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REVIEW
A NEUROSURGEON’S GUIDE TO STEM CELLS, CANCER
STEM CELLS, AND BRAIN TUMOR STEM CELLS
Samuel H. Cheshier, M.D., Ph.D.
Stanford Institute of Stem Cell Biology
and Regenerative Medicine,
Departments of Neurosurgery and
Developmental Biology,
Stanford University School of Medicine,
Stanford, California
M. Yashar S. Kalani, M.D., Ph.D.
Stanford Institute of Stem Cell Biology
and Regenerative Medicine,
Departments of Neurosurgery and
Developmental Biology,
Stanford University School of Medicine,
Stanford, California
Michael Lim, M.D.
Department of Neurosurgery,
The Johns Hopkins Hospital,
Baltimore, Maryland
Laurie Ailles, Ph.D.
Stanford Institute of Stem Cell Biology
and Regenerative Medicine,
Stanford University School of Medicine,
Stanford, California
Steven L. Huhn, M.D.
Department of Neurosurgery,
Stanford University School of Medicine,
Stanford, California,
Stem Cells, Inc.,
Palo Alto, California
Irving L. Weissman, M.D.
Stanford Institute of Stem Cell Biology
and Regenerative Medicine,
Department of Developmental Biology,
Stanford University School of Medicine,
Stanford, California
Reprint requests:
Irving L. Weissman, M.D.,
279 Campus Drive,
B257 Beckman Center,
Stanford, CA 94305.
Email: [email protected]
Received, June 22, 2008.
Accepted, April 1, 2009.
Copyright © 2009 by the
Congress of Neurological Surgeons
NEUROSURGERY
STEM CELLS AND their potential applications have become the forefront of scientific,
political, and ethical discourse. Whereas stem cells were long accepted as units of
development and evolution, it is now becoming increasingly clear that they are also
units of oncogenesis. Although the field of stem cell biology is expanding at an astounding rate, the data attained are not readily translatable for the physicians who may eventually deliver these tools to patients. Herein, we provide a brief review of stem cell and
cancer stem cell biology and highlight the scientific and clinical implications of recent
findings regarding the presence of cancer-forming stem cells in brain tumors.
KEY WORDS: Brain tumor, Brain tumor stem cell, Cancer stem cell, Stem cell
Neurosurgery 65:237–250, 2009
DOI: 10.1227/01.NEU.0000349921.14519.2A
R
ecent advancements in developmental
biology have brought stem cells into the
forefront of scientific, political, and ethical discussions. Most clinicians have an intuitive sense of what stem cells are, but the significance of stem cell biology for their practice
may not be fully appreciated. Recent experiments implicating stem cells as the source of
cancers have led to new questions about the
mechanisms of oncogenesis as well as new
treatment strategies. We provide a broad
overview of normal and cancer stem cell biology and highlight the scientific and clinical
implications of recent findings regarding the
presence of cancer-forming stem cells in brain
tumors.
STEM CELLS
Understanding how a multicellular system
develops from a single cell or cell type is one of
the central issues of modern biology. The
Greek philosopher Aristotle may have been the
first to introduce the idea of stem cells when he
debated whether the human embryo developed from a preformed individual (a homunculus) or from an undifferentiated form that
ABBREVIATIONS: AML, acute myelogenous
leukemia; BM, bone marrow; BTSC, brain tumor
stem cell; CNS, central nervous system; ES,
embryonic stem; GBM, glioblastoma multiforme;
HSC, hematopoietic stem cell; LT, long term; TS,
tumorsphere
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gradually became more specialized into the
many parts of a person. Although Aristotle
eventually favored the homunculus, debate
and controversy about human embryonic origins has continued into the modern era. It was
not until 1665, when Robert Hooke observed
the structure of cork bark under a microscope,
that an accurate description of the cellular
structure of an organism was obtained. From
that time forward, cells were known to be the
units of organization and function of tissues
and organs. Because organisms live much
longer than their differentiated cells, tissue and
organ regeneration is necessary. We now know
that most cells in a tissue or organ differentiate
when they divide. Therefore, in a particular
cellular lineage, the cells have a finite lifespan
unless replaced. Stem cells replace these lost
cells and are unique in that they self-renew
themselves, providing a perpetual source of
primitive precursors of the tissue or organ.
Till and McCulloch (90) developed the formal concept of stem cells in the 1960s through
a series of experiments involving the transplantation of limiting numbers of bone marrow (BM) cells, some of them chromosomally
marked, into irradiated mice (90, 104–106). At
low numbers, 1 in 7000 marrow cells gave
myeloerythroid (but not lymphoid) colonies 10
days later in the mouse spleen. Each colony
was derived from a single cell, and some
colonies produced more colony-forming cells;
rarely, these included lymphoid progeny. We
now call these blood colony-forming cells adult
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CHESHIER ET AL.
FIGURE 1. In the adult brain, stem cells reside in anatomic niches in the subventricular zone and the subgranular zone of the hippocampus. The neural
stem cell is a cell capable of unlimited (depicted by the solid arrow) selfrenewal and differentiation to produce committed neural progenitor cells.
tissue stem cells, this type being hematopoietic. From these
experiments, a general definition of stem cells emerged as cells
possessing the following 3 characteristics: 1) self-renewal, 2)
the ability to produce all cell types made in that tissue, and 3)
the ability to do so for a significant portion of the life of the host
(3). This definition has provided standard criteria to identify a
stem cell. Figure 1 illustrates the definition of a stem cell as it
pertains to the nervous system. The neural stem cell is a cell
with an unlimited self-renewal potential. Through asymmetric
cell division, the stem cell produces committed progeny or progenitors, which can also self-renew, but for a limited set of cell
divisions, and differentiate to produce the various cell types of
the central nervous system (CNS).
Vertebrates contain numerous types of stem cells, some operative only at specific points during development, whereas others function throughout the lifetime of an organism. The most
primitive, totipotent stem cells, are capable of giving rise to
both the embryonic and extraembryonic tissues of an organism. Totipotent stem cells include the fertilized egg and the cells
produced by the initial divisions of the ova. The product of
these cell divisions, which in mammals occurs before the entity
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Neural progenitor cells in turn are cells that also possess the ability to selfrenew, albeit to a more limited extent (depicted by the dashed arrow).
