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Glioma cancer stem cells and their role in therapy
Cestmir Altaner
Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovakia; St. Elisabeth Oncological
Institute, Cell Transplantation Center, Bratislava, Slovakia (CA)
Published in Atlas Database: May 2012
Online updated version : http://AtlasGeneticsOncology.org/Deep/GliomaStemCellsID20110.html
DOI: 10.4267/2042/48156
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Cancer stem cells - tumor-initiating cells in most
tumors - generally are characterized as the population
of cells within a tumor that have the ability for selfrenewal and aberrant differentiation, initiate
tumorigenesis, migrate, and regenerate a phenocopy of
the original patient's tumor when administrated into
immuno-compromised animals in vivo (for a review see
Soltysova et al., 2005). Cancer stem cells share many
of the properties of normal stem cells and can originate
from mutated stem cells and/or from somatic cell that
converted to cells similar to stem cells (Fig.1). These
include resistance to toxic drugs through the expression
of several ABC transporters, an active DNA repair
capacity, resistance to apoptosis, and lack of relative
quiescent cell stages.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(10)
Cancer stem cells in glioblastoma are designated by
different names. Glioblastoma stem cells, glioblastoma
stem-like cells, glioma cancer stem cells and gliomainitiating cells are regarded as synonyms. Generally it
is agreed that these cells are tumor initiating and
involved in tumor progression (Altaner, 2008b). In this
article I will call them glioma cancer stem cells
(GCSC). Biological properties of glioblastoma cells,
like resistance to chemotherapy and radiotherapy, their
infiltrative nature, proliferative behavior, and
progressive character, have strongly supported the
suspicion that glioblastomas contain GCSC. Brain
tumor mass is formed by dividing tumor cell clones, by
GCSC and other stroma forming cells.
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Glioma cancer stem cells and their role in therapy
Altaner C
cancer stem cells remain unaffected. These therapies
select for the more aggressive GCSC, leading later to
frequent tumor relapse with tumors resistant to further
conventional therapy (Fig.2).
There are several reasons why conventional therapies
for malignant glioblastomas are not curative. Highgrade brain tumors exhibit a devastating malignant
progression, characterized by widespread invasion
throughout the brain. The tumor invasion is facilitated
by normal brain parenchymal cells, which secrete
ligands that can stimulate receptors on invasive glioma
cells. Glioblastoma cells produce factors, like growth
factors, cytokines and chemokines, which support the
growth and the infiltrating character of glioblastoma
cells in paracrine and autocrine fashion (Liu, 2011).
Tso et al., (2006) observed that high-grade
glioblastomas express cellular and molecular markers
that are associated with mesenchymal stem cells. It is
not known whether glioblastoma cells are derived from
transformed stem cells or that activated genes in glioma
cells elicit mesenchymal properties of cancer cells. To
the heterogeneity of glioblastoma multiforme cells
contribute mesenchymal stem cells that home in the
tumor mass, and together with other cells make up the
tumor stroma. Secreted factors from all cells present in
the tumor mass are able to diffuse through the
peritumoral stroma, thereby influencing parenchymal
cells that surround the tumor mass and simultaneously
with hypoxic conditions are creating a permissive
microenvironment
for
malignant
progression
(Hoelzinger et al., 2007; Oka et al., 2007a). In addition,
the immunosuppressive character of MSCs might
protect the tumor cells from attack by immune cells.
The most serious reason for resistance of glioblastoma
cells is very likely the existence of cancer stem cells glioma cancer stem cells.
Glioblastoma multiforme (GBM) has a polyclonal
character being composed from clones of dividing
tumor cells and a few tumor initiating cells.
Conventional therapies like radiotherapy and cytotoxic
chemotherapy kill dividing cells, but slowly dividing
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(10)
Identification of cancer stem cells
in brain tumors
The first identification of human GCSCs that had the
capacity to initiate tumors in vivo, using the xenograft
assay approach, was reported by Singh et al., 2003 and
2004. A brain tumor fraction of CD133+ cells at a low
dose (100 live cells) produced a tumor that was serially
transplantable in NOD/SCID mouse brains and was a
phenocopy of the patient's original tumor. A dose of
105 live CD133- cells similarly injected did not cause a
tumor. Similar findings were reported for adult
glioblastomas (Yuan et al., 2004) and several childhood
brain tumors (Hemmati et al., 2003). CD133
(Prominin-1) is a transmembrane glycoprotein
consisting of five membrane domains: two Nglycosylated extracellular loops, two cytoplasmic
loops, a cytoplasmic C-terminal and an extracellular Nterminal (Yin et al., 1997; Miraglia et al., 1997).
