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ISBN:978-0-12-800249-0 ISSN:0065-230X ForinformationonallAcademicPresspublications visitourwebsiteatstore.elsevier.com PrintedandboundinUSA 14 15 16 12 11 10 9 8 7 6 5 4 3 2 1 CONTRIBUTORS AimanAlhazmi DepartmentofHumanandMolecularGenetics,VCUInstituteofMolecularMedicine, MasseyCancerCenter,VirginiaCommonwealthUniversitySchoolofMedicine, Richmond,Virginia,USA AlbertS.Baldwin LinebergerComprehensiveCancerCenter,UniversityofNorthCarolinaSchoolof Medicine,ChapelHill,NorthCarolina,USA JenniferW.Bradford LinebergerComprehensiveCancerCenter,UniversityofNorthCarolinaSchoolof Medicine,ChapelHill,NorthCarolina,USA AmyLeeBredlau DepartmentofPediatrics,andDepartmentofNeurosciences,MedicalUniversityofSouth Carolina,Charleston,SouthCarolina,USA SrikumarP.Chellappan DepartmentofTumorBiology,H.LeeMoffittCancerCenterandResearchInstitute, Tampa,Florida,USA SwadeshK.Das DepartmentofHumanandMolecularGenetics,andVCUInstituteofMolecularMedicine, VirginiaCommonwealthUniversity,SchoolofMedicine,Richmond,Virginia,USA LuniEmdad DepartmentofHumanandMolecularGenetics;VCUInstituteofMolecularMedicine,and VCUMasseyCancerCenter,VirginiaCommonwealthUniversity,SchoolofMedicine, Richmond,Virginia,USA BenedettoFarsaci LaboratoryofTumorImmunologyandBiology,CenterforCancerResearch,National CancerInstitute,NationalInstitutesofHealth,Bethesda,Maryland,USA PaulB.Fisher DepartmentofHumanandMolecularGenetics;VCUInstituteofMolecularMedicine,and VCUMasseyCancerCenter,VirginiaCommonwealthUniversity,SchoolofMedicine, Richmond,Virginia,USA DanielJ.Foster DepartmentofNeurology;DepartmentofNeurologicalSurgeryandBrainTumorResearch Center,andSandlerNeurosciencesCenter,UniversityofCalifornia,SanFrancisco, California,USA AaronFrantz DepartmentofNeurology;DepartmentofNeurologicalSurgeryandBrainTumorResearch Center,andSandlerNeurosciencesCenter,UniversityofCalifornia,SanFrancisco, California,USA ix x Contributors JohnW.Greiner LaboratoryofTumorImmunologyandBiology,CenterforCancerResearch,National CancerInstitute,NationalInstitutesofHealth,Bethesda,Maryland,USA JamesL.Gulley LaboratoryofTumorImmunologyandBiology,CenterforCancerResearch,National CancerInstitute,NationalInstitutesofHealth,Bethesda,Maryland,USA ChristopherR.Heery LaboratoryofTumorImmunologyandBiology,CenterforCancerResearch,National CancerInstitute,NationalInstitutesofHealth,Bethesda,Maryland,USA JamesW.Hodge LaboratoryofTumorImmunologyandBiology,CenterforCancerResearch,National CancerInstitute,NationalInstitutesofHealth,Bethesda,Maryland,USA BinHu DepartmentofHumanandMolecularGenetics,VirginiaCommonwealthUniversity, SchoolofMedicine,Richmond,Virginia,USA MillerHuang DepartmentofNeurology,andHelenDillerFamilyComprehensiveCancerCenter, UniversityofCalifornia,SanFrancisco,California,USA ShirinIlkhanizadeh DepartmentofNeurology,andHelenDillerFamilyComprehensiveCancerCenter, UniversityofCalifornia,SanFrancisco,California,USA CarolineJochems LaboratoryofTumorImmunologyandBiology,CenterforCancerResearch,National CancerInstitute,NationalInstitutesofHealth,Bethesda,Maryland,USA TimothyP.Kegelman DepartmentofHumanandMolecularGenetics,VirginiaCommonwealthUniversity, SchoolofMedicine,Richmond,Virginia,USA DavidN.Korones DepartmentofPediatrics,andDepartmentofPalliativeCare,UniversityofRochester, Rochester,NewYork,USA JosephW.Landry DepartmentofHumanandMolecularGenetics,VCUInstituteofMolecularMedicine, MasseyCancerCenter,VirginiaCommonwealthUniversitySchoolofMedicine, Richmond,Virginia,USA