Oncogene - Cancer = stem cells in nervous system tumors

Cancer stem cells in nervous system tumors

Sheila K Singh^1,2,=20 Ian D Clarke^1,2,=20 Takuichiro Hide^1,2=20 and Peter B Dirks^1,2

¹The Arthur and Sonia Labatt Brain Tumor = Research=20 Centre, The Hospital for Sick Children, Toronto, Canada
²Program in Developmental Biology, Department = of=20 Laboratory Medicine and Pathobiology, Division of Neurosurgery, = University of=20 Toronto, Toronto, Canada

Correspondence: PB Dirks, Hospital for Sick Children, = Suite 1504,=20 555 University Ave., Toronto, Ontario, Canada M5G 1X8. E-mail: peter.dirks@sickkids.ca

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Abstract

Most current research on human brain tumors is = focused on=20 the molecular and cellular analysis of the bulk tumor mass. However, = evidence in=20 leukemia and more recently in solid tumors such as breast cancer = suggests that=20 the tumor cell population is heterogeneous with respect to proliferation = and=20 differentiation. Recently, several groups have described the existence = of a=20 cancer stem cell population in human brain tumors of different = phenotypes from=20 both children and adults. The finding of brain tumor stem cells (BTSCs) = has been=20 made by applying the principles for cell culture and analysis of normal = neural=20 stem cells (NSCs) to brain tumor cell populations and by identification = of cell=20 surface markers that allow for isolation of distinct tumor cell = populations that=20 can then be studied in vitro and in vivo. A population of = brain=20 tumor cells can be enriched for BTSCs by cell sorting of dissociated = suspensions=20 of tumor cells for the NSC marker CD133. These CD133+ cells, which also=20 expressed the NSC marker nestin, but not differentiated neural lineage = markers,=20 represent a minority fraction of the entire brain tumor cell population, = and=20 exclusively generate clonal tumor spheres in suspension culture and = exhibit=20 increased self-renewal capacity. BTSCs can be induced to differentiate = in=20 vitro into tumor cells that phenotypically resembled the tumor from = the=20 patient. Here, we discuss the evidence for and implications of the = discovery of=20 a cancer stem cell in human brain tumors. The identification of a BTSC = provides=20 a powerful tool to investigate the tumorigenic process in the central = nervous=20 system and to develop therapies targeted to the BTSC. Specific genetic = and=20 molecular analyses of the BTSC will further our understanding of the = mechanisms=20 of brain tumor growth, reinforcing parallels between normal neurogenesis = and=20 brain tumorigenesis.

Keywords:

brain tumor stem cell, neural stem cell, flow = cytometry,=20 CD133

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Introduction

Brain tumors are typically comprised of morphologically = diverse=20 cells that express a variety of neural lineage markers. Study of brain = tumors by=20 traditional histopathology has only yielded a limited amount of = knowledge of the=20 clinical behavior of the tumor. It is recognized that tumors with vastly = different histology have a different prognosis, but often brain tumors = that=20 share similar morphology and phenotype can have a very different = prognosis and=20 response to treatment. Brain tumors of the same histologic type can also = have a=20 very different behavior in patients of different ages. Although major = advances=20 have been made in the understanding of the molecular genetic alterations = of some=20 types of brain tumors (Maher=20 et al., 2001; Wechsler-Reya=20 and Scott, 2001; Zhu=20 and Parada, 2002; Gilbertson,=20 2004), particularly medulloblastomas and malignant gliomas, and some = of=20 these identified alterations are now beginning to guide treatment, it is = not=20 clear whether all the tumor cells are equivalent in their ability to = maintain=20 the growth of the tumor. Until recently, we lacked a functional assay of = the=20 brain tumor cells that could determine which of the morphologically = diverse=20 tumor cells are capable of maintaining the growth of the tumor. The = cancer stem=20 cell hypothesis suggests that not all the cells in the tumor have the = same=20 ability to proliferate and maintain the growth of the tumor. Only a = relatively=20 small fraction of cells in the tumor, termed cancer stem cells, possess = the=20 ability to proliferate and self-renew extensively. Most of the tumor = cells lose=20 the ability to proliferate and self-renew and they differentiate into = tumor=20 cells that become the phenotypic signature of the tumor. Finding the key = cells=20 in the brain tumor population that are able to maintain the tumor will = give=20 insight into the mechanism of brain tumorigenesis and will allow us to = trace=20 back to the cell of origin in the normal brain.

