Sie sind auf Seite 1von 10

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home Genes Leukemias Solid Tumours Cancer-Prone Deep Insight Case Reports Journals Portal Teaching

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

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

May 2012

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
self-renewal 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

Cancer stem cells in glioblastoma are designated by different names. Glioblastoma stem cells, glioblastoma stem-like cells, glioma cancer stem cells and
glioma-initiating 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.
There are several reasons why conventional therapies for malignant glioblastomas are not curative. High-grade 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 26/02/16 15.15

Page 1 of 10
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 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).

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 N-glycosylated extracellular loops, two cytoplasmic loops, a cytoplasmic C-
terminal and an extracellular N-terminal (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 significantly higher than in low-grade gliomas. Interestingly, CD90 and CD133 markers were co-
expressed 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.,
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.

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 number (range 20-90%, mean 60,7%) of endothelial cells in glioblastoma carry the same genomic alterations as tumor cells, indicating that a 26/02/16 15.15

Page 2 of 10
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).

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 HIF1 or HIF2, 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 (HIF1 and HIF2) play an important role in expression of CD133 protein on stem cells. Li et al., 2009 found
that HIF2 is highly expressed in CD133-positive cells, whereas HIF1 is expressed in CD133-negative cells. Furthermore, a significant association
between HIF2-transcription levels and poor patient prognosis has been demonstrated in glioblastoma. Griguer et al., 2008 have shown that the
established glioblastoma cell line U251MG, previously recognized to be CD133-negative, developed CD133-positivity with decreasing oxygen tensions.

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 -catenin (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; 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 non-diving 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 26/02/16 15.15

Page 3 of 10
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 M ATP reduced the number of tumor spheroids in a dose-dependent manner. ATP also reduced the expression
of Nanog, CD133 and Oct-4 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 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- 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 pro-apoptopic 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; 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.

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.


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.


A novel five-transmembrane hematopoietic stem cell antigen: isolation, characterization, and molecular cloning.
Miraglia S, Godfrey W, Yin AH, Atkins K, Warnke R, Holden JT, Bray RA, Waller EK, Buck DW.
Blood. 1997 Dec 15;90(12):5013-21.
PMID 9389721

AC133, a novel marker for human hematopoietic stem and progenitor cells. 26/02/16 15.15

Page 4 of 10
Yin AH, Miraglia S, Zanjani ED, Almeida-Porada G, Ogawa M, Leary AG, Olweus J, Kearney J, Buck DW.
Blood. 1997 Dec 15;90(12):5002-12.
PMID 9389720

Yeast cytosine deaminase improves radiosensitization and bystander effect by 5-fluorocytosine of human colorectal cancer xenografts.
Kievit E, Nyati MK, Ng E, Stegman LD, Parsels J, Ross BD, Rehemtulla A, Lawrence TS.
Cancer Res. 2000 Dec 1;60(23):6649-55.
PMID 11118048

Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors.
Studeny M, Marini FC, Champlin RE, Zompetta C, Fidler IJ, Andreeff M.
Cancer Res. 2002 Jul 1;62(13):3603-8.
PMID 12097260

Cancerous stem cells can arise from pediatric brain tumors.

Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M, Kornblum HI.
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15178-83. Epub 2003 Nov 26.
PMID 14645703

Immunomodulatory effects of fetal and adult mesenchymal stem cells.

Le Blanc K.
Cytotherapy. 2003;5(6):485-9. (REVIEW)
PMID 14660044

Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line.
Kondo T, Setoguchi T, Taga T.
Proc Natl Acad Sci U S A. 2004 Jan 20;101(3):781-6. Epub 2004 Jan 7.
PMID 14711994

Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model.
Nakamura K, Ito Y, Kawano Y, Kurozumi K, Kobune M, Tsuda H, Bizen A, Honmou O, Niitsu Y, Hamada H.
Gene Ther. 2004 Jul;11(14):1155-64.
PMID 15141157

Identification of human brain tumour initiating cells.

Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB.
Nature. 2004 Nov 18;432(7015):396-401.
PMID 15549107

Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents.
Studeny M, Marini FC, Dembinski JL, Zompetta C, Cabreira-Hansen M, Bekele BN, Champlin RE, Andreeff M.
J Natl Cancer Inst. 2004 Nov 3;96(21):1593-603.
PMID 15523088

Isolation of cancer stem cells from adult glioblastoma multiforme.

Yuan X, Curtin J, Xiong Y, Liu G, Waschsmann-Hogiu S, Farkas DL, Black KL, Yu JS.
Oncogene. 2004 Dec 16;23(58):9392-400.
PMID 15558011

Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas.

Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J, Chen J, Hentschel S, Vecil G, Dembinski J, Andreeff M, Lang FF.
Cancer Res. 2005 Apr 15;65(8):3307-18.
PMID 15833864

Cancer stem cells.

Soltysova A, Altanerova V, Altaner C.

Neoplasma. 2005;52(6):435-40. (REVIEW)

PMID 16284686

HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth.
Covello KL, Kehler J, Yu H, Gordan JD, Arsham AM, Hu CJ, Labosky PA, Simon MC, Keith B.
Genes Dev. 2006 Mar 1;20(5):557-70.
PMID 16510872

Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an
aggressive phenotype.
Holmquist-Mengelbier L, Fredlund E, Lofstedt T, Noguera R, Navarro S, Nilsson H, Pietras A, Vallon-Christersson J, Borg A, Gradin K, Poellinger L, 26/02/16 15.15

Page 5 of 10
Pahlman S.
Cancer Cell. 2006 Nov;10(5):413-23.
PMID 17097563

Differential regulation of the transcriptional activities of hypoxia-inducible factor 1 alpha (HIF-1alpha) and HIF-2alpha in stem cells.
Hu CJ, Iyer S, Sataur A, Covello KL, Chodosh LA, Simon MC.
Mol Cell Biol. 2006 May;26(9):3514-26.
PMID 16611993

Bone morphogenetic proteins regulate tumorigenicity in human glioblastoma stem cells.

Piccirillo SG, Vescovi AL.
Ernst Schering Found Symp Proc. 2006;(5):59-81. (REVIEW)
PMID 17939295

Primary glioblastomas express mesenchymal stem-like properties.

Tso CL, Shintaku P, Chen J, Liu Q, Liu J, Chen Z, Yoshimoto K, Mischel PS, Cloughesy TF, Liau LM, Nelson SF.
Mol Cancer Res. 2006 Sep;4(9):607-19.
PMID 16966431

CD133(+) and CD133(-) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles.
Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ, Aigner L, Brawanski A, Bogdahn U, Beier CP.
Cancer Res. 2007 May 1;67(9):4010-5.
PMID 17483311

Tumor-targeted enzyme/prodrug therapy mediates long-term disease-free survival of mice bearing disseminated neuroblastoma.
Danks MK, Yoon KJ, Bush RA, Remack JS, Wierdl M, Tsurkan L, Kim SU, Garcia E, Metz MZ, Najbauer J, Potter PM, Aboody KS.
Cancer Res. 2007 Jan 1;67(1):22-5.
PMID 17210679

Making a tumour's bed: glioblastoma stem cells and the vascular niche.
Gilbertson RJ, Rich JN.
Nat Rev Cancer. 2007 Oct;7(10):733-6. (REVIEW)
PMID 17882276

Autocrine factors that sustain glioma invasion and paracrine biology in the brain microenvironment.
Hoelzinger DB, Demuth T, Berens ME.
J Natl Cancer Inst. 2007 Nov 7;99(21):1583-93. Epub 2007 Oct 30. (REVIEW)
PMID 17971532

Adipose tissue-derived human mesenchymal stem cells mediated prodrug cancer gene therapy.
Kucerova L, Altanerova V, Matuskova M, Tyciakova S, Altaner C.
Cancer Res. 2007 Jul 1;67(13):6304-13.
PMID 17616689

Hypoxia-inducible factor 1alpha may be a marker for vasculitic neuropathy.

