Advances in cancer research. Volume one hundred and twenty one

427 Pages·2014·15.611 MB·English

by  Kenneth D Tew, Paul B Fisher

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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,