Progenitor cells are capable of giving rise to lineage-specific progenitors that
produce neurons, astrocytes, and oligodendrocytes.
implants in the uterus, is the blastocyst. The blastocyst contains
an outer sphere of trophoblast cells, capable of binding to and
implanting into the uterus, and of helping form the placenta
(Fig. 2). Within the blastocyst are 10 to 20 pluripotent cells called
the inner cell mass. Upon implantation, these inner mass cells
will participate in the production of all tissues and organs of the
developing embryo, then fetus, then born organism. Such
pluripotent cells can produce any differentiated cell in the body,
but are usually unable to form the trophoblast cells.
The best-known pluripotent stem cell is the embryonic stem
(ES) cell. Although they are called ES cells, this is a misnomer;
according to Dorland’s Medical Dictionary, the embryo stage of
development is well after the blastocyst stage: in humans, at
about 2 weeks when the long axis forms a primitive streak
until organogenesis at about 8 weeks when the fetal stage
begins. In mice, introduction of ES cells into another mouse
blastocyst allows chimerism of all tissues, including gametes;
when such mice are mated, one can produce strains of mice
from the ES donor. ES cells are obtained from the inner cell
mass of the blastocyst and exist for only a brief stage of embryonic development. These ES cells can be manipulated in vitro,
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A NEUROSURGEON’S GUIDE TO STEM CELLS
FIGURE 2. The union of a sperm and an egg produces the first true stem cell.
This totipotent cell is capable of repeated divisions to produce the pluripotent
blastocyst. Within the blastocyst reside some 20 cells, known as the inner cell
mass, capable of giving rise to all the cells of the organism. Within the blas-
in order to introduce new genes or disrupt preexisting genes
within the ES cell genome. The widest application of ES cells
has been to produce mice with targeted disruptions of specific
genes known as “knock-out” mice. Given the ability of ES cells
to produce any cell type of an adult organism, these cells offer
great potential to be the instruments of research that can eventually lead to therapeutics in numerous human disease states.
ES cell technology has already impacted scientific knowledge
to the degree that its pioneer, Dr. Mario Capecchi, has been
awarded a Nobel Prize. However, the fact that blastocysts
(which could potentially yield a viable organism) must be
destroyed to obtain these select cells, has led to controversy in
some segments of society. Part of the controversy derives from
stating that ES cells came from embryos. Others consider the
fertilized egg to have the same rights as born humans, and so
the designation would not be relevant for them. This controversy has helped spawn techniques designed to transfer the
nucleus to an egg with inhibitors of trophoblast development,
so that no implantable blastocyst would develop; or of an adult
cell into preexisting ES cells, as well as obtaining ES cells from
the 8-cell morula stage, mimicking preimplantation genetic
diagnosis that leaves the 7 cells capable of blastocyst develop-
NEUROSURGERY
tocyst, differential signaling environments allow for the formation of ectodermal, mesodermal, and endodermal stem cells that via committed differentiation steps produce tissue-specific stem cells such as those of the brain, skin,
blood, muscle, gut, and the lung.
ment. Other types of pluripotent stem cells include gonad precursors found in fetal tissue called embryonic germ cells
(another misnomer, embryonic cells from a fetus), and embryonic carcinoma cells (e.g., teratocarcinomas), which can produce all cell types, but in a highly disorganized manner. The
last major class of stem cells, multipotent stem cells, gives rise
to a limited number of cell types. These cells can be tissue (e.g.,
mesenchymal stem cells, skin stem cells, or blood stem cells) or
organ-specific cells (neural stem cells). Multipotent stem cells
can be found in most organs of the body and are responsible for
organ growth and maintenance.
The best-characterized multipotent stem cells are the hematopoietic stem cells (HSCs), which are responsible for the continuous production of blood cells. The relative ease of isolating
HSCs, as well as a wealth of in vitro and in vivo assays, has
allowed hematopoiesis to become an important model system
for the study of stem cell biology (57, 58). The prospective isolation of HSCs required development of assays for all blood
clonal outcomes, of monoclonal antibodies that subdivide the
marrow, and of high-speed cell sorters. (For a description of a
cocktail of antibodies to purify HSCs, see ref. 43 and references therein.)
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CHESHIER ET AL.
The advancement of monoclonal antibody technology coupled with fluorescence-activated cell sorting in the 1980s
allowed scientists to characterize hematopoietic cells based on
expression of specific cell surface proteins indicated by fluorescently labeled monoclonal antibodies against these proteins (18).
For example, specific combinations of cell surface molecules
could be used to isolate T cells, B cells, and myeloid cells. In
1988, using a panel of negatively selecting monoclonal antibodies that stain mature blood cells (lineage lo or neg), coupled
with 2 other positively selecting antibodies recognizing cell surface proteins that could enrich BM for HSC activity (Thy1.1 and
Sca-1), Spangrude et al. (87) utilized fluorescence-activated cell
sorting to isolate the first pure hematopoietic multipotent stem
and progenitor cell population from mouse BM. Later experiments showed the most primitive population of HSCs (the longterm [LT] HSCs) could be isolated to homogeneity by the addition of 2 makers: strict Lineage⫺ cells that simultaneously
express high levels of the tyrosine-kinase stem cell factor receptor, c-kit (60). The end result of these experiments was determination that the Lineage⫺, Sca-1+, c-kit+, Thy1.1lo expressing cells
were the only cells in the BM capable of giving rise to LT
myeloid-erythroid and lymphoid cells when transplanted into
irradiated mice. Thus, a predetermined combination of cell surface marker antibody staining (c-kit+, Lineage⫺, Sca-1+, Thy1.1lo)
could be used to isolate pure populations of LT-HSCs from
whole BM. This result allowed for direct analysis of these cells,
rather than an indirect analysis based on functional outcomes in
transplanted animals. For instance, early studies by researchers
such as Till and McCulloch certainly implied the existence of
HSCs, yet the cells were never analyzed directly. The prospective isolation of HSCs, and their multipotent/oligopotent progenitors (single cells that produce all or few blood cell types, but
do not self-renew) revealed that all stem cells are not equal in
that some cells can produce progeny almost indefinitely (“true”
stem cells), whereas other cells are more limited in their selfrenewal capacity and are more restricted in the types of cells
they can develop into (progenitor cells) (Fig. 3). The studies
purifying HSCs provided the foundation for later experiments
in which pure HSCs and blood cell lineage-specific progenitors
were subsequently isolated in both mice and humans (83).