JasmineLau DepartmentofNeurology,andHelenDillerFamilyComprehensiveCancerCenter, UniversityofCalifornia,SanFrancisco,California,USA I.Levinger AvramandStellaGoldstein-GorenDepartmentofBiotechnologyEngineering,Ben-Gurion University,Beer-Sheva,Israel Contributors xi RaviA.Madan Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA KimberlyMayes DepartmentofHumanandMolecularGenetics,VCUInstituteofMolecularMedicine, MasseyCancerCenter,VirginiaCommonwealthUniversitySchoolofMedicine, Richmond,Virginia,USA MitchellE.Menezes DepartmentofHumanandMolecularGenetics,VirginiaCommonwealthUniversity, SchoolofMedicine,Richmond,Virginia,USA ClaudiaPalena LaboratoryofTumorImmunologyandBiology,CenterforCancerResearch,National CancerInstitute,NationalInstitutesofHealth,Bethesda,Maryland,USA AndersI.Persson DepartmentofNeurology;DepartmentofNeurologicalSurgeryandBrainTumorResearch Center,andSandlerNeurosciencesCenter,UniversityofCalifornia,SanFrancisco, California,USA SmithaPillai DepartmentofTumorBiology,H.LeeMoffittCancerCenterandResearchInstitute, Tampa,Florida,USA ZhijunQiu DepartmentofHumanandMolecularGenetics,VCUInstituteofMolecularMedicine, MasseyCancerCenter,VirginiaCommonwealthUniversitySchoolofMedicine, Richmond,Virginia,USA DevanandSarkar DepartmentofHumanandMolecularGenetics;VCUInstituteofMolecularMedicine,and VCUMasseyCancerCenter,VirginiaCommonwealthUniversity,SchoolofMedicine, Richmond,Virginia,USA CourtneySchaal DepartmentofTumorBiology,H.LeeMoffittCancerCenterandResearchInstitute, Tampa,Florida,USA JeffreySchlom LaboratoryofTumorImmunologyandBiology,CenterforCancerResearch,National CancerInstitute,NationalInstitutesofHealth,Bethesda,Maryland,USA Kwong-YokTsang LaboratoryofTumorImmunologyandBiology,CenterforCancerResearch,National CancerInstitute,NationalInstitutesofHealth,Bethesda,Maryland,USA R.Vago AvramandStellaGoldstein-GorenDepartmentofBiotechnologyEngineering,Ben-Gurion University,Beer-Sheva,Israel xii Contributors Y.Ventura AvramandStellaGoldstein-GorenDepartmentofBiotechnologyEngineering,Ben-Gurion University,Beer-Sheva,Israel SusanWang DepartmentofNeurology;DepartmentofNeurologicalSurgeryandBrainTumorResearch Center,andSandlerNeurosciencesCenter,UniversityofCalifornia,SanFrancisco, California,USA Xiang-YangWang DepartmentofHumanandMolecularGenetics;VCUInstituteofMolecularMedicine,and VCUMasseyCancerCenter,VirginiaCommonwealthUniversity,SchoolofMedicine, Richmond,Virginia,USA WilliamA.Weiss DepartmentofNeurology;HelenDillerFamilyComprehensiveCancerCenter,and DepartmentofNeurologicalSurgeryandBrainTumorResearchCenter,Universityof California,SanFrancisco,California,USA JoleneJ.Windle DepartmentofHumanandMolecularGenetics;VCUInstituteofMolecularMedicine,and VCUMasseyCancerCenter,VirginiaCommonwealthUniversity,SchoolofMedicine, Richmond,Virginia,USA RobynWong DepartmentofNeurology,andHelenDillerFamilyComprehensiveCancerCenter, UniversityofCalifornia,SanFrancisco,California,USA CHAPTER ONE Glial Progenitors as Targets for Transformation in Glioma Shirin Ilkhanizadeh*,†, Jasmine Lau*,†,1, Miller Huang*,†,1, Daniel J. Foster*,‡,§,1, Robyn Wong*,†,1, Aaron Frantz*,‡,§, Susan Wang*,‡,§, William A. Weiss*,†,‡,}, Anders I. Persson*,‡,§,2 *DepartmentofNeurology,UniversityofCalifornia,SanFrancisco,California,USA †HelenDillerFamilyComprehensiveCancerCenter,UniversityofCalifornia,SanFrancisco,California,USA ‡DepartmentofNeurologicalSurgeryandBrainTumorResearchCenter,UniversityofCalifornia, SanFrancisco,California,USA §SandlerNeurosciencesCenter,UniversityofCalifornia,SanFrancisco,California,USA }DepartmentofNeurology,UniversityofCalifornia,SanFrancisco,California,USA 1Theseauthorshavecontributedequally. 