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Relationship between neural stem cells (NSCs) and cancer stem = cells

Stem cells are functionally defined as self-renewing, = multipotent=20 cells that exhibit multilineage differentiation (Fuchs=20 and Segre, 2000; Weissman,=20 2000; Reya=20 et al., 2001). Somatic stem cells are thought to self-renew = to=20 generate all the mature cell types of a particular tissue through = proliferative=20 expansion of progenitor cells followed by differentiation into mature = cell=20 types. So far, rigorous identification and isolation of tissue-specific = stem=20 cells has been prospectively accomplished in only a few organ systems = (Reya=20 et al., 2001). The discovery that multipotential, = self-renewing NSCs=20 exist throughout life in the adult mammalian brain has only re-emerged = in the=20 past decade (Gage,=20 2000; Temple,=20 2001; Gage,=20 2002), reflecting a rediscovery of 1960s evidence that suggested = that=20 neurogenesis was occurring in the adult brain (Gross,=20 2000). The neurosphere culture system and analysis first used by Reynolds=20 and Weiss (1992) to identify NSCs has permitted in vitro=20 characterization of NSCs, but in a retrospective manner, as the = multipotential=20 floating clusters of cells (the neurospheres) are inferred to have been = derived=20 from clonal expansion of a single NSC. Prospective study of this cell = has been=20 previously limited by lack of cell surface markers necessary for its = isolation,=20 until recent reports of NSC enrichment using antibodies to the cell = surface=20 protein CD133 (Uchida=20 et al., 2000). Also, neural crest stem cells can be = prospectively=20 based on cell surface markers (Morrison=20 et al., 1999).

The concept of the cancer stem cell arose from the = observation of=20 striking similarities between the self-renewal mechanisms of stem cells = and=20 cancer cells (Reya=20 et al., 2001; Pardal=20 et al., 2003). In hematologic malignancies such as leukemia = (Blair=20 et al., 1997; Bonnet=20 and Dick, 1997) and multiple myeloma (Matsui=20 et al., 2004), and in solid tumors such as breast cancer (Al-Hajj=20 et al., 2003), rare cells were isolated with a remarkable = potential=20 for self-renewal, and these cells alone were found to drive the = formation and=20 growth of tumors. Since normal somatic stem cells must self-renew and = maintain a=20 relative balance between self-renewal and differentiation, cancer can be = contextualized as a disease of unregulated self-renewal (Reya=20 et al., 2001). NSCs possess a self-renewal machinery that is = primed=20 and can be harnessed to create a cancer cell, and their longevity = targets them=20 for the accumulation of genetic mutations. Therefore, NSCs and also = probably=20 their closely related downstream rapidly proliferating progenitors = should be=20 further investigated as possible targets of transformation in the = formation of=20 brain tumors.

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Do brain tumors arise from a transformed NSC: what is the = evidence?

The traditional hypothesis has been that brain tumors = arise from=20 the dedifferentiation of a mature brain cell in response to genetic = alterations.=20 This hypothesis prevailed because it was felt that the postnatal brain = had no=20 proliferation. It has also been considered for some time that brain = tumors may=20 arise from a transformation event in a resident immature brain cell. = With the=20 discovery of adult NSCs (early 1990s) (Reynolds=20 and Weiss, 1992; Kilpatrick=20 and Bartlett, 1993; Lois=20 and Alvarez-Buylla, 1993), it became conceivable that a normal NSC = or=20 progenitor cell that resides in the brain may be the target for = transformation=20 leading to a brain tumor.

