PERSPECTIVES

Glioma stem cells as a target for treatment

Katrin Lamszus & Hauke S. Günther

Received: 10 May 2010 /Accepted: 4 August 2010 /Published online: 25 August 2010# Springer-Verlag 2010

Abstract Glioma cells with stem cell-like propertiesrepresent a minor subfraction of the total tumor cellpopulation. These cells are highly chemo- and radio-resistent and are held responsible for the inevitablerecurrence of malignant gliomas. This review summarizescurrent strategies for targeting putative glioma stem cells.Target definition approaches comprise extrapolation andadaptation of therapies from general oncology, targetidentification by correlative molecular genetic analyses,and dedicated target discovery research. Targeting strategiesinclude inhibition of tumor-specific signaling pathways,enhancement of tumor cell differentiation, radiosensitiza-tion, indirect targeting of the tumor stem cell niche, oncolyticvirotherapy, and adhesion molecule blockade.

Keywords Glioblastoma . Stem cells . Tumor

Defining glioma stem cells

Gliomas contain a subpopulation of tumor cells that displaycharacteristics of stem cells. These glioma stem cells(GSCs) or glioma-initiating cells are distinguished by (i)the ability to self-renew, (ii) the ability to initiate braintumors upon orthotopic implantation in immunodeficientmice, (iii) the expression of neural stem cell markers, and(iv) multipotency, that is, the capacity to differentiate into

cells with a neuronal, astrocytic or oligodendroglialphenotype. GSCs constitute only a minor subpopulationof the total tumor cell pool and divide slowly, but areessential for sustaining the continuous growth of the tumor.In contrast, the bulk of tumor cells, which are supposed tobe progeny of GSCs and consist of progenitor-like cells aswell as differentiated cells, divide more rapidly but haveonly limited proliferative potential and are incapable oftumor-initiation. Compared to these bulk cells, GSCs arepreferentially equipped with chemo- and radioresistancemechanisms, so that tumor recurrences after cytotoxictreatment are believed to originate from the survivingtumor stem cells. Consequently, these cells are an importanttarget for treatment.

The cancer stem cell paradigmwas originally established forleukemia in the mid-1990s [1], and was translated to solidtumors about 10 years later [2, 3], where it initially sparkedtremendous enthusiasm. However, more recently severalcornerstones of this concept were called into question; tomention only a few: (i) transplantation in limiting cell dilutioninto immunodeficient NOD/SCID mice, the classical tool totest for tumor-initiating capacity, was found to select for cellsresisting the residual immune response, and the proportion ofcells with cancer initiating capacity turned out to beconsiderably higher when more permissive mice were used[4, 5]; (ii) CD133 was described as a highly specific tumorstem cell marker in glioma [3]; however, CD133− cells canalso be capable of self-renewal and initiate tumors, andCD133− cells can generate CD133+ cells [6–11]; (iii)clonogenicity assays, which are used to assess self-renewal,are strongly affected by the microenvironment and, forexample, the presence of serum greatly promotes clonogenicity[12].

Collectively, these studies indicate that the microenvi-ronment (niche) modulates tumor stem cell characteristics.

K. Lamszus (*) :H. S. GüntherLaboratory for Brain Tumor Biology,Department of Neurosurgery,University Medical Center Hamburg-Eppendorf,Martinistrasse 52,20246 Hamburg, Germanye-mail: lamszus@uke.uni-hamburg.de

Targ Oncol (2010) 5:211–215DOI 10.1007/s11523-010-0155-4

It was recently demonstrated that CD133 is inducible byhypoxia [13–15], so that the expression of this marker isnot a static feature of a defined GSC population but subjectto regulation by external factors. Thus, the use of CD133 asa read-out of stemness in many studies is obviouslyquestionable. It is conceivable that a subpopulation oftumor cells exists that are metabolically flexible and able toswitch between different bioenergetic pathways underalternating microenvironmental conditions. Thus, a moredynamic model is plausible, in which cancer stem cells areconsidered to be highly adaptable cells [16]. While ahierarchy of diverse cancer cells may well exist, these cellsmight all be capable of dedifferentiation and tumorpropagation [17]. According to these qualified models, allcells and not just a temporary population with stem cellcharacteristics need to be targeted and eliminated.

