col3 =3D=3D 0)) { gColLows.col3 =3D = col3Info.lastElBottom; }=0A= // check if low point in any column has changed=0A= if ((colMainInfo.valid) && (colMainInfo.lastElBottom !=3D = gColLows.main)) {=0A= colMainInfo.fix =3D true;=0A= }=0A= if ((col2Info.valid) && (col2Info.lastElBottom !=3D gColLows.col2)) {=0A= col2Info.fix =3D true;=0A= }=0A= if ((col3Info.valid) && (col3Info.lastElBottom !=3D gColLows.col3)) {=0A= col3Info.fix =3D true;=0A= }=0A= // check for columns not having same bottom points=0A= if ((colMainInfo.valid) &&=0A= (((col2Info.valid) && (colMainInfo.height < col2Info.height)) ||=0A= ((col3Info.valid) && (colMainInfo.height < col3Info.height)))) {=0A= colMainInfo.fix =3D true;=0A= }=0A= if ((col2Info.valid) &&=0A= (((colMainInfo.valid) && (col2Info.height < colMainInfo.height)) ||=0A= ((col3Info.valid) && (col2Info.height < col3Info.height)))) {=0A= col2Info.fix =3D true;=0A= }=0A= if ((col3Info.valid) &&=0A= (((colMainInfo.valid) && (col3Info.height < colMainInfo.height)) ||=0A= ((col2Info.valid) && (col3Info.height < col2Info.height)))) {=0A= col3Info.fix =3D true;=0A= }=0A= =0A= if (colToFix > -1) {=0A= if (colMainInfo.valid && colMainInfo.fix) {=0A= if ((col2Info.valid && col2Info.fix) || (col3Info.valid && = col3Info.fix)) {=0A= colToFix =3D -1;=0A= }=0A= else { colToFix =3D 1; }=0A= }=0A= else if (col2Info.valid && col2Info.fix) {=0A= if (col3Info.valid && col3Info.fix) {=0A= colToFix =3D -1;=0A= }=0A= else { colToFix =3D 2; }=0A= }=0A= else if (col3Info.valid && col3Info.fix) {=0A= colToFix =3D 3;=0A= }=0A= }=0A= =0A= if (colToFix !=3D 0) {=0A= fixColHeights(colToFix);=0A= }=0A= if (colMainInfo.valid) { gColLows.main =3D colMainInfo.lastElBottom; }=0A= if (col2Info.valid) { gColLows.col2 =3D col2Info.lastElBottom; }=0A= if (col3Info.valid) { gColLows.col3 =3D col3Info.lastElBottom; }=0A= }=0A= setTimeout("checkColHeights()", 5000);=0A= }=0A= function fixColHeights(colChanged) {=0A= if (gIsMultiCol && getSiteOption('setColSizes', true)) {=0A= var setAll =3D false;=0A= if (colChanged =3D=3D 1) {=0A= if (gColMain.length) {=0A= setObjHeight(gColMain,'auto');=0A= gColOrigHeights.main =3D getObjHeight(gColMain);=0A= }=0A= }=0A= else if (colChanged =3D=3D 2) {=0A= if (gCol2.length) {=0A= setObjHeight(gCol2,'auto');=0A= gColOrigHeights.col2 =3D getObjHeight(gCol2);=0A= }=0A= }=0A= else if (colChanged =3D=3D 3) {=0A= if (gCol3.length) {=0A= setObjHeight(gCol3,'auto');=0A= gColOrigHeights.col3 =3D getObjHeight(gCol3);=0A= }=0A= }=0A= else {=0A= if (colChanged =3D=3D -1) {=0A= // force resize all 3=0A= if (gColMain.length) { setObjHeight(gColMain,'auto'); }=0A= if (gCol2.length) { setObjHeight(gCol2,'auto'); }=0A= if (gCol3.length) { setObjHeight(gCol3,'auto'); }=0A= }=0A= gColOrigHeights.main =3D ((gColMain.length) ? = (getObjHeight(gColMain)) : 0);=0A= gColOrigHeights.col2 =3D ((gCol2.length) ? (getObjHeight(gCol2)) : 0);=0A= gColOrigHeights.col3 =3D ((gCol3.length) ? (getObjHeight(gCol3)) : 0);=0A= setAll =3D true;=0A= }=0A= if ((gColOrigHeights.main + gColOrigHeights.col2 + = gColOrigHeights.col3) > 0) {=0A= var colInfo;=0A= var maxH =3D Math.max(Math.max(gColOrigHeights.main, = gColOrigHeights.col2), gColOrigHeights.col3);=0A= if ((gColMain.length) && ((gColOrigHeights.main < maxH) || = (getObjHeight(gColMain) > maxH) || setAll)) {=0A= setObjHeight(gColMain, maxH);=0A= colInfo =3D getColInfo(gColMain);=0A= if (colInfo.valid) { gColLows.main =3D colInfo.lastElBottom; }=0A= }=0A= if ((gCol2.length) && ((gColOrigHeights.col2 < maxH) || = (getObjHeight(gCol2) > maxH) || setAll)) {=0A= setObjHeight(gCol2, maxH);=0A= colInfo =3D getColInfo(gCol2);=0A= if (colInfo.valid) { gColLows.col2 =3D colInfo.lastElBottom; }=0A= }=0A= if ((gCol3.length) && ((gColOrigHeights.col3 < maxH) || = (getObjHeight(gCol3) > maxH) || setAll)) {=0A= setObjHeight(gCol3, maxH);=0A= colInfo =3D getColInfo(gCol3);=0A= if (colInfo.valid) { gColLows.col3 =3D colInfo.lastElBottom; 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Not = available in this view