The potential that an NSC may be transformed into a = brain tumor=20 has been considered based on the observations of tumors occurring in the = brain's=20 putative stem cell or proliferative zones in a number of older = experimental=20 systems. The 'subependymal plate' or subventricular zone was suspected = many=20 years ago to contain 'embryonal rests' that were thought to give rise to = brain=20 tumors, particularly those occurring in the brain adjacent to the walls = of the=20 ventricular system (Globus=20 and Kuhlenbeck, 1944). This idea was then considered further after = the=20 identification of mitotic cells in the subependymal regions of adult = rodents and=20 primates in the 1960s (Smart,=20 1961; Altman,=20 1963; Lewis,=20 1968). In the 1970s, periventricular tumors were then demonstrated = to occur=20 in the subventricular region after intraventricular inoculation with = avian=20 sarcoma viruses, with a much higher rate of tumors occurring in neonatal = rats=20 versus adult rats (Copeland=20 et al., 1975; Copeland=20 and Bigner, 1977; Vick=20 et al., 1977). The incidence of brain tumors of a variety of = types in=20 mice inoculated with a pellet of carcinogen was much greater if the = pellet was=20 placed in the subventricular region versus the peripheral cortex (Hopewell=20 and Wright, 1969). A single dose of ethylnitrosurea administration = to=20 pregnant rats also induced periventricular tumors in the offspring (Koestner=20 et al., 1971).

The primitive cytoarchitecture and embryonic features of = many=20 malignant brain tumors have also suggested that these tumors may arise = from=20 transformed neural stem or progenitor cells (Bailey=20 and Cushing, 1926; Rubinstein,=20 1972). Childhood medulloblastoma, in particular, and other solid = pediatric=20 malignancies such as retinblastoma and neuroblastoma, have been = considered as=20 developmental processes gone awry, with suspected origin from = progenitors or=20 'blast cells' in the tissue of origin (Maris=20 and Denny, 2002). Since medulloblastoma cells often resemble = proliferating=20 external granule cells of the postnatal cerebellum, this tumor has long = been=20 thought to arise from a primitive pluripotential cerebellar stem cell or = precursor cell (Kadin=20 et al., 1970; Rubinstein,=20 1972).

The cell origin of brain tumors remains a subject of = ongoing=20 debate in the current scientific literature: do brain tumors arise from = the=20 dedifferentiation of a normal brain cell or from the transformation of a = normal=20 NSC or progenitor cell (Figure=20 1)? Several further lines of evidence suggest that brain tumors = arise from=20 the transformation of a normal NSC or progenitor cell, all of which rely = on the=20 recognition of the many functional and genetic similarities shared by = somatic=20 stem cells and cancer cells (Pardal=20 et al., 2003). Histological studies of brain tumors note the = absence=20 of expression of differentiated cell markers in primitive tumors, as = well as the=20 presence of immunostaining for nestin (Dahlstrand=20 et al., 1992; Tohyama=20 et al., 1992), a marker of NSCs (Lendahl=20 et al., 1990). Brain tumors can be very heterogeneous, being=20 comprised of cells expressing phenotypes of more than one neural = lineage,=20 implicating a multipotential cell of origin. Microarray analysis of = human=20 medulloblastomas suggests a similarity of gene expression with normal = developing=20 brain cells (Pomeroy=20 et al., 2002). In a recent study, transfection of a = medulloblastoma=20 cell line with transcription factors specified a factor-dependent = adoption of=20 either neuronal or glial cell fates (Buzanska=20 et al., 2001). Finally, mutations that dysregulate the = pathways that=20 control normal stem cell self-renewal (such as the sonic hedgehog = pathway) cause=20 brain tumors, emphasizing the mechanistic similarities between normal = stem cell=20 and cancer cell self-renewal (Dahmane=20 et al., 2001; Ruiz i=20 Altaba et al., 2002; Pardal=20 et al., 2003).

Figure=20 1.

On the left, normal NSCs in the brain undergo highly regulated = self-renewing=20 divisions to regenerate themselves and they also generate = lineage-committed=20 progenitor cells and then differentiate into the three main neural = lineages,=20 neurons, astrocytes and oligodendrocytes. On the right, multiple = mutational=20 events target a stem cell, progenitor cell or mature brain cell results = in the=20 formation of a BTSC. The BTSC has enhanced self-renewal and = proliferative=20 capacity and also differentiates aberrantly into other cells in the = tumor, which=20 then have a limited proliferative ability

Full=20 figure and legend (126K)