Notwithstanding individual preferences as to what themost appropriate definition of cancer stem cells might be,this groundbreaking new concept has revitalized ourrecognition of the importance of intratumoral heterogeneityand tumor-host interactions, and it provides a novelframework to discover new strategies, targeting a relativelyresistant tumor cell subpopulation.

Targeting GSCs

Targeted cancer therapies usually rely on the presence ofspecific molecules expressed on the tumor cells or activatedpathways, offering a selective therapeutic window. Targetidentification can either be achieved by extrapolation andadaptation of therapies from general oncology, or bycorrelative molecular genetic analyses, or by dedicatedtarget discovery research. All of these strategies have beenemployed in the attempt to identify GSC-specific targets,and these are summarized under different categories asshown in Table 1.

Signaling pathways

A number of key signaling pathways that are crucial fornormal neural stem cell development are also activated inGSCs. NOTCH is an important regulator of normalneural stem cell self-renewal and differentiation, andGSCs have higher NOTCH activity than non-stem tumorcells. The NOTCH pathway has successfully beentargeted using gamma-secretase inhibitors (GSIs), depletingCD133-positive putative GSCs and inhibiting tumor initiationand growth in vivo [18]. NOTCH blockade can furthersensitize GSCs to radiation [19]. The phosphoinositide 3-kinase (PI3K) pathway is another candidate for targeting,and a small molecule Akt inhibitor was shown to predom-inantly reduce the number of GSCs, inhibit migration and

invasion of GSCs, and to inhibit tumor growth in vivo [20].The Hedgehog pathway was also found to be activated inGSCs, and the Hedgehog inhibitor cyclopamine depletedclonogenic glioblastoma stem cells in vitro and inhibitedtumor initiation in vivo [21]. A20 (TNFAIP3) is a regulatorof the NF-κB pathway and is overexpressed in glioblastomastem cells relative to non-stem tumor cells. Knockdown ofA20 by lentiviral shRNA transfer reduced glioma stem cellself-renewal, growth and apoptotic resistance [22]. Also thec-myc pathway is required for the maintenance of GSCs andis overexpressed relative to non-stem glioma cells. LentiviralshRNA targeting of c-Myc reduced the proliferation ofGSCs, increased apoptosis and abolished tumorigenicity[23]. The polycomb group protein enhancer of zestehomologue 2 (EZH2) enhances c-Myc expression, andshRNA-mediated downregulation of EZH2 or its pharmaco-logical disruption by DZNep both impaired GSC self-renewal and tumor-initiating capacity [24]. The interleukin6 (IL6) pathway is another candidate target, since GSCspreferentially express the IL6 receptors IL6Rα and gp130.Lentiviral shRNA targeting of IL6Rα or IL-6 blockedgrowth and neurosphere formation in vitro, and bothknockdown as well as anti-IL6 antibody treatment inhibitedgrowth of GSC-derived tumors in vivo [25]. Finally, werecently discovered that CXCR4 is significantly overex-pressed in a panel of 12 glioma stem cell lines (GS cell lines)compared with 32 conventional, serum-grown glioma celllines. GS cell lines contained a minor subpopulation of cellswith high CXCR4 receptor levels, whereas conventionalglioma lines contained only cells with low levels. Treatmentwith a specific CXCR4 antagonist, AMD3100, inhibited cellmigration in vitro and reduced the growth of highly invasiveGS cell line xenografts in vivo [26].

Differentiation

The induction of differentiation is an obvious and attractiveapproach to target GSCs. Bone morphogenic proteins(BMPs) are well known for their influence on differentia-tion during neural development. BMP4 was shown totrigger an overproportional reduction in stem-like glioblas-toma cells in vitro, to abolish tumor initiation in vivo andreduce growth of established glioblastoma xenografts [27].Using an RNA interference screening approach, silencingof the adaptor protein TRRAP was found to inducedifferentiation of GSCs. Knockdown of TRRAP sensitizedcells to apoptotic stimuli, inhibited cell cycle progressionand suppressed tumor formation in vivo, suggesting thatTRRAP maintains GSCs in a stem cell-like, tumorigenicstate [28]. Retinoids have long been known to promotetumor cell differentiation, and recently all-trans retinoicacid was shown to exert an antitumor effect specifically onstem-like glioma cells [29]. However, previous clinical

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trials have so far reported limited efficacy of both all-transretinoic acid as well as cis-retinoic acid [30–32], and itremains to be seen whether any particular form of retinoicacid can be useful in combination to sensitize GSCs tocytotoxic treatment.