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No related = web pages
', false);=0A= }=0A= }=0A= }=0A= function addPatientInform(xhtmlData) {=0A= var cbA =3D $("#cb-loading-patientinform");=0A= if (gIsFrameset) {=0A= if (cbA.length) {=0A= updateCBItem(cbA, '
Not = available in this view
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No = patientINFORMation available for this article
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Not available = in this view
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No citing = articles
', false);=0A= }=0A= }=0A= }=0A= function addISIRelated(xhtmlData) {=0A= var cbA =3D $("#cb-isi-similar-articles");=0A= if (xhtmlData && !(xhtmlData.indexOf('=3D 0)) {=0A= if (cbA.length) {=0A= updateCBItem(cbA, xhtmlData, true);=0A= }=0A= }=0A= else {=0A= if (cbA.length) {=0A= updateCBItem(cbA, '
No Web of = Science related articles
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No Web of = Science citing articles
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';=0A= $("#col-2").append(newDiv);=0A= $("#col-2 #docked-nav").hide();=0A= var newDivJQuery =3D $("#docked-nav");=0A= newDivJQuery.append('
This Article
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Expand+<\/span><\/a><\/li><\/ul><\/div>');=0A= =0A= if (isIE6) {=0A= $("div#content-option-box li#content-toggle = a").css("display","inline");=0A= }=0A= =0A= $("div#content-option-box li#content-toggle a").click(=0A= function(e) {=0A= var pageDiv =3D $("div.hw-gen-page");=0A= if (pageDiv.length) {=0A= var optionbox =3D $("div#content-option-box");=0A= var colsHidden =3D pageDiv.hasClass("hide-cols");=0A= if (colsHidden) {=0A= // show all columns=0A= modClass(pageDiv,'','hide-cols');=0A= modClass($(this),'','expanded');=0A= $("div#cols-min").remove();=0A= gIsMultiCol =3D true;=0A= if (optionbox.length) {=0A= optionbox.attr("title","Expand this column");=0A= optionbox.find("span.descr").text("Expand");=0A= }=0A= checkDockedColExpandLoc(true, 0);=0A= fixColHeights(-1);=0A= }=0A= else {=0A= // hide sidebar columns=0A= gIsMultiCol =3D false;=0A= modClass(pageDiv,'hide-cols','');=0A= modClass($(this),'expanded','');=0A= if (optionbox.length) {=0A= optionbox.attr("title","Show all columns");=0A= optionbox.find("span.descr").text("Minimize");=0A= }=0A= checkDockedColExpandLoc(true, 0);=0A= var colDivs =3D '
';=0A= for (var i=3D3; i>=3D2; i--) {=0A= var col =3D $("div#col-" + i);=0A= if (col.length) {=0A= colDivs =3D colDivs + '
<\/span><\/div>';=0A= }=0A= }=0A= colDivs =3D colDivs + '<\/div>';=0A= $("div#content-block").before(colDivs);=0A= var mincol, mincolspan;=0A= for (var j =3D 2; j <=3D 3; j++) {=0A= mincol =3D $("div#col-" + j + "-min");=0A= mincolspan =3D $("div#col-" + j + "-min span.view-more");=0A= if (mincol.length && mincolspan.length) {=0A= =0A= // call publisher cleanup function=0A= if (typeof localColMinF =3D=3D 'function') {=0A= localColMinF(mincol, j);=0A= }=0A= var x =3D j;=0A= //var colid =3D "col-" + x;=0A= mincolspan.hover(=0A= function() {=0A= var parentid =3D $(this).parent().attr("id");=0A= //var closebox =3D "
x