The isolation of each cell type of blood (stem cells, restricted
progenitors, mature cells) has allowed scientists to ascertain
the hierarchical organization of the hematopoietic system based
on proliferation, differentiation, and self-renewal, and identify
important other cell types and signaling factors essential for the
process of self-renewal and commitment (Fig. 3). Such hierarchical organization exists in solid organ systems, including the
CNS (Fig. 1) (7, 15, 23, 24, 33, 35, 46, 71, 79). The successful balance of self-renewal, proliferation, and differentiation requires
a high degree of fidelity, and disturbances in the organization
can lead to disease.
NEURAL STEM CELLS
Until recently, it was unclear if the principal hierarchical
organization of the hematopoietic system applied to the CNS.
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In the hematopoietic system, multipotent stem cells capable of
extensive proliferation and self-renewal give rise to a series of
progressively more lineage-restricted progenitors with less proliferative capacity (Fig. 3). There is now growing evidence that
the CNS has a cellular organization based on self-renewal and
differentiation similar to hematopoiesis (Fig. 1). The central
and historical dogma of CNS biology was that little if any
turnover occurs within the CNS of mature vertebrates, especially in terms of new neuronal growth. This supposition was
first challenged by a study demonstrating that the hormonally
responsive growth of the hyperstriatum ventrale, pars caudalis
in canaries was in part attributable to new neuronal growth
derived from a rapidly cycling progenitor cell population
located within the subventricular zone (34). More recently,
long-term cultures of human and rodent CNS tissues have
revealed the existence of cells as a population capable of maintaining the continuous production of neurons, oligodendrocytes, and astrocytes; in some studies, they contained retroviral
tagged clonal precursors of all 3 lineages (17, 56, 73, 75, 99).
Indeed, several groups have devised methods for the isolation
of such cells from patients (102). This technique has great
potential for obtaining, harvesting, manipulating, and transplantation of these cells into patients. Although these progenitor/stem cells can grow in monolayers, their most distinctive in
vitro characteristic is their ability to form round clusters of selfadherent cells termed neurospheres (75, 99). Single cells derived
from neurospheres could produce both neurons and glia when
transferred into rodent brains. These in vivo experiments
demonstrated that a clonal population of CNS cells derived
from neurospheres in vitro contained neural tissue-specific progenitor/stem cells (75, 93, 99). In the adult human brain, neurospheres containing CNS stem cells have now been isolated
from the periventricular area of the forebrain lateral ventricles
(subventricular zone) and the dentate gyrus of the hippocampus (6, 24). Neurospheres have also been derived from adult
rats and human fetuses (6, 31, 46, 71, 82, 96, 97).
Uchida et al. (93) achieved the first prospective isolation of
human CNS stem cells when they applied the experimental
principles of HSC isolation to the characterization of cell suspensions made from the fetal subventricular zone. Fluorescenceactivated cell sorting was used to separate cells that had the
specific cell surface marker combination: CD133 + , 5E12 + ,
CD24neg/lo, CD45neg (blood cell lineage), and CD34neg (blood
vessel lineage and itinerant HSCs). Neurospheres initiated from
single clones of sorted cells of the above phenotype were able to
form new neurospheres in culture, and could differentiate into
neurons, astrocytes, and oligodendrocytes (trilineage differentiation) in vitro. The same cells demonstrated engraftment, migration, and differentiation when transplanted into the brains of
newborn immunocompromised mice (88, 93). Putative CNS
stem cells based on the above phenotype have already demonstrated potential clinical utility. These cells can halt the formation of neurological defects when injected into the brains of a
mutant mice strain that normally develop lysosomal storage
diseases (51) of the CNS such Batten disease (unpublished
observations), improve motor activity when injected into trau-
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A NEUROSURGEON’S GUIDE TO STEM CELLS
FIGURE 3. A wealth of information from the study of hematopoietic stem
cells suggests that an intricate cellular hierarchy exists whereby a hematopoietic stem cell commits to lineage-restricted stem cells and eventually to the
various cell types of the blood. Within the bone marrow, support cells, such
matically damaged spinal cords of mice (20), and migrate and
produce new neurons in ischemic rodent brain (49). Using different combinations of cell surface markers and fluorescentprotein reporter constructs, fluorescence-activated cell sorting
has also been used to isolate CNS stem cell populations from
mice (16, 52, 76).
The prospective isolation of CNS stem cells will greatly
expand our knowledge of both normal and abnormal CNS
development. The development of CNS stem cell biology may
lead to a better understanding of lineage-restricted CNS progenitors and the potential for therapeutic use. Undoubtedly,
knowledge gained from this endeavor, a better ability to
manipulate and dictate the fate of progenitor cells into coher-
NEUROSURGERY
as the stromal cells and pericytes, produce necessary signaling environments
that allow for both the maintenance of hematopoietic stem cells and their differentiation to myeloid and lymphoid cell types.
ent, functional neurological units and knowledge of migratory
patterns of normal NSCs, and the ability for effective delivery
of therapeutic genes to human neurological malignancies will
greatly expand the neuro-clinician’s arsenal to combat devastating diseases of the CNS.
The identification of CNS stem cells may also provide
insights into the development of primary brain tumors.
CANCER STEM CELLS
Cancer biology remains one of the most intensely studied
areas of scientific discourse. Although basic research has led to
a wealth of information regarding the molecular mechanisms
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CHESHIER ET AL.
responsible for the transformation of normal cells into
cancers, our concept of the
cellular biology of neoplasms
has remained poorly illuminated. The cellular constituents of solid neoplasms in clude both tumor cells and
non-tumor stromal elements
such as blood vessels, fibroblasts, hematopoietic cells,
and nontransformed cells
from the tissue of origin. Until
recently, the neoplastic tumor
cells were assumed to be a relatively homogeneous group
of cells, each capable of producing more cancer cells
within the tumor and as well
as producing metastases.
