A Neurosurgeon's Guide To Stem Cells, Cancer = Stem Cells, and... : Neurosurgery

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Neurosurgery:

August 2009 = - Volume=20 65 - Issue 2 - p 237-250

doi:=20 10.1227/01.NEU.0000349921.14519.2A

Review

A Neurosurgeon's Guide To Stem Cells, Cancer Stem = Cells,=20 and Brain Tumor Stem Cells

Cheshier, Samuel H. M.D., Ph.D.; Kalani, M. Yashar = S.=20 M.D., Ph.D.; Lim, Michael M.D.; Ailles, Laurie Ph.D.; = Huhn,=20 Steven L. M.D.; Weissman, Irving L. M.D.

Free=20 Access

Continued = Medical=20 Education

Article = Outline

Author Information

Stanford Institute of Stem Cell Biology and = Regenerative Medicine, Departments of Neurosurgery and = Developmental Biology, Stanford University School of = Medicine,=20 Stanford, California (Cheshier) (Kalani)

Department of Neurosurgery, The Johns = Hopkins=20 Hospital, Baltimore, Maryland (Lim)

Stanford Institute of Stem Cell Biology = and=20 Regenerative Medicine, Stanford University School of = Medicine,=20 Stanford, California (Ailles)

Department of Neurosurgery, Stanford = University=20 School of Medicine, Stanford, California, Stem Cells, = Inc.,=20 Palo Alto, California (Huhn)

Stanford Institute of Stem Cell Biology = and=20 Regenerative Medicine, Department of Developmental = Biology,=20 Stanford University School of Medicine, Stanford, = California=20 (Weissman)

Reprint requests: Irving = L.=20 Weissman, M.D., 279 Campus Drive, B257 Beckman Center, = Stanford, CA 94305. Email: irv@stanford.edu

Received, June 22, = 2008.

Accepted, April 1,=20 2009.

Abstract

STEM CELLS AND their potential = applications have=20 become the forefront of scientific, political, and = ethical=20 discourse. Whereas stem cells were long accepted as = units of=20 development and evolution, it is now becoming = increasingly=20 clear that they are also units of oncogenesis. = Although the=20 field of stem cell biology is expanding at an = astounding rate,=20 the data attained are not readily translatable for the = physicians who may eventually deliver these tools to = patients.=20 Herein, we provide a brief review of stem cell and = cancer stem=20 cell biology and highlight the scientific and clinical = implications of recent findings regarding the presence = of=20 cancer-forming stem cells in brain = tumors.

ABBREVIATIONS:=20 AML, acute myelogenous leukemia;=20 BM, bone marrow; = BTSC, brain=20 tumor stem cell; CNS, central nervous = system;=20 ES, embryonic stem; = GBM,=20 glioblastoma multiforme; HSC, = hematopoietic=20 stem cell; LT, long term;=20 TS, tumorsphere

Recent advancements in developmental = biology have=20 brought stem cells into the forefront of scientific,=20 political, and ethical discussions. Most clinicians = have an=20 intuitive sense of what stem cells are, but the = significance=20 of stem cell biology for their practice may not be = fully=20 appreciated. Recent experiments implicating stem cells = as the=20 source of cancers have led to new questions about the=20 mechanisms of oncogenesis as well as new treatment = strategies.=20 We provide a broad overview of normal and cancer stem = cell=20 biology and highlight the scientific and clinical = implications=20 of recent findings regarding the presence of = cancer-forming=20 stem cells in brain tumors.

Back=20 to Top | Article=20 Outline

STEM CELLS

Understanding how a multicellular system = develops=20 from a single cell or cell type is one of the central = issues=20 of modern biology. The Greek philosopher Aristotle may = have=20 been the first to introduce the idea of stem cells = when he=20 debated whether the human embryo developed from a = preformed=20 individual (a homunculus) or from an undifferentiated = form=20 that gradually became more specialized into the many = parts of=20 a person. Although Aristotle eventually favored the=20 homunculus, debate and controversy about human = embryonic=20 origins has continued into the modern era. It was not = until=20 1665, when Robert Hooke observed the structure of cork = bark=20 under a microscope, that an accurate description of = the=20 cellular structure of an organism was obtained. From = that time=20 forward, cells were known to be the units of = organization and=20 function of tissues and organs. Because organisms live = much=20 longer than their differentiated cells, tissue and = organ=20 regeneration is necessary. We now know that most cells = in a=20 tissue or organ differentiate when they divide. = Therefore, in=20 a particular cellular lineage, the cells have a finite = lifespan unless replaced. Stem cells replace these = lost cells=20 and are unique in that they self-renew themselves, = providing a=20 perpetual source of primitive precursors of the tissue = or=20 organ.

Till and McCulloch (⁹⁰)=20 developed the formal concept of stem cells in the = 1960s=20 through a series of experiments involving the = transplantation=20 of limiting numbers of bone marrow (BM) cells, some of = them=20 chromosomally marked, into irradiated mice (^{90,104-106).=20
At low numbers, 1 in 7000 marrow cells gave =
myeloerythroid=20
(but not lymphoid) colonies 10 days later in the mouse =
spleen.=20
Each colony was derived from a single cell, and some =
colonies=20
produced more colony-forming cells; rarely, these =
included=20
lymphoid progeny. We now call these blood =
colony-forming cells=20
adult tissue stem cells, this type being=20
hematopoietic. From these experiments, a general =
definition of=20
stem cells emerged as cells possessing the following 3 =

characteristics: 1) self-renewal, 2) the ability to =
produce=20
all cell types made in that tissue, and 3) the ability =
to do=20
so for a significant portion of the life of the host =
(³).=20
This definition has provided standard criteria to =
identify a=20
stem cell. Figure 1 illustrates =
the=20
definition of a stem cell as it pertains to the =
nervous=20
system. The neural stem cell is a cell with an =
unlimited=20
self-renewal potential. Through asymmetric cell =
division, the=20
stem cell produces committed progeny or progenitors, =
which can=20
also self-renew, but for a limited set of cell =
divisions, and=20
differentiate to produce the various cell types of the =
central=20
nervous system (CNS).}

Figure = 1
Image = Tools

Vertebrates contain numerous types of stem = cells,=20 some operative only at specific points during = development,=20 whereas others function throughout the lifetime of an=20 organism. The most primitive, totipotent stem cells, = are=20 capable of giving rise to both the embryonic and=20 extraembryonic tissues of an organism. Totipotent stem = cells=20 include the fertilized egg and the cells produced by = the=20 initial divisions of the ova. The product of these = cell=20 divisions, which in mammals occurs before the entity = implants=20 in the uterus, is the blastocyst. The blastocyst = contains an=20 outer sphere of trophoblast cells, capable of binding = to and=20 implanting into the uterus, and of helping form the = placenta=20 (Fig. 2). Within the = blastocyst=20 are 10 to 20 pluripotent cells called the inner cell = mass.=20 Upon implantation, these inner mass cells will = participate in=20 the production of all tissues and organs of the = developing=20 embryo, then fetus, then born organism. Such = pluripotent cells=20 can produce any differentiated cell in the body, but = are=20 usually unable to form the trophoblast cells.