2Correspondingauthor:e-mailaddress:[email protected] Contents 1. Introduction 2 2. GlialCellLineages 3 3. GliomaSubgroupsandCellofOrigin 6 4. H3F3AMutationsDriveGliomagenesisinSeparateBrainRegions 8 4.1 RegulationofDNAmethylationbyK27andG34H3F3Amutations 12 4.2 ChromosomeandMycaberrationsinH3F3Amutantglioblastoma 13 4.3 DelineatingthecelloforiginforK27andG34H3F3Amutantglioblastoma 14 5. GliomagenesisandMutationsinIsocitrateDehydrogenaseGenes 14 5.1 ModelsofIDH-mutantgliomas 17 5.2 Glialprogenitor-originforIDH-mutantgliomas 18 6. Proneural-to-MesenchymalTransitioninGlioma 20 6.1 Mesenchymalphenotypeasafunctionofgliomasubgroup 22 6.2 TranscriptionalmasterregulatorsofPMTinglioma 22 6.3 Influenceofthetumormicroenvironmentonthemesenchymalphenotype 25 7. RelationshipBetweenGSCsandGlialProgenitors 27 7.1 Polycombgenefamily 29 7.2 NOTCH 30 7.3 Sonichedgehog 30 7.4 Wingless 31 8. TargetedTherapyinGlioma 32 8.1 Epidermalgrowthfactorgenefamily 32 8.2 TargetingtheproneuralsubgroupbyPDGFRinhibition 33 8.3 Targetingthemesenchymalphenotypethroughc-METinhibition 37 8.4 Treatment-resistanceassociatedwithRTKinhibition 38 8.5 TherapeutictargetingofIDH-mutantgliomas 40 AdvancesinCancerResearch,Volume121 #2014ElsevierInc. 1 ISSN0065-230X Allrightsreserved. http://dx.doi.org/10.1016/B978-0-12-800249-0.00001-9 2 ShirinIlkanizadehetal. 9. ConcludingRemarksandFuturePerspectives 41 Acknowledgments 42 References 42 FurtherReading 65 Abstract Gliomaisthemostcommonprimarymalignantbraintumorandarisesthroughoutthe centralnervoussystem.Recentfocusonstem-like gliomacellshasimplicated neural stemcells(NSCs),aminorprecursorpopulationrestrictedtogerminalzones,asapoten- tialsourceofgliomas.Inthisreview,wefocusontherelationshipbetweenoligoden- drocyteprogenitorcells(OPCs),thelargestpopulationofcyclingglialprogenitorsinthe postnatalbrain,andgliomagenesis.OPCscangiverisetogliomas,withsignalingpath- waysassociatedwithNSCsalsoplayingkeyrolesduringOPClineagedevelopment.Gli- omascanalsoundergoaswitchfromprogenitor-tostem-likephenotypeaftertherapy, consistent with an OPC-origin even for stem-like gliomas. Future in-depth studies of OPCbiologymayshedlightontheetiologyofOPC-derivedgliomasandrevealnew therapeuticavenues. 1. INTRODUCTION Gliomas are the most common malignant primary brain tumor and associated with approximately 16,000 cancer-related deaths in UnitedStates peryear(Louisetal.,2007).Recentadvancesinthemolecularcharacteriza- tion of gliomas have defined subgroups of tumors that are genetically and epigenetically distinct (Noushmehr et al., 2010; Phillips et al., 2006; Sturm et al., 2012; Verhaak et al., 2010). The temporal and regional specificity of geneticallydistinctgliomas(Sturmetal.,2012),arguethateitherseveraldis- crete populations of precursor cells may be vulnerable to transformation, or thatmultiplegliomasubgroupsshareacommoncelloforigin.Glialcellsout- numberneuronsby10-foldinthehumanbrainandarecomposedmainlyof terminally differentiated cells and minor discrete precursor populations. Modelingofgliomainmicehasdemonstratedthatcellsatvariousdifferenti- ationstagesthroughoutglialandneuronallineageshavethepotentialtogen- erate gliomas. In this review, we present recent findings suggesting that the mostwide-spreadpopulationofcyclingcellsinthepediatricandadultbrain of