Investigations of the clonality
of cancers verified that most
neoplasms result from the
FIGURE 4. The vascular niche hypothesis proposes that in addition to the subventricular zone and the subgranular
malignant transformation of a
zone of the hippocampus, stem cells are housed adjacent to endothelial progenitor cells (EPCs). In the local signaling
single cell into a tumor cell
environments, or niches, produced by the endothelial cells, neural stem cells are capable of asymmetric division to pro(26, 27, 63). This hypothesis
duce other neural stem cells as well as committed progeny that eventually produce neurons, astrocytes, and oligodenholds that the transformed
drocytes. The process of self-renewal and commitment are tightly regulated and ensure that neoplastic growth does
not take place (left side). The tumor literature supports the existence of a similar vascular niche in brain tumors.
cell could simply replicate,
Cancer stem cells have been observed to reside in close association with endothelial cells where they are likely to make
producing new tumor cells
use of the same signaling pathways that maintain normal stem cells (right side).
with relatively equivalent biological properties. Evidence in
deregulation of the balance between proliferation and differensupport of this model is abundant in both retinoblastoma and
tiation, resulting in uncontrolled tumor growth and incomplete
colon cancer where the accumulation of sequential mutations in
differentiation (Fig. 4, right). Cancer stem cells, similarly
the cell cycle machinery causes cancerous growth. This stanhoused adjacent to endothelial cells, proliferate and produce
dard model of cancer formation was further reinforced by the
both other cancer stem cells and non-cancer stem cell tumor
intensive utilization of tumor cell lines in the context of cancer
cells. The leaky nature of blood vessels in a tumor allows for an
research. However, several experimental results conflicted with
abundance of inflammatory and BM-derived progenitor cells
the predictions of the standard model. Investigations have
within the mass of the tumor. In addition, and almost preshown that single cancer cells did not grow uniformly well in
dictably, cancer and stem cells share many molecular mechacell culture, cancer cells were not equally sensitive to theranisms mediating these complex processes (100, 101). For
peutic agents both in vitro and in vivo, and large numbers of
instance, the cell cycle machinery, self-renewal genes, and
cancer cells were usually required to produce tumors in transgrowth factors necessary for normal stem cell existence are the
plant animal models. Although it is possible that the variabilsame genes utilized by many cancer cells. Furthermore, both
ity among cancer cells in these studies resulted from inefficienstem cells and cancer cells can be transplanted into animal
cies of the assays, the observations also suggest that there are
models recapitulating normal stem cell regenerative function in
intrinsic differences between individual tumor cells. The differthe case of stem cells and tumor development with cancer cells.
ences seen among cancer cells may be explained in part by the
The prominent similarities between cancer and normal stem
principles of CNS stem cell biology.
cells have led to the development of the Cancer Stem Cell
The overlap between stem cell biology and cancer biology is
Hypothesis as proposed by Reya et al. (74). This hypothesis
striking. Both tissue stem cells and cancer cells share the abilconsists of 2 complementary and non–mutually exclusive comity to proliferate, self-renew, and give rise to differentiated
ponents. The first component postulates that normal tissue
progeny. In the case of the tissue stem cell, the balance between
stem cells are the target for transforming mutations and succesdifferentiation and proliferation must be highly regulated (Fig.
sive insults result in the eventual formation of a tumor. The sec4, left). Under normal conditions, neural stem cells residing
ond component is that within every cancer there exists a speadjacent to vascular endothelium differentiate to produce neucific subset of cells that continuously give rise to all the other
ronal and glial progeny. In the case of cancer, there is marked
242 | VOLUME 65 | NUMBER 2 | AUGUST 2009
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A NEUROSURGEON’S GUIDE TO STEM CELLS
cancer cells. This subset of tumor cells are the cancer stem cells
and are the only cells within a tumor that possess the ability to
self-renew, continuously proliferate, and can give rise to metastases. Although some tumor cells may have some proliferative
capability, only the cancer stem cell can reproduce itself and
another nonreplicating tumor cell. Furthermore, because
tumors are clonogenic, all of the heterogeneity in a tumor is
produced by the cancer stem cells. Although some of the tumor
cell diversity can result from progressive mutagenesis, there is
ample evidence supporting that the heterogeneity within cancers reflects aspects of normal differentiation processes, which
would be expected if cancer stem cells are giving rise to differentiated progeny (28, 29, 39). In other words, the histobiological properties of a cancer tend to reflect its tissue of origin
because the cancer stem cell and its progeny continue to recapitulate the phenotype of the original tissue, although in a disorganized and unproductive manner. Thus, a tumor can be
viewed as a dysfunctional organ system, in which the cancer
stem cell gives rise to phenotypically diverse (albeit dysfunctional) progeny that have limited proliferative potential and
no ability for self-renewal.
It should be noted that recent studies by Morrison et al. (72)
question some of the most important components of the cancer
stem cell hypothesis. Using melanoma as a model, the group
led by Morrison showed that nearly 1 in 4 cells possessed proliferative ability and spawned cancer. Although the final verdict has yet to be determined, it is likely that the cancer stem
cell hypothesis is applicable to some tumors and not to others,
such as melanoma.
Mutations Accumulating in Normal Stem Cells
Lead to Cancer
A well-established concept of cancer biology is that over time
a series of genetic mutations leads to the malignant transformation of a normal cell into a cancer cell. These mutations result in
the disruption of the cellular machinery controlling the cell
cycle, cell growth and inhibition, apoptosis, immune surveillance, genomic stability, differentiation, and self-renewal (65,
100). Mutations can propagate only if a cell divides, thus in cellular terms, time is synonymous with proliferative events, and
mutations occur in the context of cell divisions occurring frequently during development and more slowly in a mature
organism. This in part explains why most cancers cluster in the
pediatric group (in which more cells are dividing per unit time)
or the geriatric group (in which slowly dividing cells have been
undergoing divisions for a long period of time). The idea that
normal tissue stem cells accumulate genetic mutations leading
to cancer formation came about as a direct extension of studies
describing the cellular organization of hematopoietic cells. In
both fetal and adult tissues of mice and humans, only LT-HSCs
are capable of the continued production of myeloid-erythroid
cells (60–62). Unlike LT-HSCs that have a lifespan measured in
years, the immediate progenitors of HSCs, short-term HSCs,
myeloid restricted progenitors, and lymphoid restricted progenitors, only have lifespans of weeks to months (62). Thus,
only LT-HSCs possess the proliferative capacity and lifespan
NEUROSURGERY
necessary to accumulate the threshold of mutations leading to
cancer. Put more simply, the longevity of the tissue stem cell also
increases the risk and exposure of the cell to transforming mutations. Experimental evidence for this idea was noted in animal
models of leukemia in which mice in pre-leukemic states could
transfer leukemia only when HSCs were transplanted into
irradiated hosts (59). Miyamoto et al. (59) postulated that if
LT-HSCs were harboring mutations, then leukemic patients in
complete remission should have mutations in their remaining
HSCs because the more committed short-term HSCs are derived
from the more primitive LT-HSCs. These investigators analyzed
the LT-HSCs from Hiroshima survivors who developed acute
myelogenous leukemia (AML) and were in long-term remission. They found that a significant fraction of LT-HSCs in these
patients continued to harbor the AML pathoneumonic AML1ETO translocation mutation, but because other mutations promoting deregulated growth were not present in these patients,
they remained in remission. The mutated LT-HSC was indistinguishable from the LT-HSC without the translocation and displayed no evidence of deregulated growth in vitro.