Figure = 2
Image = Tools

The best-known pluripotent stem cell is = the=20 embryonic stem (ES) cell. Although they are called ES = cells,=20 this is a misnomer; according to Dorland's Medical = Dictionary, the embryo stage of development is = well after=20 the blastocyst stage: in humans, at about 2 weeks when = the=20 long axis forms a primitive streak until organogenesis = at=20 about 8 weeks when the fetal stage begins. In mice,=20 introduction of ES cells into another mouse blastocyst = allows=20 chimerism of all tissues, including gametes; when such = mice=20 are mated, one can produce strains of mice from the ES = donor.=20 ES cells are obtained from the inner cell mass of the=20 blastocyst and exist for only a brief stage of = embryonic=20 development. These ES cells can be manipulated in = vitro, in=20 order to introduce new genes or disrupt preexisting = genes=20 within the ES cell genome. The widest application of = ES cells=20 has been to produce mice with targeted disruptions of = specific=20 genes known as knock-out mice. Given the ability of ES = cells=20 to produce any cell type of an adult organism, these = cells=20 offer great potential to be the instruments of = research that=20 can eventually lead to therapeutics in numerous human = disease=20 states. ES cell technology has already impacted = scientific=20 knowledge to the degree that its pioneer, Dr. Mario = Capecchi,=20 has been awarded a Nobel Prize. However, the fact that = blastocysts (which could potentially yield a viable = organism)=20 must be destroyed to obtain these select cells, has = led to=20 controversy in some segments of society. Part of the=20 controversy derives from stating that ES cells came = from=20 embryos. Others consider the fertilized egg to have = the same=20 rights as born humans, and so the designation would = not be=20 relevant for them. This controversy has helped spawn=20 techniques designed to transfer the nucleus to an egg = with=20 inhibitors of trophoblast development, so that no = implantable=20 blastocyst would develop; or of an adult cell into = preexisting=20 ES cells, as well as obtaining ES cells from the = 8-cell morula=20 stage, mimicking preimplantation genetic diagnosis = that leaves=20 the 7 cells capable of blastocyst development. Other = types of=20 pluripotent stem cells include gonad precursors found = in fetal=20 tissue called embryonic germ cells (another misnomer,=20 embryonic cells from a fetus), and embryonic carcinoma = cells=20 (e.g., teratocarcinomas), which can produce all cell = types,=20 but in a highly disorganized manner. The last major = class of=20 stem cells, multipotent stem cells, gives rise to a = limited=20 number of cell types. These cells can be tissue (e.g., = mesenchymal stem cells, skin stem cells, or blood stem = cells)=20 or organ-specific cells (neural stem cells). = Multipotent stem=20 cells can be found in most organs of the body and are=20 responsible for organ growth and maintenance.

The best-characterized multipotent stem = cells are=20 the hematopoietic stem cells (HSCs), which are = responsible for=20 the continuous production of blood cells. The relative = ease of=20 isolating HSCs, as well as a wealth of in vitro and in = vivo=20 assays, has allowed hematopoiesis to become an = important model=20 system for the study of stem cell biology (^57,58). = The prospective isolation of HSCs required development = of=20 assays for all blood clonal outcomes, of monoclonal = antibodies=20 that subdivide the marrow, and of high-speed cell = sorters.=20 (For a description of a cocktail of antibodies to = purify HSCs,=20 see ref. ⁴³=20 and references therein.)

The advancement of monoclonal antibody = technology=20 coupled with fluorescence-activated cell sorting in = the 1980s=20 allowed scientists to characterize hematopoietic cells = based=20 on expression of specific cell surface proteins = indicated by=20 fluorescently labeled monoclonal antibodies against = these=20 proteins (¹⁸).=20 For example, specific combinations of cell surface = molecules=20 could be used to isolate T cells, B cells, and myeloid = cells.=20 In 1988, using a panel of negatively selecting = monoclonal=20 antibodies that stain mature blood cells (lineage=20 lo or neg), coupled = with 2=20 other positively selecting antibodies recognizing cell = surface=20 proteins that could enrich BM for HSC activity (Thy1.1 = and=20 Sca-1), Spangrude et al. (⁸⁷)=20 utilized fluorescence-activated cell sorting to = isolate the=20 first pure hematopoietic multipotent stem and = progenitor cell=20 population from mouse BM. Later experiments showed the = most=20 primitive population of HSCs (the long-term [LT] HSCs) = could=20 be isolated to homogeneity by the addition of 2 = makers: strict=20 Lineage^- cells that simultaneously express = high=20 levels of the tyrosine-kinase stem cell factor = receptor, c-kit=20 (⁶⁰).=20 The end result of these experiments was determination = that the=20 Lineage^-, Sca-1⁺, = c-kit⁺,=20 Thy1.1^lo expressing cells were the only = cells in=20 the BM capable of giving rise to LT myeloid-erythroid = and=20 lymphoid cells when transplanted into irradiated mice. = Thus, a=20 predetermined combination of cell surface marker = antibody=20 staining (c-kit⁺, Lineage^-,=20 Sca-1⁺, Thy1.1^lo) could be used = to=20 isolate pure populations of LT-HSCs from whole BM. = This result=20 allowed for direct analysis of these cells, rather = than an=20 indirect analysis based on functional outcomes in = transplanted=20 animals. For instance, early studies by researchers = such as=20 Till and McCulloch certainly implied the existence of = HSCs,=20 yet the cells were never analyzed directly. The = prospective=20 isolation of HSCs, and their multipotent/oligopotent=20 progenitors (single cells that produce all or few = blood cell=20 types, but do not self-renew) revealed that all stem = cells are=20 not equal in that some cells can produce progeny = almost=20 indefinitely (true stem cells), whereas other cells = are more=20 limited in their self-renewal capacity and are more = restricted=20 in the types of cells they can develop into = (progenitor cells)=20 (Fig. 3). The studies = purifying=20 HSCs provided the foundation for later experiments in = which=20 pure HSCs and blood cell lineage-specific progenitors = were=20 subsequently isolated in both mice and humans (⁸³).

Figure = 3
Image = Tools

The isolation of each cell type of blood = (stem=20 cells, restricted progenitors, mature cells) has = allowed=20 scientists to ascertain the hierarchical organization = of the=20 hematopoietic system based on proliferation, = differentiation,=20 and self-renewal, and identify important other cell = types and=20 signaling factors essential for the process of = self-renewal=20 and commitment (Fig. 3). Such = hierarchical=20 organization exists in solid organ systems, including = the CNS=20 (Fig. 1) (^{7,15,23,24,33,35,46=
,71,79}).=20 The successful balance of self-renewal, proliferation, = and=20 differentiation requires a high degree of fidelity, = and=20 disturbances in the organization can lead to = disease.

Back=20 to Top | Article=20 Outline

NEURAL STEM CELLS

Until recently, it was unclear if the = principal=20 hierarchical organization of the hematopoietic system = applied=20 to the CNS. In the hematopoietic system, multipotent = stem=20 cells capable of extensive proliferation and = self-renewal give=20 rise to a series of progressively more = lineage-restricted=20 progenitors with less proliferative capacity (Fig. 3). There is now = growing=20 evidence that the CNS has a cellular organization = based on=20 self-renewal and differentiation similar to = hematopoiesis (Fig. 1). The central = and=20 historical dogma of CNS biology was that little if any = turnover occurs within the CNS of mature vertebrates,=20 especially in terms of new neuronal growth. This = supposition=20 was first challenged by a study demonstrating that the = hormonally responsive growth of the hyperstriatum = ventrale,=20 pars caudalis in canaries was in part attributable to = new=20 neuronal growth derived from a rapidly cycling = progenitor cell=20 population located within the subventricular zone = (³⁴).=20 More recently, long-term cultures of human and rodent = CNS=20 tissues have revealed the existence of cells as a = population=20 capable of maintaining the continuous production of = neurons,=20 oligodendrocytes, and astrocytes; in some studies, = they=20 contained retroviral tagged clonal precursors of all 3 = lineages (^{17,56,73,75,99<=
/SUP>).=20
Indeed, several groups have devised methods for the =
isolation=20
of such cells from patients (¹⁰²).=20
This technique has great potential for obtaining, =
harvesting,=20
manipulating, and transplantation of these cells into=20
patients. Although these progenitor/stem cells can =
grow in=20
monolayers, their most distinctive in vitro =
characteristic is=20
their ability to form round clusters of self-adherent =
cells=20
termed neurospheres (^75,99). =