mammalians, the oligodendrocyte progenitor cells (OPCs), represents a likely origin for large cohorts of gliomas. We propose that more in-depth studiesofOPCbiologywillinformnovelpreventivemeasuresandtherapeu- tic interventions to reverse the fatal outcome of most glioma patients. GlialProgenitorsasTargetsforTransformationinGlioma 3 Gliomas can grossly be divided into astrocytic, oligodendrocytic, and ependymal phenotypes. Classification by the World Health Organization (WHO) distinguishes malignancy by grade (I–IV). Based on histological appearance, gliomas of most grades and types are found in children and adults. Recent molecular profiling of grade IV glio- blastoma (GBM) exemplifies that subsets of tumors in children, young adults, and adolescents, that are indistinguishable by histology, can be seg- regatedbasedongeneticalterations,broad-scalegeneexpression,andmeth- ylationpatterns.Here,wewillpresentrecentexperimentaladvancesonthe understanding of why humans are diagnosed with a certain type of glioma and where it came from. Gliomas show profound cellular heterogeneity and influences from the tumormicroenvironment;withtreatment-resistanttumorcellsdisplayinga highdegreeofstemness.Thefailuretotargetgliomastemcells(GSCs)along withtheinabilitytofullydebulktumorsthroughsurgicalresection,radiation and chemotherapy, all contribute to poor survival of glioma patients (Huse & Holland, 2010). In this review, we will discuss ways to identify GSCs, their interactions with tumor microenvironment, and therapeutic advances to target GSCs. In 2012, Yanoko Nishiyama and John Gurdon were awarded the Novel Prize in Medicine for identifying factors that can reprogram somatic cells into pluripotent stem cells. Since these factors arealsoexpressedinstem-likecancercells,itispossiblethattheyarosefrom moredifferentiatedcells.Infact,viraltransductionofoncogenesintomature neurons and astrocytes generate gliomas in mice (Friedmann-Morvinski et al., 2012). Similarly, it is plausible that OPCs also can give rise to more stem-like gliomas. 2. GLIAL CELL LINEAGES Thecentralnervoussystem(CNS)representsamosaicorganizationof neural stem cells (NSCs) and astrocyte precursors, that generate neurons, astrocytes, and oligodendrocytes with a high degree of regional specificity (Merkle, Mirzadeh, & Alvarez-Buylla, 2007; Tsai et al., 2012). The posi- tional identity is an organizing principle underlying cellular subtype diver- sification in the brain and is controlled by a homeodomain transcriptional code(Hochstim,Deneen,Lukaszewicz,Zhou,&Anderson,2008).During embryonic development, expansion and cell fate determination of neural precursors is controlled by gradients of secreted molecules along rostrocaudal and dorsoventral axes. Radial glia and embryonic NSCs 4 ShirinIlkanizadehetal. generateneurons,glialcells,andependymalcellsduringneuraldevelopment (Rakic,1990).Asaremnantfromfetaldevelopment,postnatalneurogenesis inmammaliansismainlyrestrictedtothedentategyrusofthehippocampus and the subventricular zone (SVZ) lining the lateral ventricles (Doetsch, 2003; Eriksson et al., 1998; Sanai et al., 2011), with NSCs also lining the thirdandfourthventricles(Weissetal.,1996;Xuetal.,2005).Inthepost- natal rodent cerebellum, Bergmann glia express markers associated with NSCs (Koirala & Corfas, 2010; Sottile, Li, & Scotting, 2006). In contrast torodents,functionalSVZneurogenesisinhumansceasesafter18months, indicatingthatfewSVZNSCsarepresentintheaginghumanbrain(Sanai