It should be noted that, despite the proposed necessity of
mutation accumulation in normal stem cells for cancer formation, it is very possible that a transforming event (or events) can
occur in a more mature progenitor downstream of the long-lived
stem cells, or that the effects of the mutations that accumulate in
the stem cells are manifested in a downstream progenitor. This
final transformation of a progenitor cell has experimental evidence in mouse and human leukemogenesis and neuroepithelial
tumor formation (40, 41, 44, 45, 91, 111). There is also experimental evidence suggesting that genetic alterations within lymphocytes can lead to mouse T cell leukemia independently from
HSCs (110). However, this result is not inconsistent with the
stem cell hypothesis because, upon antigen stimulation, lymphocytes regain the stem cell properties of proliferation and selfrenewal. Thus, a lymphocyte can be viewed as a unipotent stem
cell capable of giving rise to progeny that can be used in an
immune reaction or to produce new lymphocytes with different
antigen binding properties through the process of affinity maturation. The idea of stem cells as the focal point of cancer mutations is a striking contrast to more traditional models in which
any cell can be subject to mutations leading to cancer. However,
it is more parsimonious to postulate that a cell possessing the
unique ability for self-renewal and extensive proliferation is better suited to forming a tumor than a terminally differentiated cell
lacking these properties.
Cancer Stem Cells Establish and Propagate Tumors
The second component of the cancer stem cell theory postulates that a specific subset of tumor cells, the cancer stem cells,
are the only cells capable of the continued production of tumor
cells (74). Despite the assumed homogeneity of cancer cells in
the standard model of cancer cell organization, the reality of
tumors is quite different. Histologically, tumor cells can display
a large variation in appearance, often resembling the spectrum
of differentiated cell types of the tissue from which the tumor
arises. Also, only a very limited number of cancer cells from
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CHESHIER ET AL.
hematopoietic and solid malignancies can grow in vitro or in
vivo in animal transplant models (28, 29, 36, 37, 39, 86).
Investigations have shown that, in the case of hematopoietic
and some solid malignancies, only 1 in 100 to 1 in 10 000 primary tumor cells are capable of reproducing the tumor in vivo
(4, 5, 14, 60). The standard model would postulate that all cancer cells are equivalent, and that each cell has a low probability of proliferating in the setting of the experimental conditions. The cancer stem cell theory would posit that only the
cancer stem cell subset can give rise to new cells, and because
this population is rare, their activity on a per cell basis is rare.
The cancer stem cell hypothesis predicts that prospectively isolating these rare subsets of cells from the non-stem cell cancer
cell would result in markedly different cellular proliferation.
This stem cell subset should be highly enriched for in vivo and
in vitro tumor growth, and the non-stem cell fraction should be
highly depleted of these abilities.
The experimental confirmation of the cancer stem cell
hypothesis was first achieved by Bonnet and Dick (14) for
AML. They postulated that because cancer stem cells are
derived from normal stem cells, they should have similar cell
surface phenotypes. Using a panel of monoclonal antibodies
used to prospectively isolate normal human HSCs, they determined that patient-derived AML cells with the cell surface
combination of CD34+, CD38⫺, Lineage⫺ were the only cells
capable of transferring disease to immunocompromised mice.
These AML stem cells represented only a small yet variable
fraction of all tumor cells. Later investigations demonstrated
that the AML stem cells were CD90⫺, which differs from normal human HSCs that are CD90+ (1, 2). Thus, the AML stem
cell had an overlapping, but distinct, cell surface phenotype
compared with its normal counterpart. A growing number of
investigators have isolated cancer stem cells from a number of
leukemias including chronic myelogenous leukemia, blast crisis chronic myelogenous leukemia, and myeloproliferative disorders (30, 42, 45). In each case, the cancer stem cell demonstrates the unique property of serial transplantation compared
with the non-cancer stem cells derived from the same tumor.
In solid tumors, the presence of cancer stem cells was confirmed when Al-Hajj et al. (4, 5) prospectively isolated a rare
subset of human breast cancer cells with the cell surface phenotype CD44+, CD24neg/lo, Lineage⫺. Cells with this phenotype
were the only cells capable of forming new tumors upon injection into the mammary glands of immunocompromised mice.
Since then, a growing number of mouse and human solid
tumors have been fractionated on the basis of cell surface
marker expression, and the existence of cancer stem cells confirmed experimentally including human neuroepithelial
tumors, head and neck squamous cell carcinomas, and colon
cancer (19, 21, 53, 70, 85).
BRAIN TUMOR STEM CELLS
The cancer stem cells relevant to a neurosurgical practice are
those that initiate tumors of neuroepithelial origin. Bailey and
Cushing (8) were the first to articulate the concept of brain
244 | VOLUME 65 | NUMBER 2 | AUGUST 2009
tumor arising from a progenitor cell. They proposed that
tumors were derived from progenitor cells residing in the
periventricular zone. The first experimental evidence suggesting the existence of brain tumor stem cells (BTSC) was published by Hemmati et al. in 2003 (38), although data dating
back to the 1980s had suggested the existence of such cells (77,
78). It is known that brain tumor cells can grow in clusters in
defined media containing epithelial growth factor and fibroblast growth factor-2. These specialized clusters are referred to
as tumorspheres (TS) and these culture-derived spheres are
very similar to in vitro sphere formation with normal CNS
stem cells, meaning they contain a conglomerate of stem and
progenitor cells with committed neurons, glia, and oligodendrocytes. The formation of a tumor or neurosphere is a culture
phenomenon, but represents an interesting mechanism for creating differential signaling environments allowing for specialization of cells within the sphere. Hemmati et al. demonstrated
that only a rare fraction of cells cultured from medulloblastoma and ependymoma could form TSs. Furthermore, cells
from TSs could give rise to more spheres in culture and were
capable of forming tumors when transplanted into the brains of
immunocompromised mice. The investigation demonstrated
that only a rare subpopulation of cells within these tumors
were capable of proliferation and self-renewal. These properties
along with tumor engraftment with in vivo transplantation
form the hallmark characteristics of cancer stem cells. Similar
experiments by other investigators confirmed the presence of a
rare subset of TSs initiating glioblastoma multiforme (GBM)
cells that were also capable of tumor formation upon xenograft
transplantation (32, 92, 109).