Single cells derived from neurospheres could produce =
both=20
neurons and glia when transferred into rodent brains. =
These in=20
vivo experiments demonstrated that a clonal population =
of CNS=20
cells derived from neurospheres in vitro contained =
neural=20
tissue-specific progenitor/stem cells (^75,93,99=
).=20
In the adult human brain, neurospheres containing CNS =
stem=20
cells have now been isolated from the periventricular =
area of=20
the forebrain lateral ventricles (subventricular zone) =
and the=20
dentate gyrus of the hippocampus (^6,24).=20
Neurospheres have also been derived from adult rats =
and human=20
fetuses (^{6,31,46,71,82,96,97=}).}

Uchida et al. (⁹³)=20 achieved the first prospective isolation of human CNS = stem=20 cells when they applied the experimental principles of = HSC=20 isolation to the characterization of cell suspensions = made=20 from the fetal subventricular zone. = Fluorescence-activated=20 cell sorting was used to separate cells that had the = specific=20 cell surface marker combination: CD133⁺,=20 5E12⁺, CD24^neg/lo, = CD45^neg=20 (blood cell lineage), and CD34^neg (blood = vessel=20 lineage and itinerant HSCs). Neurospheres initiated = from=20 single clones of sorted cells of the above phenotype = were able=20 to form new neurospheres in culture, and could = differentiate=20 into neurons, astrocytes, and oligodendrocytes = (trilineage=20 differentiation) in vitro. The same cells demonstrated = engraftment, migration, and differentiation when = transplanted=20 into the brains of newborn immunocompromised mice = (^88,93). = Putative CNS stem cells based on the above phenotype = have=20 already demonstrated potential clinical utility. These = cells=20 can halt the formation of neurological defects when = injected=20 into the brains of a mutant mice strain that normally = develop=20 lysosomal storage diseases (⁵¹)=20 of the CNS such Batten disease (unpublished = observations),=20 improve motor activity when injected into = traumatically=20 damaged spinal cords of mice (²⁰),=20 and migrate and produce new neurons in ischemic rodent = brain=20 (⁴⁹).=20 Using different combinations of cell surface markers = and=20 fluorescent-protein reporter constructs,=20 fluorescence-activated cell sorting has also been used = to=20 isolate CNS stem cell populations from mice (^16,52,76)= .

The prospective isolation of CNS stem = cells will=20 greatly expand our knowledge of both normal and = abnormal CNS=20 development. The development of CNS stem cell biology = may lead=20 to a better understanding of lineage-restricted CNS=20 progenitors and the potential for therapeutic use.=20 Undoubtedly, knowledge gained from this endeavor, a = better=20 ability to manipulate and dictate the fate of = progenitor cells=20 into coherent, functional neurological units and = knowledge of=20 migratory patterns of normal NSCs, and the ability for = effective delivery of therapeutic genes to human = neurological=20 malignancies will greatly expand the neuro-clinician's = arsenal=20 to combat devastating diseases of the CNS.

The identification of CNS stem cells may = also=20 provide insights into the development of primary brain = tumors.

Back=20 to Top | Article=20 Outline

CANCER STEM CELLS

Cancer biology remains one of the most = intensely=20 studied areas of scientific discourse. Although basic = research=20 has led to a wealth of information regarding the = molecular=20 mechanisms responsible for the transformation of = normal cells=20 into cancers, our concept of the cellular biology of = neoplasms=20 has remained poorly illuminated. The cellular = constituents of=20 solid neoplasms include both tumor cells and non-tumor = stromal=20 elements such as blood vessels, fibroblasts, = hematopoietic=20 cells, and nontransformed cells from the tissue of = origin.=20 Until recently, the neoplastic tumor cells were = assumed to be=20 a relatively homogeneous group of cells, each capable = of=20 producing more cancer cells within the tumor and as = well as=20 producing metastases. Investigations of the clonality = of=20 cancers verified that most neoplasms result from the = malignant=20 transformation of a single cell into a tumor cell = (^26,27,63)= .=20 This hypothesis holds that the transformed cell could = simply=20 replicate, producing new tumor cells with relatively=20 equivalent biological properties. Evidence in support = of this=20 model is abundant in both retinoblastoma and colon = cancer=20 where the accumulation of sequential mutations in the = cell=20 cycle machinery causes cancerous growth. This standard = model=20 of cancer formation was further reinforced by the = intensive=20 utilization of tumor cell lines in the context of = cancer=20 research. However, several experimental results = conflicted=20 with the predictions of the standard model. = Investigations=20 have shown that single cancer cells did not grow = uniformly=20 well in cell culture, cancer cells were not equally = sensitive=20 to therapeutic agents both in vitro and in vivo, and = large=20 numbers of cancer cells were usually required to = produce=20 tumors in transplant animal models. Although it is = possible=20 that the variability among cancer cells in these = studies=20 resulted from inefficiencies of the assays, the = observations=20 also suggest that there are intrinsic differences = between=20 individual tumor cells. The differences seen among = cancer=20 cells may be explained in part by the principles of = CNS stem=20 cell biology.

The overlap between stem cell biology and = cancer=20 biology is striking. Both tissue stem cells and cancer = cells=20 share the ability to proliferate, self-renew, and give = rise to=20 differentiated progeny. In the case of the tissue stem = cell,=20 the balance between differentiation and proliferation = must be=20 highly regulated (Fig. 4, left). Under = normal=20 conditions, neural stem cells residing adjacent to = vascular=20 endothelium differentiate to produce neuronal and = glial=20 progeny. In the case of cancer, there is marked = deregulation=20 of the balance between proliferation and = differentiation,=20 resulting in uncontrolled tumor growth and incomplete=20 differentiation (Fig. 4, right). = Cancer stem=20 cells, similarly housed adjacent to endothelial cells, = proliferate and produce both other cancer stem cells = and=20 non-cancer stem cell tumor cells. The leaky nature of = blood=20 vessels in a tumor allows for an abundance of = inflammatory and=20 BM-derived progenitor cells within the mass of the = tumor. In=20 addition, and almost predictably, cancer and stem = cells share=20 many molecular mechanisms mediating these complex = processes=20 (^100,101)= .=20 For instance, the cell cycle machinery, self-renewal = genes,=20 and growth factors necessary for normal stem cell = existence=20 are the same genes utilized by many cancer cells. = Furthermore,=20 both stem cells and cancer cells can be transplanted = into=20 animal models recapitulating normal stem cell = regenerative=20 function in the case of stem cells and tumor = development with=20 cancer cells.

