CANCERSTEMCELLS

Centre for Cancer Research and

Cell Biology, Queens University
Belfast, Belfast BT9 7BL, United
Kingdom

Received July 10, 2014; accepted

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articleasdoi:10.1002/stem.1798

Cancerstemcells:Fromconcepttocure

KYLEBMATCHETT1ANDTERRYJ.LAPPIN1

STEMCELLS2014;00:000000

INTRODUCTION

Advancesinstemcellbiologyandtheneedtofindcures
for cancer patients have created a burgeoning global
researcheffortinwhichstemcellsareusedextensively
toinvestigatethepathogenesisofcancerandpotential
anticancertreatmentstrategies.
Thetheorythatcancerresultsfromanaccumulation
ofgenetic mutations was first proposed byNordling in
1953 [1] and further refined by Ashley, Knudson and
Nowell (reviewed by [2]). It postulates that inherited
mutations and environmental carcinogens can lead to
thedevelopmentofpremalignantclones,andthatafter
furthermutationsonecellreachesacriticalstatewhich
confers a survival or growth advantage over normal
cells.Thisabnormalcellisthencapableofinitiatingthe
formationofamalignanttumor.Duetotheirlongevity
stem cells have been widely held to be the subset of
cellsmostlikelytoaccumulatethenumberofmutations
requiredtogenerateacancercell.
Theconceptofcancerstemcells(CSCs)ispredicated
ontheexistenceofnormaltissuestemcells,whichcan
either undergo division to produce new stem cells, or
differentiate into more specialized cells. Although the
termcancerstemcelliswidelyusedintheliterature,
consensus on a universal definition for CSCs is lacking.
Recently, however, Nguyen and colleagues have de
finedCSCsasthecellswithinamalignantclonalpopu
STEMCELLS2014;00:0000www.StemCells.com

lationthatcanpropagatethecancerundertheassump
tion that these cells must be eradicated to achieve
cures[3].
Thisdefinitionnotonly atteststo the clonal nature
ofcancersarisingfrommultiplesequentialgeneticand
epigeneticevents,andthephenotypicheterogeneityof
tumors,butalsorecognizesthatnotallofthecellswith
inthemalignantpopulationhavestemcelllikeproper
ties.Recentworkdemonstratingstemcellplasticityin
mammary tumors indicates that the concept of CSC
hierarchical organization may not hold for all tumors
andunderlinestheneedforindependentinvestigations
of tumors originating in different tissues [3]. Nonethe
less,manycancersappeartobeorganizedhierarchically
andtoharborasmallnumberofCSCscapableofrenew
ingtumorgrowth,apropertylackingintheirprogeny.
ThisreviewwillfocusonrecentCSCresearchinthe
context of hematological and somatic tissue malignan
cies, and progress in the characterization of signaling
pathways, transcription factors, and other molecules
involvedintumorigenesis.

Hematologicalmalignancies
CSCs have been well characterized in hematological
malignancies. The stem cell origin of chronic myeloid
leukemia(CML)wasconfirmedsome20yearsagowhen
severalgroupsidentifiedandisolatedCMLcellscapable