Radiosensitization

Gliomas show only a moderate response to radio- andchemotherapy. Resistance mechanisms are preferentiallyactivated in cancer stem cells, and in GSCs in particular,display activation of the DNA damage checkpoint responseas well as an increase in DNA repair capacity. CD133expressing putative GSCs survive radiation in vitro and invivo at increased proportions relative to cells lackingCD133 expression [33]. They repair radiation-inducedDNA damage more effectively than CD133-negative tumorcells, and their radioresistance could be reversed usingsmall molecule inhibitors of the Chk1 and Chk2 checkpointkinases. Thus, targeting the DNA damage checkpointresponse in GSCs might represent a promising therapeuticstrategy. In addition, as mentioned above, inhibition of theNOTCH pathway using GSIs may also sensitize GSCs toradiotherapy [19]. Interestingly an analysis that correlatedclinical outcome with gene expression profiles showed thata stem cell-related “self-renewal” signature dominatedby HOX genes was a predictor of poor survival inglioblastoma patients treated with chemoradiotherapy [34].

GSCs have further been demonstrated to be relativelyresistant to chemotherapy with temozolomide [35], al-though this issue is controversial [36]. Chemoresistancecan in part be explained by elevated expression of drugtransporter genes such as ABCG2 and ABCA3 [37]. Itremains to be demonstrated which other resistance mech-anisms contribute to GSC chemoresistance and whethertheir blockade can sensitize cells to treatment.

Indirect targeting of the GSC niche

Several studies suggest that GSCs preferentially reside inperivascular areas, termed the “vascular niche”, wherethey receive paracrine cues from endothelial cells thatmimic the normal neural stem cell niche and where theymaintain a stem-like state [38]. Disruption of nichehomeostasis therefore is another theoretically attractivetargeting approach. Compared with non stem-like gliomacells, GSCs secrete elevated levels of vascular endothelialgrowth factor (VEGF) and have a strong angiogenic effect[39], suggesting mutual interdependence of the GSCcompartment and the vascular compartment. Bevacizumab,an anti-VEGF antibody with potent antiangiogenic activity,was found to suppress angiogenesis and growth of GSC-derived xenografts, whereas it had limited efficacy againstxenografts derived from non-GSC populations [39]. Inanother study, treatment with bevacizumab ablated self-renewing cells from glioblastoma xenografts and arrested

Table 1 Successful targeting of glioma stem cells

Targeting strategy Target Tool Reference

Signaling pathway inhibition NOTCH γ-secretase inhibitors Fan et al., 2010 [18]

PI3K pathway AKT inhibitors Eyler et al., 2008 [20]

SHH pathway Cyclopamine Bar et al., 2007 [21]

NF-kappaB pathway shRNA against A20 (TNFAIP3) Hjelmeland et al, 2010 [22]

c-Myc pathway shRNA against c-Myc Wang et al., 2008 [23]

c-Myc pathway shRNA against EZH2 or DZNep Suva et al., 2009 [24]

IL6 shRNA/antibody Wang et al., 2009 [25]

CXCR4 AMD3100 Lamszus et al., 2010 [26]

Differentiation BMP receptors BMP4 Piccirillo et al., 2006 [27]

TRRAP Wurdak et al., 2010 [28]

Retinoic acid receptors All-trans retinoic acid Campos et al., 2010 [29]

Radiosensitization Chk1, Chk2 Small molecule inhibitors Bao et al., 2006 [33]

NOTCH pathway γ-secretase inhibitors Wang et al., 2010 [19]

Indirect targeting of the GSC niche VEGF Bevacizumab Bao et al., 2006 [39]

VEGF Bevacizumab Calabrese et al., 2007 [38]

VEGFR-2 DC101(+cyclophosphamide) Folkins et al., 2007 [40]