Figure = 4
Image = Tools

The prominent similarities between cancer = and normal=20 stem cells have led to the development of the Cancer = Stem Cell=20 Hypothesis as proposed by Reya et al. (⁷⁴).=20 This hypothesis consists of 2 complementary and = non-mutually=20 exclusive components. The first component postulates = that=20 normal tissue stem cells are the target for = transforming=20 mutations and successive insults result in the = eventual=20 formation of a tumor. The second component is that = within=20 every cancer there exists a specific subset of cells = that=20 continuously give rise to all the other cancer cells. = This=20 subset of tumor cells are the cancer stem cells and = are the=20 only cells within a tumor that possess the ability to=20 self-renew, continuously proliferate, and can give = rise to=20 metastases. Although some tumor cells may have some=20 proliferative capability, only the cancer stem cell = can=20 reproduce itself and another nonreplicating tumor = cell.=20 Furthermore, because tumors are clonogenic, all of the = heterogeneity in a tumor is produced by the cancer = stem cells.=20 Although some of the tumor cell diversity can result = from=20 progressive mutagenesis, there is ample evidence = supporting=20 that the heterogeneity within cancers reflects aspects = of=20 normal differentiation processes, which would be = expected if=20 cancer stem cells are giving rise to differentiated = progeny=20 (^28,29,39)= .=20 In other words, the histobiological properties of a = cancer=20 tend to reflect its tissue of origin because the = cancer stem=20 cell and its progeny continue to recapitulate the = phenotype of=20 the original tissue, although in a disorganized and=20 unproductive manner. Thus, a tumor can be viewed as a=20 dysfunctional organ system, in which the cancer stem = cell=20 gives rise to phenotypically diverse (albeit = dysfunctional)=20 progeny that have limited proliferative potential and = no=20 ability for self-renewal.

It should be noted that recent studies by = Morrison=20 et al. (⁷²)=20 question some of the most important components of the = cancer=20 stem cell hypothesis. Using melanoma as a model, the = group led=20 by Morrison showed that nearly 1 in 4 cells possessed=20 proliferative ability and spawned cancer. Although the = final=20 verdict has yet to be determined, it is likely that = the cancer=20 stem cell hypothesis is applicable to some tumors and = not to=20 others, such as melanoma.

Back=20 to Top | Article=20 Outline

Mutations Accumulating in Normal Stem = Cells Lead to=20 Cancer

A well-established concept of cancer = biology is that=20 over time a series of genetic mutations leads to the = malignant=20 transformation of a normal cell into a cancer cell. = These=20 mutations result in the disruption of the cellular = machinery=20 controlling the cell cycle, cell growth and = inhibition,=20 apoptosis, immune surveillance, genomic stability,=20 differentiation, and self-renewal (^65,100).= =20 Mutations can propagate only if a cell divides, thus = in=20 cellular terms, time is synonymous with proliferative = events,=20 and mutations occur in the context of cell divisions = occurring=20 frequently during development and more slowly in a = mature=20 organism. This in part explains why most cancers = cluster in=20 the pediatric group (in which more cells are dividing = per unit=20 time) or the geriatric group (in which slowly dividing = cells=20 have been undergoing divisions for a long period of = time). The=20 idea that normal tissue stem cells accumulate genetic=20 mutations leading to cancer formation came about as a = direct=20 extension of studies describing the cellular = organization of=20 hematopoietic cells. In both fetal and adult tissues = of mice=20 and humans, only LT-HSCs are capable of the continued=20 production of myeloid-erythroid cells (^60-62). = Unlike LT-HSCs that have a lifespan measured in years, = the=20 immediate progenitors of HSCs, short-term HSCs, = myeloid=20 restricted progenitors, and lymphoid restricted = progenitors,=20 only have lifespans of weeks to months (⁶²).=20 Thus, only LT-HSCs possess the proliferative capacity = and=20 lifespan necessary to accumulate the threshold of = mutations=20 leading to cancer. Put more simply, the longevity of = the=20 tissue stem cell also increases the risk and exposure = of the=20 cell to transforming mutations. Experimental evidence = for this=20 idea was noted in animal models of leukemia in which = mice in=20 pre-leukemic states could transfer leukemia only when = HSCs=20 were transplanted into irradiated hosts (⁵⁹).=20 Miyamoto et al. (⁵⁹)=20 postulated that if LT-HSCs were harboring mutations, = then=20 leukemic patients in complete remission should have = mutations=20 in their remaining HSCs because the more committed = short-term=20 HSCs are derived from the more primitive LT-HSCs. = These=20 investigators analyzed the LT-HSCs from Hiroshima = survivors=20 who developed acute myelogenous leukemia (AML) and = were in=20 long-term remission. They found that a significant = fraction of=20 LT-HSCs in these patients continued to harbor the AML=20 pathoneumonic AML1-ETO translocation mutation, but = because=20 other mutations promoting deregulated growth were not = present=20 in these patients, they remained in remission. The = mutated=20 LT-HSC was indistinguishable from the LT-HSC without = the=20 translocation and displayed no evidence of deregulated = growth=20 in vitro.

It should be noted that, despite the = proposed=20 necessity of mutation accumulation in normal stem = cells for=20 cancer formation, it is very possible that a = transforming=20 event (or events) can occur in a more mature = progenitor=20 downstream of the long-lived stem cells, or that the = effects=20 of the mutations that accumulate in the stem cells are = manifested in a downstream progenitor. This final=20 transformation of a progenitor cell has experimental = evidence=20 in mouse and human leukemogenesis and neuroepithelial = tumor=20 formation (^{40,41,44,45,91,111=}).=20 There is also experimental evidence suggesting that = genetic=20 alterations within lymphocytes can lead to mouse T = cell=20 leukemia independently from HSCs (¹¹⁰).=20 However, this result is not inconsistent with the stem = cell=20 hypothesis because, upon antigen stimulation, = lymphocytes=20 regain the stem cell properties of proliferation and=20 self-renewal. Thus, a lymphocyte can be viewed as a = unipotent=20 stem cell capable of giving rise to progeny that can = be used=20 in an immune reaction or to produce new lymphocytes = with=20 different antigen binding properties through the = process of=20 affinity maturation. The idea of stem cells as the = focal point=20 of cancer mutations is a striking contrast to more = traditional=20 models in which any cell can be subject to mutations = leading=20 to cancer. However, it is more parsimonious to = postulate that=20 a cell possessing the unique ability for self-renewal = and=20 extensive proliferation is better suited to forming a = tumor=20 than a terminally differentiated cell lacking these=20 properties.

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Cancer Stem Cells Establish and Propagate = Tumors

The second component of the cancer stem = cell theory=20 postulates that a specific subset of tumor cells, the = cancer=20 stem cells, are the only cells capable of the = continued=20 production of tumor cells (⁷⁴).=20 Despite the assumed homogeneity of cancer cells in the = standard model of cancer cell organization, the = reality of=20 tumors is quite different. Histologically, tumor cells = can=20 display a large variation in appearance, often = resembling the=20 spectrum of differentiated cell types of the tissue = from which=20 the tumor arises. Also, only a very limited number of = cancer=20 cells from hematopoietic and solid malignancies can = grow in=20 vitro or in vivo in animal transplant models (^{28,29,36,37,39,86}).=20 Investigations have shown that, in the case of = hematopoietic=20 and some solid malignancies, only 1 in 100 to 1 in 10 = 000=20 primary tumor cells are capable of reproducing the = tumor in=20 vivo (^4,5,14,60= ).=20 The standard model would postulate that all cancer = cells are=20 equivalent, and that each cell has a low probability = of=20 proliferating in the setting of the experimental = conditions.=20 The cancer stem cell theory would posit that only the = cancer=20 stem cell subset can give rise to new cells, and = because this=20 population is rare, their activity on a per cell basis = is=20 rare. The cancer stem cell hypothesis predicts that=20 prospectively isolating these rare subsets of cells = from the=20 non-stem cell cancer cell would result in markedly = different=20 cellular proliferation. This stem cell subset should = be highly=20 enriched for in vivo and in vitro tumor growth, and = the=20 non-stem cell fraction should be highly depleted of = these=20 abilities.