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of expansion in vitro, based on the characteristics that
delineatenormalHSCs[2].
Hematopoieticstemcelltransplantation(HSCT)isa
potentiallycurativeoptionforpatientswithacutemye
loidleukemia(AML).Betterunderstandingofthebiolo
gyofleukemicstemcells,andthepracticeofriskstrati
fication using cytogenetics and molecular markers, has
enhancedtheselectionofpatientsmostlikelytobene
fit from allogeneic transplantation. In their concise re
view, Hamiltonand Copelan discussthe theoretical as
pectsoftransplantation,analyzeclinicaldata,andpro
viderecommendationsfortheuseofHSCTinAML[4].
AML and the myelodysplastic syndromes (MDS)
arise from transformed immature hematopoietic cells
followingtheaccumulationofmultiplegeneticandepi
genetic perturbations in hematopoietic stem cells and
committed progenitor cells. Pandolfi and colleagues
review recent advances in the understanding of this
series of transforming events that initially gives rise to
preleukemiastemcellswhichprecedetheformationof
fullytransformedleukemiastemcells[5].
Although focal adhesion kinase (FAK) activity is im
plicated in many cancer phenotypes, little is known
about its role in AML. FAK splice variant expression is
deregulatedinprimitiveleukemiccellsinAMLpatients
with poor prognosis. Targeting FAK was found to effi
ciently eliminate leukemic cells in vitro suggesting that
FAK may be a useful therapeutic target for improved
treatment of this subset of AML patients with poor
prognosis[6].
LIM domain only 2 (LMO2) is one of the most fre
quentlyoverexpressedoncogenesinhumanacuteTcell
lymphoblastic leukemia (TALL). Analysis of CD2Lmo2
transgenic thymic progenitor cells revealed that they
were blocked in differentiation, quiescent, and immor
talizedinvitroonOP9DL1stromalcells.Thesecellular
eventsareconsistentwithatranscriptionalsignaturein
Lmo2transgenicTcellprogenitorcellsthatisalsopre
sent in HSCs and in early Tcell precursor ALL [7]. The
TELAML1fusiongeneoftenarisesbeforebirthcreating
apersistentpreleukemicclonecapableofconvertingto
precursorBcellleukemiaaftertheaccumulationofsec
ondary genetic mutations. TELAML1mediated self
renewal is associated with a transcriptional program
sharedwithembryonicstemcells(ESCs),afindingthat
may provide a basis for targeting the TELAML1 tran
scriptionprogram[8].
The Friend erythroleukemia virus has been a long
standingmodelsystemforinvestigatingthemultistage
process of leukemia progression and the mechanisms
thatregulateerythroiddevelopment.Buildingonearlier
work indicating that Friend virus activates the BMP4
dependent stress erythropoiesis pathway, Paulsons
group showed that the two stages of Friend virus
induced disease are caused by infection of specific
stress progenitor populations in the spleen, thereby
establishing a new model for Friend virusinduced leu
kemia and demonstrating its utility as a model system
forleukemiastemcellselfrenewal[9].
www.StemCells.com

In two recent articles Bonnets group presented a

new tool to identify chemoresistance and selfrenewal
mechanismsinprimaryhumanAMLinitiatingcells[10]
andIchimreportedonkinaseindependentmechanisms
of resistance of leukemia stem cells to tyrosine kinase
inhibitors[11].
Recent developments in diagnostic and therapeutic
approacheshaveimprovedtheprogressionfreesurviv
alratesinHodgkinsLymphoma.Amongthesearefunc
tionalimaging,refinementofclinicalprognosticfactors
andthedevelopmentofnovelmarkerswhichfacilitate
improved patient selection and timing for autologous
stemcelltransplantation[12].
Premature ovarian failure occurs in a high propor
tionofpatientswhoreceiveconventionalchemothera
pyormyeloablativetherapywithHSCT.Theauthorsof
a phase II study involving 60 patients who underwent
either myeloablative or nonmyeloablative regimens
reportedthatthegonadotropinreleasinghormoneana
log,leuprolide,didnotpreserveovarianfunction,high
lighting the need to investigate other approaches to
protectovarianfunction[13].