Oka N, Kawasaki T, Mizutani K, Sugiyama H, Akiguchi I.
Neuropathology. 2007a Dec;27(6):509-15.

PMID 18021370

VEGF promotes tumorigenesis and angiogenesis of human glioblastoma stem cells.

Oka N, Soeda A, Inagaki A, Onodera M, Maruyama H, Hara A, Kunisada T, Mori H, Iwama T.
Biochem Biophys Res Commun. 2007b Aug 31;360(3):553-9. Epub 2007 Jun 27.
PMID 17618600

Most C6 cells are cancer stem cells: evidence from clonal and population analyses.
Zheng X, Shen G, Yang X, Liu W.
Cancer Res. 2007 Apr 15;67(8):3691-7.
PMID 17440081

Prodrug cancer gene therapy.

Altaner C.
Cancer Lett. 2008a Nov 8;270(2):191-201. Epub 2008 May 27. (REVIEW)
PMID 18502571

Glioblastoma and stem cells.

Altaner C.
Neoplasma. 2008b;55(5):369-74. (REVIEW) 26/02/16 15.15

Page 6 of 10
PMID 18665745

CD133 identifies perivascular niches in grade II-IV astrocytomas.

Christensen K, Schroder HD, Kristensen BW.
J Neurooncol. 2008 Nov;90(2):157-70. Epub 2008 Jul 9.
PMID 18612800

CD133 is a marker of bioenergetic stress in human glioma.

Griguer CE, Oliva CR, Gobin E, Marcorelles P, Benos DJ, Lancaster JR Jr, Gillespie GY.
PLoS One. 2008;3(11):e3655. Epub 2008 Nov 5.
PMID 18985161

Cytosine deaminase expressing human mesenchymal stem cells mediated tumour regression in melanoma bearing mice.
Kucerova L, Matuskova M, Pastorakova A, Tyciakova S, Jakubikova J, Bohovic R, Altanerova V, Altaner C.
J Gene Med. 2008 Oct;10(10):1071-82.
PMID 18671316

CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells.
Wang J, Sakariassen PO, Tsinkalovsky O, Immervoll H, Boe SO, Svendsen A, Prestegarden L, Rosland G, Thorsen F, Stuhr L, Molven A, Bjerkvig R,
Enger PO.
Int J Cancer. 2008 Feb 15;122(4):761-8.
PMID 17955491

Human CD133+ progenitor cells promote the healing of diabetic ischemic ulcers by paracrine stimulation of angiogenesis and activation of Wnt
Barcelos LS, Duplaa C, Krankel N, Graiani G, Invernici G, Katare R, Siragusa M, Meloni M, Campesi I, Monica M, Simm A, Campagnolo P,
Mangialardi G, Stevanato L, Alessandri G, Emanueli C, Madeddu P.
Circ Res. 2009 May 8;104(9):1095-102. Epub 2009 Apr 2.
PMID 19342601

CD133+ and nestin+ tumor-initiating cells dominate in N29 and N32 experimental gliomas.
Bexell D, Gunnarsson S, Siesjo P, Bengzon J, Darabi A.
Int J Cancer. 2009 Jul 1;125(1):15-22.
PMID 19291792

Histocompatibility testing of cultivated human bone marrow stromal cells - a promising step towards pre-clinical screening for allogeneic stem
cell therapy.
Koppula PR, Chelluri LK, Polisetti N, Vemuganti GK.
Cell Immunol. 2009;259(1):61-5. Epub 2009 Jun 6.
PMID 19577229

Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells.

Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, Shi Q, Cao Y, Lathia J, McLendon RE, Hjelmeland AB, Rich JN.
Cancer Cell. 2009 Jun 2;15(6):501-13.
PMID 19477429

Detection of cancer stem cells from the C6 glioma cell line.