A special cell population with tumor-forming ability (i.e.,
tumorigenicity) has also been prospectively isolated from
glioma cell lines (50, 85). C6 glioma cells growing in vitro contain a rare subset of cells that can be separated by fluorescenceactivated cell sorting on the basis of the cell’s ability to efflux
Hoechst, the vital deoxyribonucleic acid staining dye (50). The
Hoechst effluxing cells, termed side population, seemed to contain the in vitro and in vivo growth potential of the cell line.
This information suggests that a cancer stem cell or progenitor
is also active in a well-established tumor cell line. Later experiments confirmed that the dye exclusion ability in the glioma
cell line was attributable to the presence of multidrug resistance
transporters on the cell surface (66). This is an interesting finding given that multidrug resistance is known to be highly
expressed in other normal tissue stem cell populations, including HSCs (13, 25, 94).
The identification of a cell surface marker, which could
prospectively isolate cancer stem cell–containing populations
from primary tumor specimens, was first achieved by Singh
et al. (84, 85) in a series of experiments published in 2004. Singh
et al. used the normal CNS stem cell surface antigen, CD133, to
fractionate fresh medulloblastoma and GBM specimens. The
investigation demonstrated that CD133+ expression was measured in a minority of tumor cells, but were also highly enriched
for the ability to produce TSs in vitro (84). Subsequent experiments demonstrated that these CD133+ tumor cells were the
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A NEUROSURGEON’S GUIDE TO STEM CELLS
only cells capable of forming new tumors when implanted into
the brains of immunocompromised mice (85). Singh et al.
showed that as few as 100 CD133+ cells were capable of forming tumors in vivo, whereas 100 000 CD133⫺ cells did not result
in tumor formation in vivo. CD133+ has also been recently used
to isolate BTSCs from TSs derived from ependymoma cultures
(89). These studies represent the first significant experimental
evidence of possible BTSCs.
Further experimentation is required to confirm these results
and subsequent studies are needed to then fully characterize
the tumor stem cell. Thus far, the results are based on the utilization of only a single cell surface marker, CD133, which is
also shared by HSCs and normal tissue CNS stem cells.
However, no stem cell population has been prospectively isolated to relative homogeneity on the basis of a single cell surface marker. In fact, neither the experiment by Singh et al. nor
any subsequent study utilizing CD133 as a marker for BTSCs
included an in vivo limit dilution experiment comparing sorted
cell populations with whole tumor, which is currently the only
method able to ascertain the relative purity of any given sorted
population.
In general, multiple markers are required to purify tissue
stem cells. In the case of HSCs, 10 to 15 separate monoclonal
antibodies are needed to isolate a pure stem cell population,
and in the case of human fetal CNS stem cells, a combination
of at least 4 antibodies has been necessary to isolate a relatively
homogeneous stem cell population (61, 93). The need for cell
purity is not a trivial matter, as this homogeneity is critical for
the accurate determination of gene and protein expression patterns specific for BTSCs. In the case of leukemia whereby the
data are strong and multiple markers are available, it is possible to isolate culprit stem cells to purity. Because of the lack of
reproducible markers, identification of stem cells for brain
tumors, most notably GBM, has been very difficult. In these
cases in which markers are not available, larger cell numbers
including non-cancer stem cells, have been injected to reproduce growth of the tumor. With identification of other markers,
it will be possible to purify brain tumor–initiating stem cells
and reduce input numbers necessary to generate tumors in
xenografts. These BTSC-specific gene and protein profiles will
be the foundation for the development of BTSC-specific therapies as well as help determine the relationship of BTSCs to
their normal CNS stem cell counterparts.
Using a different marker, Ogden et al. (64) separated human
GBM on the basis of cell surface marker A2B5 and CD133. The
key finding of this study was to note that tumor cell formation
segregated into the A2B5+ fraction. However, in their study,
both A2B5+ CD133+ and A2B5+ CD133⫺ cells could give rise to
tumors in a potent manner when transplanted into the brains of
immunocompromised host mice. Several groups have questioned the validity of CD133 as a BTSC marker (12, 47). Furthermore, our own analysis of patient GBM and medulloblastoma
cell surface protein expression revealed that a significant number of these cells do not express detectable levels CD133 protein
(unpublished results). It could be hypothesized that cell surface antigens associated with tumor stem cell markers should be
NEUROSURGERY
TABLE 1. Properties of neural stem cells and cancer stem cellsa
Neural stem cells
Cancer stem cells
Cell surface marker
CD133
CD133; A2B5
Self-renewal
Unlimited
Unlimited
Proliferation
Low
Variable
Location
SVZ, SGZ of
hippocampus
Variable
Proximity to vessel
Adjacent
Adjacent
Signaling pathway
regulating fate
EGF, bFGF, Wnt,
Shh, TGFβ
EGF, bFGF, PDGF,
Wnt, Shh, TGFβ
Chemosensitivity
Sensitive
Variable with some
resistance
Radiation
Sensitive
Variable with some
resistance
a
SVZ, subventricular zone; SGZ, subgranular zone; EGF, epidermal growth factor;
bFGF, basic fibroblast growth factor; Shh, sonic hedgehog; TGF, transforming growth
factor.
measurably expressed across the majority of patient specimens.
Furthermore, in vivo analysis of CD133+ and CD133⫺ cells
derived from adult GBM tumors demonstrated growth in both
populations, and at least 2 instances wherein the CD133⫺ cells
formed large tumors in a mouse xenotransplant model (unpublished observations, Weissman laboratory). We are not suggesting that CD133 is not a potential BTSC marker, but we stipulate
that CD133 may be a reliable marker within a tumor sample, but
not necessarily between tumor samples. A more durable marker
should be able to prospectively isolate BTSCs across the majority of brain tumor samples. At this time, the sum of all experiments represents only a relatively few number of tumor samples, thus more experiments with careful designs and controls
are needed to discover multiple markers that can be utilized to
prospectively isolate BTSCs.