Recent experiments in mice further suggest that neural = progenitors=20 may be transformed into brain tumors. By investigating the mechanisms = underlying=20 gliomagenesis, Holland and co-workers have found that undifferentiated = neural=20 precursor cells may be more sensitive to transformation than = differentiated=20 cells (Holland=20 et al., 1998; Holland=20 et al., 2000). Using a retroviral system that allows for gene = expression in apparently different brain cell populations driven by = different=20 promoters, they directed the expression of oncogenes to brain cells = expressing=20 glial fibrillary acidic protein (GFAP, presumed to be expressed by=20 differentiated astrocytes) or cells expressing nestin (presumed to mark = neural=20 stem or progenitor cells), and they found that malignant glial tumors = arise most=20 efficiently after oncogene transfer to nestin-expressing brain cells. = The=20 interpretation of cell of origin remains unclear as a GFAP-positive cell = in the=20 subventricular zone has recently been suggested to be the adult NSC (Doetsch=20 et al., 1999). The same researchers also suggest that a=20 differentiated neural cell such as an astrocyte may be equally = permissive to=20 transformation as a progenitor, if it has a key genetic alteration such = as loss=20 of tumor suppressor Ink4a-Arf (Bachoo=20 et al., 2002; Uhrbom=20 et al., 2002). These data support a view that dysregulation = of=20 specific genetic pathways, rather than cell of origin, may dictate the = emergence=20 and phenotype of high-grade gliomas.

Although brain tumors may arise from a dedifferentiated = cell that=20 has accumulated a series of oncogenic mutations, an NSC may be seen as a = more=20 permissive and likely compartment for transformation, since it already = has the=20 self-renewal machinery primed and it has a long lifespan favoring the=20 accumulation of mutations. A progenitor cell is also a possible target = if the=20 genetic alteration allows it to reacquire the ability to self-renew. A=20 mutational event occurring in a progenitor may not be as dangerous as in = a stem=20 cell, as this cell normally has limited self-renewal ability and it = typically=20 becomes clonally exhausted as it generates differentiated cells. Whether = the=20 transforming event of a brain tumor occurs in an NSC or in a more = differentiated=20 cell type that has reacquired stem cell characteristics remains to be = proven. It=20 is conceivable that an astrocytoma arises from an oncogenic event in an=20 astrocyte-restricted progenitor or mature astrocyte, leading to an = astrocyte=20 phenotype. However, it is also possible that the oncogenic event = occurred in an=20 NSC and this event causes a block in differentiation (Pereira=20 et al., 1998) that allows the transformed cell to = differentiate down=20 astrocytic lineages but not neuronal or oligodendrocyte lineages. The = cell of=20 origin may come down to a question of probability, any normal brain cell = can=20 give rise to a tumor, but the number and potency of the genetic = alteration may=20 determine the ease at which the cell becomes transformed. The structural = organization of the brain, the integrity of which is demanded to = preserve=20 function, suggests that differentiated and morphologically complex cells = such as=20 neurons must be exceedingly resistant to proliferation.

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Prospective identification of a cancer stem cell from human brain=20 tumors

Regardless of the possible cell of origin, recent = evidence=20 suggests that brain tumors contain small numbers of cells with NSC = properties.=20 These cells have the ability to self-renew, proliferate and = differentiate, and=20 uniquely maintain the tumor growth. Although qualitative reports of = sphere=20 formation in cultured brain tumor cells exist (Mackillop=20 et al., 1985) and stem-like cells have been observed in brain = tumor=20 cultures (Ignatova=20 et al., 2002), a prospectively isolated population of cancer = stem=20 cells from brain tumors had not been described until recently (Singh=20 et al., 2003). The existence of cancer stem cells, first = proven in=20 the context of acute myeloid leukemia (AML), required sorting by surface = markers=20 to distinguish leukemic stem cells from the remaining AML cells, which = had=20 limited proliferative potential (Blair=20 et al., 1997; Bonnet=20 and Dick, 1997). This established a hierarchy of clonally derived=20 populations within the cancer, originating from malignant cancer stem = cells,=20 which have extensive proliferative potential, to differentiated cancer = cells,=20 which have limited proliferative potential. The relative paucity of good = NSC=20 markers presented an obstacle to the establishment of this type of = hierarchy=20 within brain tumors. Nestin, the best CNS stem cell marker to date, was = a=20 nonspecific cytoplasmic intermediate filament, and the nature of cell = sorting=20 required a cell surface marker. An excellent candidate was found in = CD133, a=20 novel 120 kDa five-transmembrane cell surface protein originally = shown to=20 be a hematopoietic stem cell marker, and recently found to be a marker = of normal=20 human NSCs (Corbeil=20 et al., 1998; Uchida=20 et al., 2000; Tamaki=20 et al., 2002).