Further characterization of GCSCs led to conclusions
that they are stem-like cells. They express high levels
of stem cell genes involved in self-renewal and genes
that regulate neural stem proliferation and
differentiation commitment, such as Sox2, Notch,
Bmi1, Sonic hedgehog, Musashi-1, CD133, endothelin
3 (Hemmati et al., 2003; Chen et al., 2010; Tso et al.,
2006; Liu et al., 2011). Obviously, key mechanisms
that control the activity of normal neural progenitors
are altered in brain tumors. Recently, using tissue
microarrays, CD90 was identified as a marker for
GCSCs in primary human high-grade gliomas.
Expression levels of CD90 were in good correlation
with WHO grades, in high-grade gliomas, and were
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Glioma cancer stem cells and their role in therapy
Altaner C
number (range 20-90%, mean 60,7%) of endothelial
cells in glioblastoma carry the same genomic
alterations as tumor cells, indicating that a significant
portion of the vascular endothelium has a neoplastic
origin. The connection between neural stem cells and
the endothelial compartment seems to be critical in
glioblastoma, where GCSCs closely interact with the
vascular niche and promote angiogenesis through the
release of vascular endothelial growth factor (VEGF)
and stromal-derived factor 1. The neoplastic origin of
glioblastoma capillaries is supported by experiments in
immunocompromised
mice
with
subcutaneous
xenografts induced by inoculation of GCSCs. The
vessels in tumor xenografts were found to be primarily
composed of human endothelial cells (Ricci et al.,
2010).
significantly higher than in low-grade gliomas.
Interestingly, CD90 and CD133 markers were coexpressed in GBM, where 100% of the CD133+ cells
were also positive for CD90, but only a small part of
CD90+ cells were positive for CD133, indicating that
the CD133+ stem-like cells are a subpopulation of
CD90+ cells in GBMs in vivo (He et al., 2011). Careful
histochemical analysis of CD133(+) cells revealed that
different cell phenotypes exist according to their in situ
localization. CD133(+) niches contain stem-like cells
with a lower proliferation index than CD133(+) single
cells, which have an endothelial differentiation profile,
suggesting a role in angiogenesis (Christensen et al.,
2011).
There are some doubts that CD133 is a universal
marker for brain tumor stem cells. The biological
function of the CD133 protein is unknown, and there is
experimental evidence for the existence of both
CD133+ve and CD133-ve populations in tumor
initiating cells (Beier et al., 2007; Wang et al., 2008).
The biological role of CD133+ progenitor cells seems
rather wide and promiscuous. For instance, Barcelos et
al., 2009 reported that CD133+ progenitor cells
promoted the healing of ischemic ulcers by stimulating
angiogenesis and activating the Wnt pathway.
Role of hypoxia in GBM
Hypoxia or the so called "hypoxic niche" plays a
crucial role in controlling the GCSC molecular and
phenotypic profile. GCSCs may be maintained in vivo
in a hypoxic niche. Therefore, targeting the hypoxic
pathways therapeutically might be a promising
additional therapy (for a review see Barr, 2011).
Hypoxic environment of the GBM contributes to
creation of a specialized hypoxic niche where GCSCs
reside. The hypoxic niche regulates tumorigenic
capacity primarily through the hypoxia-inducible
factors HIF1α or HIF2α, reflected in the level of
ZNF217 gene overexpression.
The activity of protein phosphatase 2A (PP2A), a
regulator of cell cycle in human GBM, is induced by
hypoxia. It was found that patients with higher PP2A
activity had significantly worse survivals compared to
patients with low levels. PP2A appears to reduce the
metabolic demand of hypoxic GCSCs and enhances
tumor cell survival (Hofstetter et al., 2012 ). Persano et
al. 2011 proposed the theory of the three-concentric
layer model for GBM mass. According to this model,
GBM stem cells reside preferentially within the
hypoxic core of the tumor mass, while more
differentiated cells are mainly localized along the
peripheral and vascularized part of the tumor.