Zhou XD, Wang XY, Qu FJ, Zhong YH, Lu XD, Zhao P, Wang DH, Huang QB, Zhang L, Li XG.
J Int Med Res. 2009 Mar-Apr;37(2):503-10.
PMID 19383245

TGF-beta Receptor Inhibitors Target the CD44(high)/Id1(high) Glioma-Initiating Cell Population in Human Glioblastoma.
Anido J, Saez-Borderias A, Gonzalez-Junca A, Rodon L, Folch G, Carmona MA, Prieto-Sanchez RM, Barba I, Martinez-Saez E, Prudkin L, Cuartas I,
Raventos C, Martinez-Ricarte F, Poca MA, Garcia-Dorado D, Lahn MM, Yingling JM, Rodon J, Sahuquillo J, Baselga J, Seoane J.
Cancer Cell. 2010 Dec 14;18(6):655-68.
PMID 21156287

Toward brain tumor gene therapy using multipotent mesenchymal stromal cell vectors.
Bexell D, Scheding S, Bengzon J.
Mol Ther. 2010 Jun;18(6):1067-75. Epub 2010 Apr 20. (REVIEW)
PMID 20407426

Adipose tissue-derived mesenchymal stem cells expressing prodrug-converting enzyme inhibit human prostate tumor growth.
Cavarretta IT, Altanerova V, Matuskova M, Kucerova L, Culig Z, Altaner C.
Mol Ther. 2010 Jan;18(1):223-31. Epub 2009 Oct 20.
PMID 19844197 26/02/16 15.15

Page 7 of 10
A hierarchy of self-renewing tumor-initiating cell types in glioblastoma.
Chen R, Nishimura MC, Bumbaca SM, Kharbanda S, Forrest WF, Kasman IM, Greve JM, Soriano RH, Gilmour LL, Rivers CS, Modrusan Z, Nacu S,
Guerrero S, Edgar KA, Wallin JJ, Lamszus K, Westphal M, Heim S, James CD, VandenBerg SR, Costello JF, Moorefield S, Cowdrey CJ, Prados M,
Phillips HS.
Cancer Cell. 2010 Apr 13;17(4):362-75.
PMID 20385361

Brain tumor stem cells: the cancer stem cell hypothesis writ large.
Dirks PB.
Mol Oncol. 2010 Oct;4(5):420-30. Epub 2010 Aug 10. (REVIEW)
PMID 20801091

Immunological aspects of allogeneic mesenchymal stem cell therapies.

Griffin MD, Ritter T, Mahon BP.
Hum Gene Ther. 2010 Dec;21(12):1641-55. (REVIEW)
PMID 20718666

Tumor cell behaviour modulation by mesenchymal stromal cells.

Kucerova L, Matuskova M, Hlubinova K, Altanerova V, Altaner C.
Mol Cancer. 2010 May 28;9:129.
PMID 20509882

Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells.

Ricci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T, Maira G, Parati EA, Stassi G, Larocca LM, De Maria R.
Nature. 2010 Dec 9;468(7325):824-8. Epub 2010 Nov 21.
PMID 21102434

Notch promotes radioresistance of glioma stem cells.

Wang J, Wakeman TP, Lathia JD, Hjelmeland AB, Wang XF, White RR, Rich JN, Sullenger BA.
Stem Cells. 2010 Jan;28(1):17-28.
PMID 19921751

Glioblastoma, cancer stem cells and hypoxia.

Bar EE.
Brain Pathol. 2011 Mar;21(2):119-29. doi: 10.1111/j.1750-3639.2010.00460.x. Epub 2010 Nov 30. (REVIEW)
PMID 21054626

Stem cell based cancer gene therapy.