The experimental confirmation of the = cancer stem=20 cell hypothesis was first achieved by Bonnet and Dick = (¹⁴)=20 for AML. They postulated that because cancer stem = cells are=20 derived from normal stem cells, they should have = similar cell=20 surface phenotypes. Using a panel of monoclonal = antibodies=20 used to prospectively isolate normal human HSCs, they=20 determined that patient-derived AML cells with the = cell=20 surface combination of CD34⁺, = CD38^-,=20 Lineage^- were the only cells capable of=20 transferring disease to immunocompromised mice. These = AML stem=20 cells represented only a small yet variable fraction = of all=20 tumor cells. Later investigations demonstrated that = the AML=20 stem cells were CD90^-, which differs from = normal=20 human HSCs that are CD90⁺ (^1,2).=20 Thus, the AML stem cell had an overlapping, but = distinct, cell=20 surface phenotype compared with its normal = counterpart. A=20 growing number of investigators have isolated cancer = stem=20 cells from a number of leukemias including chronic = myelogenous=20 leukemia, blast crisis chronic myelogenous leukemia, = and=20 myeloproliferative disorders (^30,42,45)= .=20 In each case, the cancer stem cell demonstrates the = unique=20 property of serial transplantation compared with the=20 non-cancer stem cells derived from the same tumor.

In solid tumors, the presence of cancer = stem cells=20 was confirmed when Al-Hajj et al. (^4,5)=20 prospectively isolated a rare subset of human breast = cancer=20 cells with the cell surface phenotype = CD44⁺,=20 CD24^neg/lo, Lineage^-. Cells with = this=20 phenotype were the only cells capable of forming new = tumors=20 upon injection into the mammary glands of = immunocompromised=20 mice. Since then, a growing number of mouse and human = solid=20 tumors have been fractionated on the basis of cell = surface=20 marker expression, and the existence of cancer stem = cells=20 confirmed experimentally including human = neuroepithelial=20 tumors, head and neck squamous cell carcinomas, and = colon=20 cancer (^{19,21,53,70,85<=
/SUP>).}

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BRAIN TUMOR STEM CELLS

The cancer stem cells relevant to a = neurosurgical=20 practice are those that initiate tumors of = neuroepithelial=20 origin. Bailey and Cushing (⁸)=20 were the first to articulate the concept of brain = tumor=20 arising from a progenitor cell. They proposed that = tumors were=20 derived from progenitor cells residing in the = periventricular=20 zone. The first experimental evidence suggesting the = existence=20 of brain tumor stem cells (BTSC) was published by = Hemmati et=20 al. in 2003 (³⁸),=20 although data dating back to the 1980s had suggested = the=20 existence of such cells (^77,78). = It is known that brain tumor cells can grow in = clusters in=20 defined media containing epithelial growth factor and=20 fibroblast growth factor-2. These specialized clusters = are=20 referred to as tumorspheres (TS) and these = culture-derived=20 spheres are very similar to in vitro sphere formation = with=20 normal CNS stem cells, meaning they contain a = conglomerate of=20 stem and progenitor cells with committed neurons, = glia, and=20 oligodendrocytes. The formation of a tumor or = neurosphere is a=20 culture phenomenon, but represents an interesting = mechanism=20 for creating differential signaling environments = allowing for=20 specialization of cells within the sphere. Hemmati et = al.=20 demonstrated that only a rare fraction of cells = cultured from=20 medulloblastoma and ependymoma could form TSs. = Furthermore,=20 cells from TSs could give rise to more spheres in = culture and=20 were capable of forming tumors when transplanted into = the=20 brains of immunocompromised mice. The investigation=20 demonstrated that only a rare subpopulation of cells = within=20 these tumors were capable of proliferation and = self-renewal.=20 These properties along with tumor engraftment with in = vivo=20 transplantation form the hallmark characteristics of = cancer=20 stem cells. Similar experiments by other investigators = confirmed the presence of a rare subset of TSs = initiating=20 glioblastoma multiforme (GBM) cells that were also = capable of=20 tumor formation upon xenograft transplantation = (^32,92,109= ).

A special cell population with = tumor-forming ability=20 (i.e., tumorigenicity) has also been prospectively = isolated=20 from glioma cell lines (^50,85). = C6 glioma cells growing in vitro contain a rare subset = of=20 cells that can be separated by fluorescence-activated = cell=20 sorting on the basis of the cell's ability to efflux = Hoechst,=20 the vital deoxyribonucleic acid staining dye (⁵⁰).=20 The Hoechst effluxing cells, termed side = population,=20 seemed to contain the in vitro and in vivo growth = potential of=20 the cell line. This information suggests that a cancer = stem=20 cell or progenitor is also active in a = well-established tumor=20 cell line. Later experiments confirmed that the dye = exclusion=20 ability in the glioma cell line was attributable to = the=20 presence of multidrug resistance transporters on the = cell=20 surface (⁶⁶).=20 This is an interesting finding given that multidrug = resistance=20 is known to be highly expressed in other normal tissue = stem=20 cell populations, including HSCs (^13,25,94)= .

The identification of a cell surface = marker, which=20 could prospectively isolate cancer stem = cell-containing=20 populations from primary tumor specimens, was first = achieved=20 by Singh et al. (^84,85)=20 in a series of experiments published in 2004. Singh et = al.=20 used the normal CNS stem cell surface antigen, CD133, = to=20 fractionate fresh medulloblastoma and GBM specimens. = The=20 investigation demonstrated that CD133⁺ = expression=20 was measured in a minority of tumor cells, but were = also=20 highly enriched for the ability to produce TSs in = vitro=20 (⁸⁴).=20 Subsequent experiments demonstrated that these=20 CD133⁺ tumor cells were the only cells = capable of=20 forming new tumors when implanted into the brains of=20 immunocompromised mice (⁸⁵).=20 Singh et al. showed that as few as 100 = CD133⁺ cells=20 were capable of forming tumors in vivo, whereas 100 = 000=20 CD133^- cells did not result in tumor = formation in=20 vivo. CD133⁺ has also been recently used to = isolate=20 BTSCs from TSs derived from ependymoma cultures = (⁸⁹).=20 These studies represent the first significant = experimental=20 evidence of possible BTSCs.

Further experimentation is required to = confirm these=20 results and subsequent studies are needed to then = fully=20 characterize the tumor stem cell. Thus far, the = results are=20 based on the utilization of only a single cell surface = marker,=20 CD133, which is also shared by HSCs and normal tissue = CNS stem=20 cells. However, no stem cell population has been = prospectively=20 isolated to relative homogeneity on the basis of a = single cell=20 surface marker. In fact, neither the experiment by = Singh et=20 al. nor any subsequent study utilizing CD133 as a = marker for=20 BTSCs included an in vivo limit dilution experiment = comparing=20 sorted cell populations with whole tumor, which is = currently=20 the only method able to ascertain the relative purity = of any=20 given sorted population.