Clinical implications arising from the three layer model
of GCSC distribution in GBM recommend to
neurosurgeons the complete removal of the central
region of tumor in order to reduce the residual GCSC
population. Unfortunately, GCSCs, even in very low
numbers, are present in the more peripheral regions of
the tumor, the likely reason for tumor recurrence, even
after total removal of the primary tumor mass.
Hypoxia inducible transcription factors (HIF1α and
HIF2α) play an important role in expression of CD133
protein on stem cells. Li et al., 2009 found that HIF2α
is highly expressed in CD133-positive cells, whereas
HIF1α is expressed in CD133-negative cells.
Furthermore, a significant association between HIF2αtranscription levels and poor patient prognosis has been
demonstrated in glioblastoma. Griguer et al., 2008 have
Glioblastoma stem cells and the
vascular niche
Cell microenvironment, the so-called stem cell niche,
plays an important role in maintenance of stem cells
(Lathia et al., 2011). Vascular endothelial growth factor
promotes the proliferation of vascular endothelial cells
and the neurogenesis of neural stem cells. From
experiments with GCSCs, derived from glioblastoma
infected with retrovirus expressing VEGF (Oka et al.,
2007b; Gilbertson and Rich, 2007), it seems likely that
glioblastoma stem cells are dependent on cues from
aberrant vascular niches that mimic the normal neural
stem cell niche. Mao et al., 2011 examined the role of
the ZNF217 oncogene that is frequently amplified in
many kinds of tumors. It is associated with aggressive
tumor behavior and poor clinical prognosis. They found
that the ZNF217 gene was amplified in 32% and over
expressed in 71,2% of GBMs.
Glioblastomas harbor multiple cell types, some with
stem cell-like properties. Interaction of these tumor
cells with tumor-associated parenchymal cells, such as
vascular cells, microglia, peripheral immune cells, and
neural precursor cells, also play a vital role in
controlling the course of pathology. Microglial cells,
which can contribute up to 30% of a brain tumor mass,
play a role in glioblastoma cell invasiveness. Mutual
interaction of all these cells, and trophic factors
secreted by them, influence tumor behavior. The
multiple interactions between parenchymal and tumor
cells were reviewed by Charles et al. (2011).
Studies on mechanisms of tumor vasculogenesis in
glioblastoma revealed that newly formed vessels might
be of GCSCs origin. It was shown that a variable
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(10)
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shown that the established glioblastoma cell line
U251MG, previously recognized to be CD133negative, developed CD133-positivity with decreasing
oxygen tensions.
rather, they might constitute most cells within the
tumor bulk (Mazzoleni and Galli, 2012; Kondo et al.,
2004; Zheng et al., 2007; Zhou et al., 2009).
Development of novel chemotherapeutic agents
targeted to glioblastoma stem cells is of great interest.
It is likely that all agents molecularly targeted to
GCSCs will have cytostatic, but not cytotoxic
inhibitory effects. Obviously, the combination of
targeted cytostatic effects together with toxic effects to
GCSCs and to the vascular niche would be necessary to
achieve the elimination of those highly resistant nondiving cells. Some examples of inhibitors mainly acting
on pathways important for GCSCs survival have been
mentioned. Sai et al. 2012 found that a novel small
molecule inhibitor of the JAK2/STAT3 pathway,
WP1193, induced cell-cycle arrest and apoptosis in
glioblastoma stem-like cells. WP1193 significantly
decreased the proliferation of established glioma cell
lines in vitro and inhibited the growth of glioma in
vivo. Zhuang et al., 2012 reported that curcumin, a
natural compound with low toxicity to normal cells,
significantly induced differentiation of GCsCs in vivo
and in vitro by inducing autophagy.
The Notch1-mediated signaling pathway has a central
role in the maintenance of neural stem cells and
contributes to growth and progression of glioblastomas.
Fassl et al., 2011 demonstrated that the Notch1 receptor
promotes survival of glioblastoma cells by regulation
of the anti-apoptotic Mcl-1 protein. They have shown
that inhibition of the Notch1 pathway overcomes
apoptosis resistance and sensitizes glioblastoma cells to
apoptosis induced by ionizing radiation. Similar
observations were reported by Wang et al., 2010.
Inhibition of Sonic hedgehog and Notch pathways
enhances sensitivity of CD133\+ glioma stem cells to
temozolomide therapy (Ulasov et al., 2011).