Cihova M, Altanerova V, Altaner C.
Mol Pharm. 2011 Oct 3;8(5):1480-7. Epub 2011 Jul 25. (REVIEW)
PMID 21755953

Deadly teamwork: neural cancer stem cells and the tumor microenvironment.
Lathia JD, Heddleston JM, Venere M, Rich JN.
Cell Stem Cell. 2011 May 6;8(5):482-5. (REVIEW)
PMID 21549324

Autocrine endothelin-3/endothelin receptor B signaling maintains cellular and molecular properties of glioblastoma stem cells.
Liu Y, Ye F, Yamada K, Tso JL, Zhang Y, Nguyen DH, Dong Q, Soto H, Choe J, Dembo A, Wheeler H, Eskin A, Schmid I, Yong WH, Mischel PS,
Cloughesy TF, Kornblum HI, Nelson SF, Liau LM, Tso CL.
Mol Cancer Res. 2011 Dec;9(12):1668-85. Epub 2011 Oct 19.
PMID 22013079

Radioresistance of glioma stem cells: intrinsic characteristic or property of the 'microenvironment-stem cell unit'?
Mannino M, Chalmers AJ.
Mol Oncol. 2011 Aug;5(4):374-86. Epub 2011 May 20. (REVIEW)
PMID 21659010

Overexpression of ZNF217 in glioblastoma contributes to the maintenance of glioma stem cells regulated by hypoxia-inducible factors.
Mao XG, Yan M, Xue XY, Zhang X, Ren HG, Guo G, Wang P, Zhang W, Huo JL.
Lab Invest. 2011 Jul;91(7):1068-78. doi: 10.1038/labinvest.2011.56. Epub 2011 Apr 11.
PMID 21483406

The three-layer concentric model of glioblastoma: cancer stem cells, microenvironmental regulation, and therapeutic implications.
Persano L, Rampazzo E, Della Puppa A, Pistollato F, Basso G.
ScientificWorldJournal. 2011;11:1829-41. Epub 2011 Oct 23. (REVIEW)
PMID 22125441 26/02/16 15.15

Page 8 of 10
Inhibition of Sonic hedgehog and Notch pathways enhances sensitivity of CD133(+) glioma stem cells to temozolomide therapy.
Ulasov IV, Nandi S, Dey M, Sonabend AM, Lesniak MS.
Mol Med. 2011 Jan-Feb;17(1-2):103-12. Epub 2010 Oct 15.
PMID 20957337

Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells.
Zhu TS, Costello MA, Talsma CE, Flack CG, Crowley JG, Hamm LL, He X, Hervey-Jumper SL, Heth JA, Muraszko KM, DiMeco F, Vescovi AL, Fan
Cancer Res. 2011 Sep 15;71(18):6061-72. Epub 2011 Jul 25.
PMID 21788346

Human adipose tissue-derived mesenchymal stem cells expressing yeast cytosinedeaminase::uracil phosphoribosyltransferase inhibit
intracerebral rat glioblastoma.
Altanerova V, Cihova M, Babic M, Rychly B, Ondicova K, Mravec B, Altaner C.
Int J Cancer. 2012 May 15;130(10):2455-63. doi: 10.1002/ijc.26278. Epub 2011 Aug 24.
PMID 21732344

Intra-arterial delivery of bevacizumab after blood-brain barrier disruption for the treatment of recurrent glioblastoma: progression-free
survival and overall survival.
Burkhardt JK, Riina H, Shin BJ, Christos P, Kesavabhotla K, Hofstetter CP, Tsiouris AJ, Boockvar JA.
World Neurosurg. 2012 Jan;77(1):130-4. Epub 2011 Nov 21.
PMID 22405392

The brain tumor microenvironment.

Charles NA, Holland EC, Gilbertson R, Glass R, Kettenmann H.
Glia. 2012 Mar;60(3):502-14.