etal.,2011).Giventheextensiveself-renewalcapacityofNSCs,thesecells havebeensuggestedasthecelloforiginforgliomas(Fig.1.1).Considering thelowabundanceofNSCsandthewidedistributionofgliomasthrough- out the human postnatal brain, it is puzzling how such a rare and anatom- ically restricted cell type could represent the origin of the most common primary malignant brain tumor. A first wave of oligodendrocyte progenitors arises from the embryonic ventral forebrain, followed by a second wave originating from the lateral and caudal ganglionic eminences, and finally a third wave arises within Figure1.1 Distributionofneuralprecursorpopulationsinthepostnatalbrain.OPCsare the most widely distributed population of cycling cells in forebrain and hindbrain regions.Incontrast,adiscretepopulationofNSCsisfoundintheSVZliningthelateral ventricles. GlialProgenitorsasTargetsforTransformationinGlioma 5 the postnatal cortex (Kessaris et al., 2006). In the developing mouse brain and spinal cord, the first oligodendrocyte-lineage cells appear around embryonicday12.5(E12.5)(Zuo&Nishiyama,2013).Thecellsarechar- acterizedbyexpressionofthebasichelix–loop–helix(bHLH)transcription factorsOLIG1,OLIG2,NKX2.2,theSry-relatedhighmobilitygroupbox gene (SOX10), and platelet-derived growth factor receptor alpha (PDGFRA) (Zuo & Nishiyama, 2013). At E14.5, PDGFRA positive cells also express the chondroitin sulfate proteoglycan neuro-glial 2 (NG2) (in humans CSPG4) in the ventral mouse forebrain (Nishiyama, Lin, Giese, Heldin,& Stallcup,1996). WhileOLIG2is requiredfor generation ofoli- godendrocyte specification, the bHLH factor ASCL1 promotes oligodendrogenesis by repressing DLX1/2, a transcriptional repressor of OLIG2 (Ligon et al., 2006; Petryniak, Potter, Rowitch, & Rubenstein, 2007). Other prerequisites for oligodendrogenesis include the SOXE pro- teinsSOX8,SOX9,andSOX10(Stoltetal.,2003).Incontrast,theSOXD proteinsSOX5andSOX6inhibitoligodendrocytespecification(Stoltetal., 2006).Inaddition,thedevelopmentallyexpressedgenesNOTCH-1,wing- less (WNT), and sonic hedgehog (SHH), normally associated with NSCs, block differentiation and maintain an undifferentiated state in OPCs (Zuo & Nishiyama, 2013) (Fig. 1.1B). Asthemostwidelydistributedpopulationofcyclingcellsinthepostnatal brain, OPCs, also referred to as polydendrocytes, represent a fourth major type of glia in the CNS (Zuo & Nishiyama, 2013). In fact, approximately 0 70% of 5-bromo-2-deoxyuridine (BrdU)-incorporating cells in the adult rat brain co-express NG2 (Dawson, Polito, Levine, & Reynolds, 2003; Lasiene, Matsui, Sawa, Wong, & Horner, 2009). An elegant study showed thatOPCsareunderhomeostaticcontroltoensuregenerationofappropri- ate numbers of myelin-producing oligodendrocytes (Hughes, Kang, Fukaya,&Bergles,2013).AsOPCsarerecruitedtofocalinjuries,aprolif- erativeburstofOPCssurroundingtheinjuryrestoresthecelldensity.Doall OPCshavethesameproliferativecapacityorrespondtodifferentenviron- mentcues?PDGFAactsasapotentmitogenofOPCsexpressingPDGFRA (Hall, Giese, & Richardson, 1996). Additionally, in white matter, but not gray matter, OPCs proliferate in response to PDGF by activating WNT and phosphatidylinositol 3-kinase (PI3K) (Hill, Patel, Medved, Reiss, & Nishiyama, 2013). Similar to NSCs, the mitogen epidermal growth factor (EGF) induces symmetrical cell division in adult OPCs (Sugiarto et al., 2011) (Fig. 1.2). Treatment of human OPCs with histone deacetylase (HDAC) inhibitors prevents differentiation into oligodendrocytes,