Since the discovery of BTSCs, a number of laboratories have
investigated mechanisms specifically regulating the biology of
these cells as opposed to whole tumors. CNS stem cells and
BTSCs share many similarities (Table 1). Similar to normal CNS
stem cells, BTSCs reside next to blood vessels (vascular niche
hypothesis) (95). The study of normal stem cells has implicated
members of Wnt, sonic hedgehog, and transforming growth
factor-β as important regulators of stem cell growth and development (11, 55). Interestingly, the vascular niche has been
shown to produce many of these factors (95). A recent study
from the Hopkins group has shown the importance of the
transforming growth factor-β family member bone morphogenetic protein to the regulation of BTSCs (69). They demonstrated that activation of bone morphogenetic protein 4 greatly
inhibits the growth of tumors via its direct effect on reducing
BTSC growth. In a different experiment, abrogation of the sonic
hedgehog pathway, an important developmental signaling
pathway, greatly reduced the ability of GBM tumor spheres to
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CHESHIER ET AL.
grow tumor in vivo, and greatly reduced the sphere-forming
ability of CD133+ GBM cells (10). Sonic hedgehog is implicated
in maintaining cells in an undifferentiated state, and molecules
capable of blocking this signal can potentially induce differentiation of the BTSCs. Similarly, the Wnt signaling pathway has
been shown to be an important regulator of neural stem cell
self-renewal (48) and may serve a similar role in brain tumors.
Furthermore, just as normal stem cells are relatively resistant to
the effects of irradiation and chemotherapy, BTSCs seem to
possess similar properties. For instance, Rich et al. (9) demonstrated that CD133+ GBM cells were highly radio resistant and
this resistance was mediated by the up-regulation of DNA
repair mechanisms. Also, the ability of GBM tumor spheres to
grow in vitro and in vivo was inhibited to a lesser degree than
control cells when exposed to a number of standard chemotherapeutic agents including temozolomide (54, 77).
Is cancerous growth the result of proliferation of a stem cell
or a more committed progenitor? In most systems, it is not
clear whether the culprit involved in oncogenesis is a “stem
cell” or a “progenitor cell.” Part of the problem arises from the
fact that the definitions of a stem and progenitor cell are functional; the lack of markers allowing for the prospective isolation
of the normal and cancerous CNS stem cell further complicates
studies of the stem versus progenitor origin of brain tumors. In
the case of medulloblastoma, 2 recent articles (80, 107) illustrate
that accumulation of mutations within a specific progenitor is
responsible for the formation and progression of this tumor.
The authors used labeling experiments to mark specific Olig2
progenitor populations and showed that accumulation of
mutations within this and only this progenitor population
results in medulloblastoma formation. It is important to note
that evidence in other systems is sparse at best. It is possible
that in some tumors accumulation of mutations in a progenitor
causes tumor formation, whereas in others mutations in the
parent stem cell are the cause; the jury is still out on this topic.
These findings underscore the importance of the types of data
that can be derived from the study of brain cancers from a stem
cell perspective.
WHY EVERY NEUROSURGEON SHOULD
CARE ABOUT BTSCS
Despite advances in the molecular biology of cancer, surgical
technique, radiotherapy, and chemotherapy, limited progress
has been made in reducing the mortality associated with CNS
tumors. The historic model of cancer holds that most tumor
cells are relatively homogeneous with respect to proliferative
and self-renewal potentials. The cancer stem cell theory suggests that this model is inaccurate and this may account for
some failures in cancer treatment. Specifically, current treatment
modalities were designed to measure success by reductions in
tumor bulk and volume; however, in this approach, there is no
way to confirm that the cancer stem cells, if present, are being
eliminated. Assuming that the cancer stem cell theory is accurate, then debulking tumors is a less fruitful task than the identification and elimination of the BTSCs in guaranteeing the elim-
246 | VOLUME 65 | NUMBER 2 | AUGUST 2009
ination of the malignancy. The prospective isolation of BTSCs
will provide better targets for the development of new therapies
and to new ways to measure treatment efficacy. New agents
could target the molecular mechanisms supporting the growth
of these cells rather than the confusing multitude of pathways
present within normal cells or the bulk of nonproliferating
tumor cells. For example, prospective isolation of BTSCs may
allow for design of pharmaceuticals targeting cancer stem
cell–specific signaling pathways (108). In addition, gene and
protein array analysis (22, 68, 81), as well as high-throughput
screening of biological and synthesized molecules, could lead to
small molecule and immune-based therapies (67, 98) directed
specifically against unique BTSC antigens. Efforts using array
and immune-based technologies are already in preclinical trials
for hematologic malignancies. Given the devastating nature of
neurological malignancies, the interval between isolation of
pure BTSCs and phase I trials will hopefully be short. Currently,
new techniques in molecular imaging and biomarkers in combination with imaging protocols are beginning to help quantify
and locate BTSCs before, during, and after treatment (103).
What is the role of the neurosurgeon in the setting of these
potential BTSC-specific therapies? Neurosurgeons are currently
at the forefront of the research being performed to isolate and
characterize these cells. The collection of patient tumor samples is the first step in any study attempting to identify BTSCs,
and the role of the interested neurosurgeon in this process is
invaluable. The surgical technique undertaken will help determine the integrity of the tumor specimen and thus ultimately
the quality and quantity of potential BTSCs. Surgery will remain
the mainstay of initial treatment of malignant neuroepithelial
tumors for the foreseeable future, but the development of potential local therapies directed against residual BTSCs will also fall
within the neurosurgeon’s realm. The ability to rapidly characterize the gene and protein profiles of tumors and perhaps the
isolation of tumor stem cells has great potential to yield patientspecific therapies. Future therapies could be based on the
response seen for individual and patient-specific BTSC testing
when screened against conventional and experimental agents.
The field of cancer and stem cell biology will no doubt contribute to improved understanding of disease and potential new
treatments. An exciting future awaits neurosurgeons as practices evolve into a combination of surgical and cell therapeutics,
resulting in better outcomes for patients with brain cancer.
Disclosure
Samuel H. Cheshier, M.D., Ph.D., is a fellow of the Giannini Foundation and
a Van Wagner Fellow. M. Yashar S. Kalani, M.D., Ph.D., is a fellow of the Paul &
Daisy Soros Foundation, the Hanbery Society, and of the Howard Hughes
Medical Institute. Steven L. Huhn, M.D., is an investigator at Stem Cells, Inc.
Irving L. Weissman, M.D., is a consultant for Stem Cells, Inc.
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Acknowledgments
Samuel H. Cheshier, M.D., Ph.D., and M. Yashar S. Kalani, M.D., Ph.D., contributed equally to this article. We thank Kristin Cox, B.A., for editing the manuscript and Bo Aye, B.A., of Aye Media Group for help with the figures.
COMMENTS
I
n this timely review by the laboratory led by the modern father of the
cancer stem cell hypothesis, the reader will find both historical as well
as current concepts that are driving the experimental work in this very
exciting area of biological medicine. The hypothesis that not all cells in
a cancer possess the same capacity to renew the tumor has stirred the
imagination of scientists to devise new experiments and therapeutic
targets, and thus it deserves to be considered as “paradigm-shifting.”