In general, multiple markers are required = to purify=20 tissue stem cells. In the case of HSCs, 10 to 15 = separate=20 monoclonal antibodies are needed to isolate a pure = stem cell=20 population, and in the case of human fetal CNS stem = cells, a=20 combination of at least 4 antibodies has been = necessary to=20 isolate a relatively homogeneous stem cell population = (^61,93). = The need for cell purity is not a trivial matter, as = this=20 homogeneity is critical for the accurate determination = of gene=20 and protein expression patterns specific for BTSCs. In = the=20 case of leukemia whereby the data are strong and = multiple=20 markers are available, it is possible to isolate = culprit stem=20 cells to purity. Because of the lack of reproducible = markers,=20 identification of stem cells for brain tumors, most = notably=20 GBM, has been very difficult. In these cases in which = markers=20 are not available, larger cell numbers including = non-cancer=20 stem cells, have been injected to reproduce growth of = the=20 tumor. With identification of other markers, it will = be=20 possible to purify brain tumor-initiating stem cells = and=20 reduce input numbers necessary to generate tumors in=20 xenografts. These BTSC-specific gene and protein = profiles will=20 be the foundation for the development of BTSC-specific = therapies as well as help determine the relationship = of BTSCs=20 to their normal CNS stem cell counterparts.

Using a different marker, Ogden et al. = (⁶⁴)=20 separated human GBM on the basis of cell surface = marker A2B5=20 and CD133. The key finding of this study was to note = that=20 tumor cell formation segregated into the = A2B5⁺=20 fraction. However, in their study, both = A2B5⁺=20 CD133⁺ and A2B5⁺ = CD133^- cells=20 could give rise to tumors in a potent manner when = transplanted=20 into the brains of immunocompromised host mice. = Several groups=20 have questioned the validity of CD133 as a BTSC marker = (^12,47).=20 Furthermore, our own analysis of patient GBM and=20 medulloblastoma cell surface protein expression = revealed that=20 a significant number of these cells do not express = detectable=20 levels CD133 protein (unpublished results). It could = be=20 hypothesized that cell surface antigens associated = with tumor=20 stem cell markers should be measurably expressed = across the=20 majority of patient specimens. Furthermore, in vivo = analysis=20 of CD133⁺ and CD133^- cells = derived from=20 adult GBM tumors demonstrated growth in both = populations, and=20 at least 2 instances wherein the CD133^- = cells=20 formed large tumors in a mouse xenotransplant model=20 (unpublished observations, Weissman = laboratory). We=20 are not suggesting that CD133 is not a potential BTSC = marker,=20 but we stipulate that CD133 may be a reliable marker = within a=20 tumor sample, but not necessarily between tumor = samples. A=20 more durable marker should be able to prospectively = isolate=20 BTSCs across the majority of brain tumor samples. At = this=20 time, the sum of all experiments represents only a = relatively=20 few number of tumor samples, thus more experiments = with=20 careful designs and controls are needed to discover = multiple=20 markers that can be utilized to prospectively isolate=20 BTSCs.

Since the discovery of BTSCs, a number of=20 laboratories have investigated mechanisms specifically = regulating the biology of these cells as opposed to = whole=20 tumors. CNS stem cells and BTSCs share many = similarities (Table 1). Similar to = normal CNS=20 stem cells, BTSCs reside next to blood vessels = (vascular niche=20 hypothesis) (⁹⁵).=20 The study of normal stem cells has implicated members = of Wnt,=20 sonic hedgehog, and transforming growth factor-=CE=B2 = as important=20 regulators of stem cell growth and development = (^11,55).=20 Interestingly, the vascular niche has been shown to = produce=20 many of these factors (⁹⁵).=20 A recent study from the Hopkins group has shown the = importance=20 of the transforming growth factor-=CE=B2 family member = bone=20 morphogenetic protein to the regulation of BTSCs = (⁶⁹).=20 They demonstrated that activation of bone = morphogenetic=20 protein 4 greatly inhibits the growth of tumors via = its direct=20 effect on reducing BTSC growth. In a different = experiment,=20 abrogation of the sonic hedgehog pathway, an important = developmental signaling pathway, greatly reduced the = ability=20 of GBM tumor spheres to grow tumor in vivo, and = greatly=20 reduced the sphere-forming ability of = CD133⁺ GBM=20 cells (¹⁰).=20 Sonic hedgehog is implicated in maintaining cells in = an=20 undifferentiated state, and molecules capable of = blocking this=20 signal can potentially induce differentiation of the = BTSCs.=20 Similarly, the Wnt signaling pathway has been shown to = be an=20 important regulator of neural stem cell self-renewal = (⁴⁸)=20 and may serve a similar role in brain tumors. = Furthermore,=20 just as normal stem cells are relatively resistant to = the=20 effects of irradiation and chemotherapy, BTSCs seem to = possess=20 similar properties. For instance, Rich et al. (⁹)=20 demonstrated that CD133⁺ GBM cells were = highly=20 radio resistant and this resistance was mediated by = the=20 up-regulation of DNA repair mechanisms. Also, the = ability of=20 GBM tumor spheres to grow in vitro and in vivo was = inhibited=20 to a lesser degree than control cells when exposed to = a number=20 of standard chemotherapeutic agents including = temozolomide=20 (^54,77).<= /P>

Table = 1
Image = Tools

Is cancerous growth the result of = proliferation of a=20 stem cell or a more committed progenitor? In most = systems, it=20 is not clear whether the culprit involved in = oncogenesis is a=20 stem cell or a progenitor cell. Part of the problem = arises=20 from the fact that the definitions of a stem and = progenitor=20 cell are functional; the lack of markers allowing for = the=20 prospective isolation of the normal and cancerous CNS = stem=20 cell further complicates studies of the stem versus = progenitor=20 origin of brain tumors. In the case of = medulloblastoma, 2=20 recent articles (^80,107) = illustrate that accumulation of mutations within a = specific=20 progenitor is responsible for the formation and = progression of=20 this tumor. The authors used labeling experiments to = mark=20 specific Olig2 progenitor populations and showed that=20 accumulation of mutations within this and only this = progenitor=20 population results in medulloblastoma formation. It is = important to note that evidence in other systems is = sparse at=20 best. It is possible that in some tumors accumulation = of=20 mutations in a progenitor causes tumor formation, = whereas in=20 others mutations in the parent stem cell are the = cause; the=20 jury is still out on this topic. These findings = underscore the=20 importance of the types of data that can be derived = from the=20 study of brain cancers from a stem cell = perspective.

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WHY EVERY NEUROSURGEON SHOULD CARE ABOUT = BTSCs

Despite advances in the molecular biology = of cancer,=20 surgical technique, radiotherapy, and chemotherapy, = limited=20 progress has been made in reducing the mortality = associated=20 with CNS tumors. The historic model of cancer holds = that most=20 tumor cells are relatively homogeneous with respect to = proliferative and self-renewal potentials. The cancer = stem=20 cell theory suggests that this model is inaccurate and = this=20 may account for some failures in cancer treatment.=20 Specifically, current treatment modalities were = designed to=20 measure success by reductions in tumor bulk and = volume;=20 however, in this approach, there is no way to confirm = that the=20 cancer stem cells, if present, are being eliminated. = Assuming=20 that the cancer stem cell theory is accurate, then = debulking=20 tumors is a less fruitful task than the identification = and=20 elimination of the BTSCs in guaranteeing the = elimination of=20 the malignancy. The prospective isolation of BTSCs = will=20 provide better targets for the development of new = therapies=20 and to new ways to measure treatment efficacy. New = agents=20 could target the molecular mechanisms supporting the = growth of=20 these cells rather than the confusing multitude of = pathways=20 present within normal cells or the bulk of = nonproliferating=20 tumor cells. For example, prospective isolation of = BTSCs may=20 allow for design of pharmaceuticals targeting cancer = stem=20 cell-specific signaling pathways (¹⁰⁸).=20 In addition, gene and protein array analysis (^22,68,81)= ,=20 as well as high-throughput screening of biological and = synthesized molecules, could lead to small molecule = and=20 immune-based therapies (^67,98)=20 directed specifically against unique BTSC antigens. = Efforts=20 using array and immune-based technologies are already = in=20 preclinical trials for hematologic malignancies. Given = the=20 devastating nature of neurological malignancies, the = interval=20 between isolation of pure BTSCs and phase I trials = will=20 hopefully be short. Currently, new techniques in = molecular=20 imaging and biomarkers in combination with imaging = protocols=20 are beginning to help quantify and locate BTSCs = before,=20 during, and after treatment (¹⁰³).