The first prospective in vitro identification and = characterization of a cancer stem cell from human brain tumors of = different=20 phenotypes was reported based on cell sorting for CD133 on acutely = dissociated=20 brain tumor cell populations (Figure=20 2) (Singh=20 et al., 2003). The brain tumor stem cell (BTSC) represented a = fraction of the total cells comprising the tumor and was isolated from = low- and=20 high-grade tumors from both children and adults. The BTSC was = exclusively=20 isolated with the cell fraction expressing the NSC surface marker CD133. = There=20 are three pieces of evidence that support that these cells are BTSCs: = (1) they=20 generate clusters of clonally derived cells resembling neurospheres, (2) = they=20 self-renew and proliferate, and (3) they differentiate to recapitulate = the=20 phenotype of the tumor from which they were derived. In defining a class = of=20 BTSCs that can be prospectively isolated from a wide range of brain = tumors, we=20 support the application of principles of leukemogenesis to solid tumors: = namely,=20 the principle that only a small subset of cancer stem cells is enriched = for=20 clonogenic capacity, and that these cells alone are capable of tumor=20 propagation. Importantly, we have recent unpublished data that support = the fact=20 that BTSCs can also initiate tumors in vivo.

Figure=20 2.

Cancer stem cells are identified from solid human brain tumors after = acute=20 dissociation of the solid tumor mass and then cell sorting for surface = markers.=20 CD133 identified a small subpopulation of the brain tumor cells that was = uniquely able to propagate the tumor in stem cell and tumorigenic = assays. CD133-=20 cells cannot expand the tumor population because they lack the ability = to=20 self-renew

Full=20 figure and legend (152K)

Another recent report by Hemmati=20 et al. (2003) substantiated the finding of cancer stem cells = in=20 pediatric brain tumors. They found that pediatric brain tumors contained = neural=20 stem-like cells, termed 'tumor-derived progenitors', that showed the = capacity=20 for sphere formation, self-renewal and multipotential differentiation. = In=20 addition, these cells were shown by RT=E2=80=93PCR to express many genes = characteristic=20 of NSCs, including musashi-1, Sox2, bmi-1 and CD133. = Further=20 reports are emerging documenting the presence of BTSCs in human adult = brain=20 tumors. The description of BTSCs from a number of groups describes a = class of=20 cells that may drive tumorigenesis in an increasing number of brain = tumors.

The application of principles for the study of normal = NSCs to=20 brain tumor cell populations establishes a link between normal = neurogenesis and=20 brain tumorigenesis. Brain tumors are not only phenotypically = heterogeneous but=20 are also functionally heterogeneous. Brain tumors exhibit phenotypic=20 heterogeneity, being composed of cells expressing both undifferentiated = and=20 differentiated markers. In vitro analysis of brain tumor cells = sorted for=20 CD133 expression indicates that the capacity for tumor cell self-renewal = and=20 proliferation exclusively resides in the minority CD133+ cell fraction. = These=20 results suggest that CD133 represents a new cell surface marker of the = BTSC =E2=80=93 a=20 novel cell type with increased potential for self-renewal that drives = brain=20 tumorigenesis. The data also suggest that brain tumors are comprised of=20 populations of proliferating tumor stem cells that are differentiating = into the=20 more mature cell types that characterize the tumor. Purification of = CD133+ cells=20 in brain tumors implies that a hierarchy may exist in the tumor cell = population,=20 as not all tumor cells were capable of maintaining the tumor in culture. = This=20 apparent hierarchy may be functionally elucidated as more surface = markers for=20 NSCs emerge and further tumor subpopulations identified. As normal NSCs = are also=20 found in the CD133 population of the normal human fetal brain, and that = tumors=20 of all phenotypes studied contained nestin+/CD133+/lineage- cells, it = suggests=20 that the cell of origin for a brain tumor may be a normal NSC. Future=20 investigations of the BTSC may lead to further insight of this = possibility. Much=20 further work is required to determine the ability of BTSCs to initiate = and=20 maintain tumor growth in vivo, and to determine how these cells = determine=20 brain tumor phenotype.