The main problem relates to how one identifies a cell as being a cancer
stem cell: in fact, recent literature has questioned whether the hypothesis is valid or whether some of the findings that appear to be validating it depend on the animal model used to define such stem cells rather
than being an intrinsic property of the stem cell itself. Regardless, scientific discovery in biological systems almost never provides unequivocal answers; the important issue is that the cancer stem cell hypothesis is providing a new framework that recognizes intrinsic differences
and growth capacities among different cells in a cancer, thus simplifying our understanding of why some cells in a neoplastic mass appear
to be more resistant to therapy than others.
E. Antonio Chiocca
Columbus, Ohio
I
n this review, Cheshier et al. provide a neurosurgeon’s overview of
stem cells, especially leading to the potential for targeted treatments in
primary brain tumors. A considerable amount of basic information is
provided for the neurosurgeon, including the important definition of a
stem cell, i.e., a cell capable of self-renewal, producing all cell types.
They explore the difference between stem cells and multipotential cells,
which may be important for repair where not all types of cells are made.
The authors then go on to explain that the term “embryonic stem cells”
is a misnomer, as these are actually taken from the blastocyst stage,
which is 2 weeks earlier than the embryonic stage of development. The
review then moves on to discuss the idea of using monoclonal antibodies for cell sorting. This concept, coupled with fluorescence-activated
cell sorting in the 1980s, allowed us to develop more and more knowledge by first isolating stem cells from hematopoietic lines and, more
recently, by using this methodology in studying brain cancer.
The concept, of course, is that many cancers may not be adult cells
gone bad, but rather the self-renewing stem cells within our tissue that
go bad. The difference is important as we discover invariable brain
monoclonal markers, in that there may be a selective signature to each
person’s tumor. Therefore, individual immunotargeted therapies may
become possible. From these sorts of studies we have been able to
develop particular lines of individual tumors. Very recent studies have
suggested that we are able to identify characteristics more susceptible
to one chemotherapy or radiation over another. In this view, the true
VOLUME 65 | NUMBER 2 | AUGUST 2009 | 249
CHESHIER ET AL.
targets for brain cancer are not all the cells, as presently targeted, but
rather particular cells within the tumor where targeted therapies may
decrease toxicity and give hope for successful therapies.
Robert J. Dempsey
Madison, Wisconsin
W
e read with great interest the article by Cheshier et al., in which
the authors outline the history of stem cells and summarize
recent evidence supporting the existence of brain tumor stem cells
(BTSCs). The review brings important attention to the nascent field of
BTSC biology, where several groups have now shown that only a few
cells within the tumor parenchyma are responsible for perpetuating the
growth of malignant tissue (8, 12, 13). We would like to emphasize
here a few additional points to underline the importance of the BTSC
hypothesis to the neurosurgeon and, in light of recent evidence, examine why current treatment modalities fail to manage the growth and
spread of neurological malignancies.
The BTSC hypothesis suggests that unless all cancer-regenerating
stem cells are destroyed, even if the majority of the tumor stroma is
debulked, the disease will recur (5). Today’s standard treatment paradigms are nonspecific and fail to target the highly metastatic BTSC
population within a tumor which is responsible for tumor regrowth (5).
Rather, these modalities only destroy the bulk of the tumor stromal
cells, which are likely nonregenerating. Walter Dandy was the first to
note the recurrence of malignant glioma in the contralateral hemisphere
after radical hemispherectomy (7), suggesting that, despite radical
resection, micrometastatic nests of BTSCs migrate, divide, and cause
the malignancy to recur at a nearby site.
Many emerging reports now suggest that BTSCs are exquisitely
resistant to chemotherapy and radiation, more so than their tumor
stroma counterparts. For example, Liu et al. (9) have shown that BTSCs
upregulate many antiapoptotic genes and are less susceptible to traditional chemotherapy agents. Bao et al. (2) have shown that BTSCs survive ionizing radiation to a greater extent than their tumor stromal
counterparts and are able to preferentially turn on DNA damage repair
genes. These reports indicate that our traditional therapies inherently
are doomed to failure because they are unable to destroy the underlying tumor-perpetuating cells. New methods that specifically target
BTSCs need to be developed.
There are now 5 new promising avenues for destroying BTSCs (14).
The first is by inducing the differentiation of BTSCs into more committed cell lines with little regenerative capacity. Piccirillo et al. (11) recently
showed that activation of the bone morphogenetic protein 4 signaling
cascade induces a prodifferentiation effect on glioblastoma multiforme–derived BTSCs and inhibits the tumorigenicity of BTSCs. The
second strategy targets the intracellular pathways that help to promote
the proliferation of BTSCs. Sonic Hedgehog (SHH), a primitive protein
involved in central nervous system organization during development,
has been shown to be a promising inhibitory target for clinical therapy
(6) that inhibits the growth of some brain tumors (3). The third strategy
would be to disrupt the niches where BTSCs reside. Calabrese et al. (4)
recently showed that BTSCs reside in vasculature niches and that
antiangiogenic antibodies, such as bevacizumab, are able to eradicate
cancer-regenerating stem cells. The fourth strategy would be to deliver
therapeutic genes to BTSCs using other stem cells. For example, many
groups, in addition to our own, have shown the efficacy of delivering
prodrug-converting enzymes to brain tumors using either neural stem
cells (1) or mesenchymal stem cells (10), both of which are able to track
metastatic disease produced by migrating BTSCs. The fifth, and final,
strategy we propose may inhibit the invasiveness of BTSCs and would
250 | VOLUME 65 | NUMBER 2 | AUGUST 2009
help to reduce the spread of disease and localize tumor-regenerating
cells for more adequate excision. Our laboratory is extensively studying
the role of ion channels, which is a conserved mechanism used by many
cells as a strategy for pseudopod extension and migration, to use as a
target for inhibition (unpublished data).
In light of the recent discovery of BTSCs, it is clear that our current
treatment modalities are archaic and destined to fail unless new treatments that specifically destroy cancer-regenerating stem cells are implemented. A better understanding of the markers that identify these cells
and the intracellular pathways dependent on their growth and proliferation, as well as the discovery of areas where these cells reside, will help
enhance the tools necessary to fight these cells and eradicate brain tumors.
Hasan A. Zaidi
Thomas Kosztowski
Alfredo Quiñones-Hinojosa
Baltimore, Maryland
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