PMID 22379614

Notch1 signaling promotes survival of glioblastoma cells via EGFR-mediated induction of anti-apoptotic Mcl-1.
Fassl A, Tagscherer KE, Richter J, Berriel Diaz M, Alcantara Llaguno SR, Campos B, Kopitz J, Herold-Mende C, Herzig S, Schmidt MH, Parada LF,
Wiestler OD, Roth W.
Oncogene. 2012 Jan 16. doi: 10.1038/onc.2011.615. [Epub ahead of print]
PMID 22249262

CD90 is identified as a candidate marker for cancer stem cells in primary high-grade gliomas using tissue microarrays.
He J, Liu Y, Zhu T, Zhu J, Dimeco F, Vescovi AL, Heth JA, Muraszko KM, Fan X, Lubman DM.
Mol Cell Proteomics. 2012 Jun;11(6):M111.010744. Epub 2011 Dec 27.
PMID 22203689

Protein phosphatase 2A mediates dormancy of glioblastoma multiforme-derived tumor stem-like cells during hypoxia.
Hofstetter CP, Burkhardt JK, Shin BJ, Gursel DB, Mubita L, Gorrepati R, Brennan C, Holland EC, Boockvar JA.
PLoS One. 2012;7(1):e30059. Epub 2012 Jan 11.
PMID 22253878

The brain microenvironment preferentially enhances the radioresistance of CD133(+) glioblastoma stem-like cells.
Jamal M, Rath BH, Tsang PS, Camphausen K, Tofilon PJ.
Neoplasia. 2012 Feb;14(2):150-8.
PMID 22431923

Wnt activation is implicated in glioblastoma radioresistance.

Kim Y, Kim KH, Lee J, Lee YA, Kim M, Lee SJ, Park K, Yang H, Jin J, Joo KM, Lee J, Nam DH.
Lab Invest. 2012 Mar;92(3):466-73. doi: 10.1038/labinvest.2011.161. Epub 2011 Nov 14.
PMID 22083670

Extracellular ATP reduces tumor sphere growth and cancer stem cell population in glioblastoma cells.
Ledur PF, Villodre ES, Paulus R, Cruz LA, Flores DG, Lenz G.
Purinergic Signal. 2012 Mar;8(1):39-48. Epub 2011 Aug 5.
PMID 21818572

Gliomagenesis: a game played by few players or a team effort?

Mazzoleni S, Galli R.
Front Biosci (Elite Ed). 2012 Jan 1;4:205-13. (REVIEW)
PMID 22201865

Induction of cell-cycle arrest and apoptosis in glioblastoma stem-like cells by WP1193, a novel small molecule inhibitor of the JAK2/STAT3
pathway. 26/02/16 15.15

Page 9 of 10
Sai K, Wang S, Balasubramaniyan V, Conrad C, Lang FF, Aldape K, Szymanski S, Fokt I, Dasgupta A, Madden T, Guan S, Chen Z, Alfred Yung WK,
Priebe W, Colman H.
J Neurooncol. 2012 May;107(3):487-501. Epub 2012 Jan 17.
PMID 22249692

Glioblastoma angiogenesis: VEGF resistance solutions and new strategies based on molecular mechanisms of tumor vessel formation.
Takano S.
Brain Tumor Pathol. 2012 Apr;29(2):73-86. doi: 10.1007/s10014-011-0077-6. Epub 2012 Jan 6. (REVIEW)
PMID 22218709

Curcumin promotes differentiation of glioma-initiating cells by inducing autophagy.

Zhuang W, Long L, Zheng B, Ji W, Yang N, Zhang Q, Liang Z.
Cancer Sci. 2012 Apr;103(4):684-90. doi: 10.1111/j.1349-7006.2011.02198.x. Epub 2012 Jan 30.
PMID 22192169


Written 2012-05 Cestmir Altaner

Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovakia; St. Elisabeth Oncological Institute, Cell Transplantation
Center, Bratislava, Slovakia

Atlas of Genetics and Cytogenetics in Oncology and Haematology indexed on : Sat Oct 31 17:25:17 CET 2015

Home Genes Leukemias Solid Tumours Cancer-Prone Deep Insight Case Reports Journals Portal Teaching

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

For comments and suggestions or contributions, please contact us 26/02/16 15.15

Page 10 of 10