Glioblastoma cells grown in neural stem cell medium,
supplemented with epidermal growth factor and basic
fibroblast growth factor form spheroids are regarded as
GCSCs . Ledur et al., 2012 reported that human U87
glioma form spheroids expressing the markers of
glioma cancer stem cells CD133, Oct-4, and Nanog.
However, messenger RNAs for several purinergic
receptors were differently expressed in spheroids when
compared to a cell monolayer not containing spheroids.
Treatment of human gliomas U87 or U343, as well as
rat C6 gliomas, with 100 µM ATP reduced the number
of tumor spheroids in a dose-dependent manner. ATP
also reduced the expression of Nanog, CD133 and Oct4 showing that the purinergic system affects GCSC
biology.
To block brain tumor stem cell self renewal and
promote differentiation particularly if terminally
differentiated cell types can be generated, such as
neurons, may be another useful strategy for
glioblastoma treatment (for a review see Dirks, 2010).
Piccirillo and Vescovi, 2006 have shown that
promotion of bone morphogenic protein 4 signaling can
Tumor microenvironment and
GCSCs
Radiotherapy is the most effective non-surgical therapy
for GBM patients. However, patients succumb due to
tumor recurrence within a year. It was shown that
treatment with ionizing radiation enriched the
glioblastoma cell population with GCSCs positive for
activated stem cell-associated pathways such as βcatenin (ABC), Sox2 and Wnt. (Kim et al., 2012). The
molecular mechanism of radiation resistance of GBM
is mediated by selection of subpopulation of GCSCs
with activated stem cells genes in addition;
radioresistance of GBM is not simply an intrinsic
characteristic of glioma stem cells but a result of
interactions
between
these
cells
and
microenvironmental factors (Mannino and Chalmers,
2011). Recently Jamal and colleagues, 2012
experimentally proved that the brain microenvironment
preferentially enhances the radioresistance of
CD133(+) glioblastoma stem cells. They compared the
response of CD133(+) glioblastoma stem cells with
non-stem cell populations to irradiation under in vitro
and intracerebral growth conditions. Radioresponse of
CD133(+) glioblastoma stem cells and non-stem cells
did not differ under in vitro growth conditions, while
CD133(+) cells were radioresistant under orthotopic
growth conditions. These findings are consistent with
the suspected role for GCSCs as a determinant of GBM
radioresistance, Obviously, the brain microenvironment
is responsible for radioresistance of glioblastoma cells
(Jamal et al., 2012).
There is evidence suggesting that activation of NOTCH
signaling is required for propagation of GCSCs. One
important function of endothelial cells in glioblastoma
multiforme is to create a niche that helps promoting
self-renewal of GCSCs. Zhu et al., 2011 clarified the
molecular mechanism whereby endothelial cells
provide the source of NOTCH ligands. They found that
NOTCH ligands were expressed in endothelial cells
adjacent to NESTIN and NOTCH receptor-positive
cancer cells in primary GBMs. Therefore, targeting
both GCSCs and their niche may provide a novel
strategy to deplete GCSCs and improve GBM
treatment. Burkhardt et al., 2012 hypothesized that
intra-arterial chemotherapy might selectively target
GCSCs residing in the perivascular stem cell niche.
Therapy targeted to brain tumor
initiating cells
It is believed, that in most cancers therapy targeted to
cancer stem cells might be curative. However, multiple
evidence has recently indicated that GCSCs may not
represent a restricted and infrequent GBM component;
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(10)
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Bexell et al., 2010). This property might facilitate the
migration of MSCs to highly vascularised
glioblastomas. MSCs lack major histocompatibility
complex MHC-II and show only minimal MHC-I
expression (LeBlanc, 2003; Koppula et al., 2009;
Griffin et al., 2010). Thanks to their non imunogenic
character, allogeneic MSCs can substitute for
autologous stem cells. We and others (Danks et al.,
2007; Nakamura et al., 2004; Nakamizo et al., 2005)
are encouraged by the results of stem cell driven
enzyme prodrug therapy experiments to treat
glioblastoma multiforme, a tumor with fatal prognosis.
Our experiments took the advantage of the fact that
human AT-MSCs are not immunogenic in treatment of
rat glioblastoma C6 growing intracebroventriculary.
The cell population of C6 rat glioblastoma has been
shown to be composed primarily of cancer stem cells.