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BTSC: a new target for future brain tumor therapy

Current diagnostic and prognostic criteria for brain = tumors rely=20 on the histopathological and molecular features of the global tumor = population,=20 and may not be sufficient to determine the key molecular alterations in = a rarer=20 tumor stem cell fraction. Molecular analysis of the BTSC population may = lead to=20 the identification of novel pathways important for the proliferation,=20 self-renewal and differentiation of these cells that opens up new = targets for=20 therapy. It will likely be important to study the effect of activation = of=20 oncogenes or inactivation of tumor suppressor genes in the stem cell as = opposed=20 to other brain cells, as these alterations are predicted to have = different=20 effects in stem cells versus differentiated cells. Rapid prospective=20 purification of the BTSC may allow clinicians to pinpoint the = transformed cell=20 within a lineage hierarchy, and target it with appropriately tailored = drug and=20 molecular therapies. The cancer stem cell hypothesis predicts that even = if a=20 brain tumor shows substantial decrease in size in response to a therapy, = if the=20 cancer stem cells are spared, the tumor will regrow and the patient will = have a=20 clinical relapse.

A functional analysis of the BTSC using in vitro = clonogenic=20 assays and in vivo transplantation assays may also provide a = novel means=20 for testing of new treatment strategies that focus on the eradication of = the=20 tumor maintaining BTSC. The functional analysis of the BTSCs may give = new=20 insight into patient prognosis that may then guide the aggressiveness of = treatment. For example, it was observed that malignant brain tumors had = a higher=20 stem cell (CD133+) index than low-grade tumors (Singh=20 et al., 2003), and tumors that had the same histology could = have very=20 different stem cell indices, suggesting that the stem cell index may be=20 predictive of prognosis, even if the tumors are otherwise histologically = indistinguishable. Furthermore, tumors that shared the same stem cell = index=20 could have stem cells that have different self renewal abilities in = vitro=20 (Singh=20 et al., 2003), suggesting further distinction between = individual=20 patient's tumors.

The fact that BTSCs can be differentiated into cells = that express=20 more mature markers supports that further exploration of the dynamic = tumor=20 differentiation process may lead to differentiation therapy. The = presence of a=20 BTSC will also have important implications for understanding brain tumor = dissemination if these are the cells that migrate and establish CNS = metastasis.=20 The identification of a BTSC provides a powerful tool to investigate the = tumorigenic process in the central nervous system and further reinforces = the=20 link between normal neurogenesis and brain tumorigenesis.

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Notes

Note added to proof

Brain tumor cell lines also contain cancer stem = cells. Study of=20 a 'side population' of the C6 rat glioma cell line, based on the = abilities of=20 cells to exclude the fluorescent dye Hoechst 33342, demonstrates that = this=20 minority fraction of cells in this cell line exclusively have neural = stem=20 cell-like properties in vitro, and tumorigenic ability in = vivo=20 following transplantation into the peritoneal cavity of nude mice (Kondo=20 et al., 2004).

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Acknowledgements

Dr Dirks laboratory is supported by the National Cancer = Institute=20 of Canada, the Hospital for Sick Children Research Institute and the = Arthur and=20 Sonia Labatt Brain Tumor Research Center and from donations to his = laboratory=20 from the Jack Baker family and the Jessica Durigon family. Dr Singh's = fellowship=20 is supported by the Neurosurgery Research and Education Foundation with = funds=20 from the American Brain Tumor Association. We apologize to investigators = of=20 important research that was not cited in this review.

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A=20 GLI1-p53 inhibitory loop controls neural stem cell and tumour cell=20 numbers

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Review

Cancer stem cells in nervous system tumors

Abstract

Keywords:

Introduction

Relationship between neural stem cells (NSCs) and cancer stem = cells

Do brain tumors arise from a transformed NSC: what is the = evidence?

Figure=20 1.

Prospective identification of a cancer stem cell from human brain=20 tumors

Figure=20 2.

BTSC: a new target for future brain tumor therapy

Notes

References

Acknowledgements

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