BreastCancer
Two interesting papers report on radiation effects in
breastcancerstemcells.Lagadecandcolleaguesfound
that ionizing radiation reprogrammed differentiated
breastcancercellsintoinducedbreastcancerstemcells
(BCSCs) that showed enlarged mammosphere for
mation, increased tumorigenicity and expressed the
same stemnessrelated genes as BCSCs from non
irradiated samples. The authors concluded that radia
tion contributes to the increased BCSC numbers seen
after classical anticancer treatment [14]. Vieira and
colleagues found that Pcadherin confers resistance to
xrayinducedcelldeathandmediatesstemcellproper
tiesinbasallikebreastcancer[15].
KeyaspectsoftheroleofBCSCsonthepathogenesis
of breast cancer are examined in articles devoted to
breast cancer initiation, progression and therapy [16],
theregulationofbreastcancerstemcellsbyglobalsig
nalingnetworks[17],mevalonatemetabolism[18],and
a novel role for tumorassociated macrophages in the
regulation of a recently identified paracrine
EGFR/Stat3/Sox2 signaling pathway [19]. Utilizing a
novelmousemammarycancerstemcellmodel,epithe
lialtumorinitiatingcells(ETICs)thatexpressbothbasal
and luminal mammary cell lineages were found to re
tain the potential to generate heterogeneous tumors.
This may eventually enable the identification of thera
peutic agents to target particular breast cancer sub
types[20].
Stateoftheart intravital imaging techniques have
demonstrated remarkable stem cell plasticity in mam
mary tumors [21] and enabled the assessment of the
remodeling of endogenous mammary epithelium by
breastcancercells[22].
Woodwards group treated the aggressive breast
cell lines SUM159 and MDA231, as well as primary
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breastcancercells derivedfrompatients, withthehis
tone deacetylase (HDAC) inhibitors valproic acid or
suberoylanilidehydroxamicacidandfoundincreasesin
ALDH activity, mammosphereforming efficiency and
tumorinitiating capacity of nonstemlike cells, medi
ated through the WNT/catenin signaling pathway.
Thus,atleastinvitro,HDACinhibitorscanpromotethe
expansion of breast CSCs through dedifferentiation,
which may have important clinical implications [23].
Phosphosulindac (OXT328), a novel derivative of the
nonsteroidalantiinflammatorydrugsulindac,hasbeen
reportedtoselectivelytargetBCSCsbothinvitroandin
human breast cancer xenografts [24]. In preclinical
modelsoftriplenegativebreastcancer,thesecretase
inhibitor PF03084014 showed synergistic effects with
docetaxelthroughmultiplemechanisms,indicatingthat
it may have the potential to enhance taxane therapy
[25].
Eliminationoftumorinitiatingcellsbyinhibitingthe
p90 ribosomal S6 kinase through inactivation of the Y
box binding protein1 in triplenegative breast cancers
[26] and inhibition of EZH2, which is required for both
breast and pancreatic cancer stem cell maintenance
[27],mayalsoofferrationalapproachestotherapyfor
sometypesofbreastcancer.

Gliomaandglioblastoma
Severallines of investigationindicate that glioma stem
cells(GSCs)contributetotherapeuticresistanceinhigh
grade glioma, and that eradication of GSCs is essential
to achieve complete therapeutic response. To gain in
sightsintothepathogenesisofhighgradegliomasand
glioblastoma multiforme, Nakanos group investigated
theroleofMELKinGSCs[28],[29].Raihasbeencharac
terised as a new regulator of neural progenitor migra
tion and glioblastoma invasion [30] while CD133 has
beenfoundtobeessentialforthemaintenanceofGSCs
[30]. Cellular plasticity is reported to confer migratory
and invasive advantages on a population of GSCs that
invade peritumoral tissue [31]. Numb regulates GSC
fateandgrowthbyderegulatingEGFRandSCFubiquitin
ligaseactivity[32]andIGF1receptorsignalingregulates
adaptive radioprotection in GSCs [33]. REST regulates
the oncogenic properties of glioma cells [34] and the
tumorigenic potential of miR18A* in GSCs requires
NOTCH1signaling[35].
Leeandcolleaguesreportthatinhibitionofpololike
kinase 1 (PLK1) kills glioblastoma multiforme brain tu
morcellspartlythroughlossofSOX2anddelaystumor
progression in vivo [36]. Other groups have demon
stratedthatConnexin43reversesthemalignantcharac
teristics of glioma stem cells by regulating Ecadherin
[37]andthatcancer cell heterogeneityin glioblastoma
can be counteracted by targeting the cytosolic innate
immune receptors RIGI and MDA5 [38]. Interestingly,
GSCscanbetargetedbymetforminactivationofFOXO3
viaAMPK[39].
YuanandcolleaguesfoundthatGSCsexhibitedlow
mitochondrial respiration and high glycolytic activity.
www.StemCells.com