What is the role of the neurosurgeon in = the setting=20 of these potential BTSC-specific therapies? = Neurosurgeons are=20 currently at the forefront of the research being = performed to=20 isolate and characterize these cells. The collection = of=20 patient tumor samples is the first step in any study=20 attempting to identify BTSCs, and the role of the = interested=20 neurosurgeon in this process is invaluable. The = surgical=20 technique undertaken will help determine the integrity = of the=20 tumor specimen and thus ultimately the quality and = quantity of=20 potential BTSCs. Surgery will remain the mainstay of = initial=20 treatment of malignant neuroepithelial tumors for the=20 foreseeable future, but the development of potential = local=20 therapies directed against residual BTSCs will also = fall=20 within the neurosurgeon's realm. The ability to = rapidly=20 characterize the gene and protein profiles of tumors = and=20 perhaps the isolation of tumor stem cells has great = potential=20 to yield patient-specific therapies. Future therapies = could be=20 based on the response seen for individual and = patient-specific=20 BTSC testing when screened against conventional and=20 experimental agents. The field of cancer and stem cell = biology=20 will no doubt contribute to improved understanding of = disease=20 and potential new treatments. An exciting future = awaits=20 neurosurgeons as practices evolve into a combination = of=20 surgical and cell therapeutics, resulting in better = outcomes=20 for patients with brain cancer.

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Disclosure

Samuel H. Cheshier, M.D., Ph.D., is a = fellow of the=20 Giannini Foundation and a Van Wagner Fellow. M. Yashar = S.=20 Kalani, M.D., Ph.D., is a fellow of the Paul & = Daisy Soros=20 Foundation, the Hanbery Society, and of the Howard = Hughes=20 Medical Institute. Steven L. Huhn, M.D., is an = investigator at=20 Stem Cells, Inc. Irving L. Weissman, M.D., is a = consultant for=20 Stem Cells, Inc.

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Acknowledgments

Samuel H. Cheshier, M.D., Ph.D., and M. = Yashar S.=20 Kalani, M.D., Ph.D., contributed equally to this = article. We=20 thank Kristin Cox, B.A., for editing the manuscript = and Bo=20 Aye, B.A., of Aye Media Group for help with the = figures.

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Back=20 to Top | Article=20 Outline

COMMENTS

In this timely review by the laboratory = led by the=20 modern father of the cancer stem cell hypothesis, the = reader=20 will find both historical as well as current concepts = that are=20 driving the experimental work in this very exciting = area of=20 biological medicine. The hypothesis that not all cells = in a=20 cancer possess the same capacity to renew the tumor = has=20 stirred the imagination of scientists to devise new=20 experiments and therapeutic targets, and thus it = deserves to=20 be considered as paradigm-shifting. The main problem = relates=20 to how one identifies a cell as being a cancer stem = cell: in=20 fact, recent literature has questioned whether the = hypothesis=20 is valid or whether some of the findings that appear = to be=20 validating it depend on the animal model used to = define such=20 stem cells rather than being an intrinsic property of = the stem=20 cell itself. Regardless, scientific discovery in = biological=20 systems almost never provides unequivocal answers; the = important issue is that the cancer stem cell = hypothesis is=20 providing a new framework that recognizes intrinsic=20 differences and growth capacities among different = cells in a=20 cancer, thus simplifying our understanding of why some = cells=20 in a neoplastic mass appear to be more resistant to = therapy=20 than others.

E. Antonio Chiocca

Columbus, Ohio

In this review, Cheshier et al. provide a = neurosurgeon's overview of stem cells, especially = leading to=20 the potential for targeted treatments in primary brain = tumors.=20 A considerable amount of basic information is provided = for the=20 neurosurgeon, including the important definition of a = stem=20 cell, i.e., a cell capable of self-renewal, producing = all cell=20 types. They explore the difference between stem cells = and=20 multipotential cells, which may be important for = repair where=20 not all types of cells are made. The authors then go = on to=20 explain that the term embryonic stem cells is a = misnomer, as=20 these are actually taken from the blastocyst stage, = which is 2=20 weeks earlier than the embryonic stage of development. = The=20 review then moves on to discuss the idea of using = monoclonal=20 antibodies for cell sorting. This concept, coupled = with=20 fluorescence-activated cell sorting in the 1980s, = allowed us=20 to develop more and more knowledge by first isolating = stem=20 cells from hematopoietic lines and, more recently, by = using=20 this methodology in studying brain cancer.

The concept, of course, is that many = cancers may=20 not be adult cells gone bad, but rather the = self-renewing stem=20 cells within our tissue that go bad. The difference is = important as we discover invariable brain monoclonal = markers,=20 in that there may be a selective signature to each = person's=20 tumor. Therefore, individual immunotargeted therapies = may=20 become possible. From these sorts of studies we have = been able=20 to develop particular lines of individual tumors. Very = recent=20 studies have suggested that we are able to identify=20 characteristics more susceptible to one chemotherapy = or=20 radiation over another. In this view, the true targets = for=20 brain cancer are not all the cells, as presently = targeted, but=20 rather particular cells within the tumor where = targeted=20 therapies may decrease toxicity and give hope for = successful=20 therapies.

Robert J. Dempsey

Madison, Wisconsin

We read with great interest the article = by Cheshier=20 et al., in which the authors outline the history of = stem cells=20 and summarize recent evidence supporting the existence = of=20 brain tumor stem cells (BTSCs). The review brings = important=20 attention to the nascent field of BTSC biology, where = several=20 groups have now shown that only a few cells within the = tumor=20 parenchyma are responsible for perpetuating the growth = of=20 malignant tissue (^{8,=20
12, 13}). We would like to emphasize here a = few=20 additional points to underline the importance of the = BTSC=20 hypothesis to the neurosurgeon and, in light of recent = evidence, examine why current treatment modalities = fail to=20 manage the growth and spread of neurological = malignancies.

The BTSC hypothesis suggests that unless = all=20 cancer-regenerating stem cells are destroyed, even if = the=20 majority of the tumor stroma is debulked, the disease = will=20 recur (⁵).=20 Today's standard treatment paradigms are nonspecific = and fail=20 to target the highly metastatic BTSC population within = a tumor=20 which is responsible for tumor regrowth (⁵).=20 Rather, these modalities only destroy the bulk of the = tumor=20 stromal cells, which are likely nonregenerating. = Walter Dandy=20 was the first to note the recurrence of malignant = glioma in=20 the contralateral hemisphere after radical = hemispherectomy=20 (⁷),=20 suggesting that, despite radical resection, = micrometastatic=20 nests of BTSCs migrate, divide, and cause the = malignancy to=20 recur at a nearby site.

Many emerging reports now suggest that = BTSCs are=20 exquisitely resistant to chemotherapy and radiation, = more so=20 than their tumor stroma counterparts. For example, Liu = et al.=20 (⁹)=20 have shown that BTSCs upregulate many antiapoptotic = genes and=20 are less susceptible to traditional chemotherapy = agents. Bao=20 et al. (²)=20 have shown that BTSCs survive ionizing radiation to a = greater=20 extent than their tumor stromal counterparts and are = able to=20 preferentially turn on DNA damage repair genes. These = reports=20 indicate that our traditional therapies inherently are = doomed=20 to failure because they are unable to destroy the = underlying=20 tumor-perpetuating cells. New methods that = specifically target=20 BTSCs need to be developed.