Therapeutic experiments were designed to simulate
scenarios for future clinical applications for high-grade
glioblastoma therapy by direct injections of therapeutic
stem cells into the tumor. The results revealed that
genetically modified therapeutic stem cells labeled with
super paramagnetic iron nanoparticles still have the
tumor tropism when injected to a distant intracranial
site and effectively inhibited glioblastoma growth after
5-FC therapy (Altanerova et al., 2012). Intratumoral
administration of therapeutic stem cells improved the
survival in a cell dose-dependent manner. Furthermore,
the repeated administration of therapeutic cells and
continuous intracerebroventricular delivery of 5-FC led
to an increased number of animals being completely
cured.
enhance GCSCs differentiation and attenuate
tumorigenic phenotype. Thus the differentiation
therapy being successful in treatment of acute
promyelocytic leukemia might be another approach
worth to be studied.
Glioblastomas are highly vascular tumors. Therefore, it
was expected that agents targeting angiogenesis may
have efficacy. Recent preclinical and clinical
investigations have revealed that agents targeting
angiogenesis did not fulfill these expectations. Reasons
for failure and new strategies based on molecular
mechanisms of tumor vessel formation have been
discussed by Tokano, 2012. Using patient derived
specimens of glioblastoma, a subpopulation of GCSCs
was identified being enriched for CD44(high)/Id1(high)
cells, which tend to be located in a perivascular niche.
It was found that growth of the CD44(high)/Id1(high)
cells was inhibited by TGF-β inhibitors. Repression of
DNA-binding protein (Id)-1 and -3 transcription factors
decreased the GCSCs population that might inhibit the
capacity of cells to initiate tumors (Anido et al., 2010).
Stem cell based gene therapy
Statistic data of cancer patient survival revealed that the
most successful cancer therapy is surgery when applied
early. Elimination of both dividing tumor cells and
cancer stem cells before they can spread could provide
a cure. This is usually not possible with high-grade
brain tumors. At present, the standard therapy for GBM
patients, consisting of tumor debulking, followed by
radiotherapy and chemotherapy, is not a curative
approach. There is increasing evidence that cytotoxic
therapies select for more aggressive GTSCs. Recently
developed tumor targeting therapy, driven by
mesenchymal (stromal) stem cells (MSCs ) possessing
tumor tropic properties, brought hope for a novel
therapeutic modality (Studeny et al., 2002; Studeny et
al., 2004; Kucerova et al., 2007; Kucerova et al., 2008;
Kucerova et al., 2010; Cavarretta et al., 2010; for a
review see Altaner, 2008a). Prodrug cancer gene
therapy mediated by MSCs transduced with yeast
CD::UPRT might be one of several treatments with
potential for curative therapy of high-grade brain
tumors (Altanerova et al., 2012). The stem cell driven
cytosine deaminase/5-FC system represents an
attractive tool for activating the prodrug directly within
the tumor mass, resulting in high local 5-FU
concentrations without systemic toxicity. Expression of
the yeast CD::UPRT fused gene (Kievit et al., 2000)
and formation of 5-FU cause inhibition of both DNA
and RNA synthesis, consequently leading to death of
dividing and non-dividing cells, thus attacking GCSCs.
In addition, mesenchymal stem cells transduced with
cytosine deaminase induce the expression of proapoptopic genes in tumor cells (Cihova et al., 2011).
Mesenchymal stem cells have many attributes that
support their use as a tumor specific therapeutic vehicle
in clinical practice. It has been shown that MSCs share
some characteristics with pericytes (Bexell et al., 2009;
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(10)
Conclusions and remarks
Glioblastoma multiforme is a very complex tumor,
containing the glioma tumor stem cells possesing
properties fully in agreement with the name for the
tumor. GTSCs are able to survive standard
glioblastoma therapy. There are very likely numerous
variants changing their character and gene expression
influenced by the tumor microenvironment. It would be
very difficult to find therapeutically efficient
molecularly targeted drugs because of the promiscuous
character of these cells. It is believed that the tumor
tropic character of mesenchymal stem cells or neural
stem cells, engineered to express suicide genes, might
be therapeutic modality that could bring some progress
for survival of GBM patients.
Acknowledgements
We want to thank to the Slovak League against Cancer
and FIDURA Capital Consult GmbH, Munich,
Germany for support of our stem cells studies and to
Dr. A. Robert Neurath from Virotech, USA for reading
the manuscript and comments.
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