";=0A= if (parentid !=3D null) {=0A= var colstr =3D "div#" + = parentid.substring(0,parentid.indexOf('-min'));=0A= var col =3D $(colstr);=0A= if (col.length) {=0A= //col.prepend(closebox);=0A= var header =3D $("#header");=0A= var headerHeight =3D (header.length ? getObjHeight(header) : = 0);=0A= col.css("top", '' + headerHeight + "px");=0A= modClass(col,"palette","");=0A= col.css("height","auto");=0A= /=0A= $("#col-hover-close a").click(=0A= function(e) {=0A= var ancestors =3D $(this).parents();=0A= modClass(ancestors.eq(1), "", "palette");=0A= $("#col-hover-close").remove();=0A= e.preventDefault();=0A= }=0A= );=0A= /=0A= col.hover(=0A= function() {},=0A= function() {=0A= modClass($(this),"","palette");=0A= //$("#col-hover-close").remove();=0A= $(this).css("top",'');=0A= =0A= }=0A= );=0A= }=0A= }=0A= },=0A= function() {}=0A= );=0A= }=0A= else {=0A= }=0A= }=0A= }=0A= }=0A= e.preventDefault();=0A= }=0A= );=0A= =0A= / article navigation docking block /=0A= / this won't work in IE 6, so skip it /=0A= if (!isIE6) {=0A= gViewportW =3D getViewportDim().x;=0A= checkDockedColExpandLoc(true, 2000);=0A= checkColExpandDocking();=0A= $(window).scroll(function() { checkColExpandDocking(); });=0A= }=0A= =0A= });=0A= =0A= function checkColExpandDocking() {=0A= var header =3D $("#header");=0A= var headerTopOffset =3D (header.length ? header.offset().top : 0);=0A= var headerHeight =3D (header.length ? getObjHeight(header) : 0);=0A= if (headerHeight > 0) {=0A= var offsets =3D getPageOffset();=0A= var headerBottom =3D (headerTopOffset + headerHeight) - offsets.y + 50;=0A= if (gHeaderScrollPos !=3D offsets.y) {=0A= gHeaderScrollPos =3D offsets.y;=0A= if ((headerBottom <=3D 0) && !gColExpandDocked) {=0A= / dock the col expand button /=0A= gColExpandDocked =3D true;=0A= addDockedColExpand();=0A= checkDockedColExpandLoc(true, 0);=0A= }=0A= else if (gColExpandDocked && (headerBottom > 0)) {=0A= / undock the col expand button */=0A= gColExpandDocked =3D false;=0A= removeDockedColExpand();=0A= }=0A= }=0A= }=0A= }=0A= function addDockedColExpand() {=0A= var optionbox =3D $("div#content-option-box");=0A= if (optionbox.length) {=0A= optionbox.hide().addClass('option-box-docked').fadeIn(250);=0A= }=0A= }=0A= function checkDockedColExpandLoc(forceLocate, timerLen) {=0A= if (gColExpandDocked) {=0A= var newViewportW =3D getViewportDim().x;=0A= if (forceLocate || (newViewportW !=3D gViewportW)) {=0A= var dockedExpand =3D $("div#content-option-box");=0A= if (dockedExpand.length) {=0A= var newLeft =3D $("#content-block").offset().left +=0A= (gIsMultiCol ? gDockedBoxLeft : gDockedBoxNoColsLeft);=0A= if ((newViewportW - 50) < newLeft) {=0A= newLeft =3D (newViewportW - 50);=0A= }=0A= dockedExpand.css("left", ('' + newLeft + 'px'));=0A= }=0A= gViewportW =3D newViewportW;=0A= }=0A= }=0A= if (timerLen && (timerLen > 0)) {=0A= checkColExpandDocking();=0A= setTimeout("checkDockedColExpandLoc("+ forceLocate + "," + timerLen + = ")", timerLen);=0A= }=0A= }=0A= =0A= function removeDockedColExpand() {=0A= var optionbox =3D $("div#content-option-box");=0A= if (optionbox.length) {=0A= optionbox.removeClass('option-box-docked');=0A= }=0A= }=0A= ------=_NextPart_000_0000_01CA6063.D58BACD0--

Brain tumour stem cells: the undercurrents of = human brain=20 cancer and their relationship to neural stem cells

Abstract

1. Introduction

2. Applying neural stem cell biology to brain cancer

3. Cancer stem cells in solid tumours

4. Identification of brain tumour stem cells

5. Cells of origin for brain cancer

6. Developmental signalling in brain tumour stem cell function

7. The stem cell niche: implications for brain tumours

8. Summary

Acknowledgments

Footnotes

References

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