There are now 5 new promising avenues for = destroying BTSCs (¹⁴).=20 The first is by inducing the differentiation of BTSCs = into=20 more committed cell lines with little regenerative = capacity.=20 Piccirillo et al. (¹¹)=20 recently showed that activation of the bone = morphogenetic=20 protein 4 signaling cascade induces a = prodifferentiation=20 effect on glioblastoma multiforme-derived BTSCs and = inhibits=20 the tumorigenicity of BTSCs. The second strategy = targets the=20 intracellular pathways that help to promote the = proliferation=20 of BTSCs. Sonic Hedgehog (SHH), a primitive protein = involved=20 in central nervous system organization during = development, has=20 been shown to be a promising inhibitory target for = clinical=20 therapy (⁶)=20 that inhibits the growth of some brain tumors (³).=20 The third strategy would be to disrupt the niches = where BTSCs=20 reside. Calabrese et al. (⁴)=20 recently showed that BTSCs reside in vasculature = niches and=20 that antiangiogenic antibodies, such as bevacizumab, = are able=20 to eradicate cancer-regenerating stem cells. The = fourth=20 strategy would be to deliver therapeutic genes to = BTSCs using=20 other stem cells. For example, many groups, in = addition to our=20 own, have shown the efficacy of delivering = prodrug-converting=20 enzymes to brain tumors using either neural stem cells = (¹)=20 or mesenchymal stem cells (¹⁰),=20 both of which are able to track metastatic disease = produced by=20 migrating BTSCs. The fifth, and final, strategy we = propose may=20 inhibit the invasiveness of BTSCs and would help to = reduce the=20 spread of disease and localize tumor-regenerating = cells for=20 more adequate excision. Our laboratory is extensively = studying=20 the role of ion channels, which is a conserved = mechanism used=20 by many cells as a strategy for pseudopod extension = and=20 migration, to use as a target for inhibition = (unpublished=20 data).

In light of the recent discovery of = BTSCs, it is=20 clear that our current treatment modalities are = archaic and=20 destined to fail unless new treatments that = specifically=20 destroy cancer-regenerating stem cells are = implemented. A=20 better understanding of the markers that identify = these cells=20 and the intracellular pathways dependent on their = growth and=20 proliferation, as well as the discovery of areas where = these=20 cells reside, will help enhance the tools necessary to = fight=20 these cells and eradicate brain tumors.

Hasan A. Zaidi

Thomas Kosztowski

Alfredo Qui=C3=B1ones-Hinojosa

Baltimore, Maryland

1. Aboody KS, Brown A, Rainov NG, Bower = KA, Liu=20 S, Yang W, Small JE, Herrlinger U, Ourednik V, Black = PM,=20 Breakefield XO, Snyder EY: Neural stem cells display = extensive=20 tropism for pathology in adult brain: Evidence from=20 intracranial gliomas. Proc Natl Acad Sci = USA=20 97:12846-12851, 2000.

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2. Bao S, Wu Q, McLendon RE, Hao Y, Shi = Q,=20 Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN: Glioma = stem=20 cells promote radioresistance by preferential = activation of=20 the DNA damage response. Nature = 444:756-760,=20 2006.

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3. Bar EE, Chaudhry A, Lin A, Fan X, = Schreck K,=20 Matsui W, Piccirillo S, Vescovi AL, DiMeco F, Olivi A, = Eberhart CG: Cyclopamine-mediated hedgehog pathway = inhibition=20 depletes stem-like cancer cells in glioblastoma. = Stem=20 Cells 25:2524-2533, 2007.

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4. Calabrese C, Poppleton H, Kocak M, = Hogg TL,=20 Fuller C, Hamner B, Oh EY, Gaber MW, Finklestein D, = Allen M,=20 Frank A, Bayazitov IT, Zakharenko SS, Gajjar A, = Davidoff A,=20 Gilbertson RJ: A perivascular niche for brain tumor = stem=20 cells. Cancer Cell 11:69-82, 2007. =

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5. Chaichana KL, McGirt MJ, Frazier J, = Attenello=20 F, Guerrero-Cazares H, Qui=C3=B1ones-Hinojosa A: = Relationship of=20 glioblastoma multiforme to the lateral ventricles = predicts=20 survival following tumor resection. J=20 Neurooncol 89:219-224, 2008.

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6. Dahmane N, Sanchez P, Gitton Y, = Palma V, Sun=20 T, Beyna M, Weiner H, Ruiz i Altaba A: The Sonic = Hedgehog-Gli=20 pathway regulates dorsal brain growth and = tumorigenesis.=20 Development 128:5201-5212, 2001. =

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7. Dandy W: Removal of the right = cerebral=20 hemisphere for certain tumors with hemiplegia. = Jour=20 AMA 90:823-825, 1928.

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8. Galli R, Binda E, Orfanelli U, = Cipelletti B,=20 Gritti A, De Vitis S, Fiocco R, Foroni C, Dimeco F, = Vescovi A:=20 Isolation and characterization of tumorigenic, = stem-like=20 neural precursors from human glioblastoma. = Cancer=20 Res 64:7011-7021, 2004.

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9. Liu G, Yuan X, Zeng Z, Tunici P, Ng = H,=20 Abdulkadir IR, Lu L, Irvin D, Black KL, Yu JS: = Analysis of=20 gene expression and chemoresistance of CD133+ cancer = stem=20 cells in glioblastoma. Mol Cancer = 5:67, 2006.=20

Cited=20 Here... | PubMed

10. Nakamizo A, Marini F, Amano T, Khan = A,=20 Studeny M, Gumin J, Chen J, Hentschel S, Vecil G, = Dembinski J,=20 Andreeff M, Lang FF: Human bone marrow-derived = mesenchymal=20 stem cells in the treatment of gliomas. Cancer = Res 65:3307-3318, 2005.

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11. Piccirillo SG, Reynolds BA, Zanetti = N,=20 Lamorte G, Binda E, Broggi G, Brem H, Olivi A, Dimeco = F,=20 Vescovi AL: Bone morphogenetic proteins inhibit the=20 tumorigenic potential of human brain tumour-initiating = cells.=20 Nature 444:761-765, 2006.

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12. Singh SK, Clarke ID, Terasaki M, = Bonn VE,=20 Hawkins C, Squire J, Dirks PB: Identification of a = cancer stem=20 cell in human brain tumors. Cancer = Res=20 63:5821-5828, 2003.

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13. Singh SK, Hawkins C, Clarke ID, = Squire JA,=20 Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB: = Identification of human brain tumour initiating cells. = Nature 432:396-401, 2004.

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14. Zaidi HA, Kosztowski TA, DeMico F,=20 Qui=C3=B1ones-Hinojosa A: Origins and clinical = implications of the=20 brain tumor stem cell hypothesis. J=20 Neurooncol (in press).

Cited=20 Here...

Keywords:

Brain tumor; Brain tumor stem cell; = Cancer stem=20 cell, Stem cell

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Articles in PubMed by Samuel H. = Cheshier,=20 M.D., Ph.D.=20 This article in PubMed=20 Articles in Google Scholar by Samuel = H.=20 Cheshier, M.D., Ph.D.=20 Other=20 articles in this journal by Samuel H. Cheshier, = M.D.,=20 Ph.D.=20 =

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