Oncolytic virotherapy Abnormal p16INK4/Rb cells Oncolytic Adenovirus Delta-24-RGD Jiang et al., 2007 [41]

Neoplastic cells Oncolytic herpes simplex virus Wakimoto et al., 2009 [42]

Adhesion molecule inhibition L1CAM shRNA Bao et al., 2008 [43]

Only studies are included that provide in vitro as well as in vivo preclinical evidence of successful GSC targeting

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tumor growth [38]. In a third study, the combination ofantiangiogenic therapy using an anti-VEGF receptor anti-body with cytotoxic treatment resulted in efficient reductionof the GSC population in vivo, however, antiangiogenictreatment alone had no such effect, suggesting that disruptionof the niche sensitized GSCs to chemotherapy [40].Bevacizumab is currently in phase III clinical trials for treatingnewly diagnosed glioblastoma, and it will be interesting todetermine whether this treatment leads to depletion of tumorcells expressing stem cell markers in patients.

Oncolytic virotherapy

Oncolytic viruses are natural or genetically modifiedviruses that preferentially infect and lyse cancer cells whilesparing nonneoplastic cells. Delta-24-RGD is an oncolyticadenovirus that selectively replicates in cancer cells with anabnormal Rb pathway and displays enhanced tropism toglioma cells [41]. Mice bearing intracranial xenografts ofglioblastoma stem cell lines survived significantly longerupon treatment with Delta-24-RGD, and autophagic tumorcell death appeared to be the most likely mechanism. Anoncolytic herpes simplex virus (oHSV) was also describedto inhibit self-renewal of GSCs, to cause cell death, and toprolong survival of mice bearing invasive GSC culture-derived xenografts [42].

Adhesion molecule inhibition

L1CAM is a neuronal cell adhesion molecule that regulatesneural cell growth, survival, and migration, as well asaxonal outgrowth and neurite extension during develop-ment. It is overexpressed in gliomas as well as othercancers and thus represents a potential cell surface target.L1CAM was found to be present on most CD133+ gliomacells, whereas CD113− cells were typically L1CAM-negative. Lentiviral shRNA targeting of L1CAM disruptedneurosphere formation, induced apoptosis and inhibitedgrowth of CD133-positve GSCs; furthermore, L1CAMknockdown inhibited GSC-derived tumor formation in vivoand increased the survival of tumor-bearing animals [43].

Future considerations

Further GSC targeting strategies are also currently beingexplored, an important one of which is immunotherapy, andthis complex area of research, which includes vaccinationapproaches as well as attempts to overcome tumor-inducedimmunosuppressive mechanisms, is covered in a separatearticle in this issue (Hatiboglu et al. [44]). In addition,interesting results are to be expected from the emergingfield of MicroRNA (miRNA) research. These are small

non-coding RNAs, which downregulate gene expressionpost-transcriptionally during various crucial cell processessuch as apoptosis, differentiation and development. Severalrecent studies identified aberrant miRNA expression ingliomas, and linked some of them to GSC maintainanceand growth [45, 46], although specific targeting agentsother than transfection/transduction-based techniques arenot yet available.

A major concern in the design of any GSC-targetingtherapy is to avoid damaging normal adult neural stem/progenitor cells, which share similar gene and antigenexpression profiles with GSCs. Adult neural stem cellsserve many important functions, especially tissue repairafter injury, including traumatic, ischemic, tumor-associated or treatment-induced tissue destruction. Inaddition, endogenous neural precursor cells were foundto possess significant intrinsic anti-tumor activity: theyare attracted by gliomas in vivo, inhibit glioma cellgrowth and induce apoptosis [47]. Thus, one of the mostimportant challenges lies in the definition of a specific-enough therapeutic window within which the GSCs can besuccessfully targeted and eliminated, while normal neuralstem/progenitor cells are saved.

Acknowledgement The authors´ work is supported by the DeutscheForschungsgemeinschaft (LA 1300/3-1 and LA 1300/4-1), theDeutsche Krebshilfe e.V., and the Johannes Bauer Stiftung fürHirntumorforschung.

Conflict of interest statement The authors have no conflict ofinterest to declare.

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