The GSCs were sensitive to the glycolytic inhibitor 3

BrOP but resistant to conventional therapy such as
carmustineandtemozolomide(TMZ).Combinationof3
BrOPwithcarmustine,butnotwithTMZ,wasstrikingly
synergisticandkilledGSCsthroughdepletionofcellular
ATP and inhibition of the repair of carmustineinduced
DNA damage, leading to impaired sphereforming abil
ity in vitro and enhanced survival of mice inoculated
withGSCs[40].
Inclinicaltrials,oncolyticviraltherapieshaveshown
promise for thetreatment of glioblastoma.Sgubinand
colleagues found that oncolytic Herpes simplex virus
counteracts the hypoxiainduced modulation of
glioblastoma stemlike cells, suggesting that further
developmentofthisapproachiswarranted[41].
WerbowetskiOglivie and colleagues have shown
that neural precursors derived from transformed hu
man embryonic cells (NthESCs) exhibit features of
human brain tumors, and so can provide a model sys
tem to investigate the initiation and progression of
primitive humanneuralcancers that are difficult to in
vestigateusingsomaticsources[42].
CD133 is highly expressed in the CSCs of glioblas
toma multiforme and appears to be associated with
resistance of the CSCs to treatment with radiationand
chemotherapy. In studies designed to target CD133 by
cytotoxicTcells(CTLs)theYugroupculturedshortpep
tide fragments of CD133 with dendritic cells that func
tion as antigenpresenting cells in the immune system.
Two potential human leukocyte antigen (HLA)A*0201
restricted CD133 epitopes, CD133405 and CD133753,
showedpotentialasantiCSCantigensinGBM.Autolo
gous monocytederived dendritic cells pulsed with ei
ther of the epitopes stimulated CTLs to efficiently rec
ognizetheCD133epitopespresentedinT2HLAA*0201
cells,andtospecificallylyseCD133+HLAA*0201+GBM
CSCs.Immunizationofmicewiththemurinehomologs
oftheCD133epitopesdemonstratedimmunogenicityin
the absence of autoimmune damage. The study sup
portstheuseofCD133specificepitopevaccinestotar
getCSCsinglioblastoma,andarguesforaclinicaltrialto
assessthesafetyofthisapproach[43].

Colorectalcancer
Inaconcisereviewofcolorectalcancer(CRC)stemcells
Vaiopoulosandcolleaguesdiscussarecentlyintroduced
CSCmodelincolorectalcancer,biomarkersusedforCSC
identification, and various novel therapeutic approach
es[44].
Screening of new anticancer drugs is generally per
formed on conventional tumor cell lines but this ap
proach is controversial because the cell lines may not
recapitulateCSCpopulationsinprimarytumors.Muraro
andcolleaguestestedapanelof10establishedCRCcell
lines and found that CD133+, CD166+CD44+, and
CD24+CD44+ phenotypes failed to reliably identify cell
populationswithstemcellfunctionalfeatures[45].
In an effort to identify CSC markers with greater
specificity than CD44 and CD133, Medemas group de
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veloped monoclonal antibodies against the Wnt target
Lgr5andshowedthatLgr5isaselectivemarkerforhu
man CRC stem cells [46]. Separately, Lgr5positive CRC
stem cells have been reported to undergo a reversible
transition to drugresistant Lgrnegative cells and to
havethepotentialfortumorreconstitution[47].
EmbryonicNANOG(NANOG1)isanimportantregu
lator of pluripotency and its expression is positively
regulatedbycJUNandcatenin/TCF4.Thesetwofac
torstogetherhavebeenpostulatedtodriveasubpopu
lationofCRCtumorcellsthatadoptastemlikepheno
typeviatheNANOG1promoter[48].Coloncancercells
are dependent on Pololike kinase 1 for proliferation
[49], consistent with its essential role in glioblastoma
multiforme brain tumor cells in tumor progression in
mice[36].Inthequesttoreducemetastaticprogression
from primary CRC, a vaccine targeting CSCs was found
toefficientlyreducebothtumorvolumeandoccurrence
oflivermetastasesinaratcoloncarcinomamodel[50].

Melanoma
Theexistenceofmelanomastemcellshasbeenwidely
debated. Two recent papers provide strong evidence
that a population of cells with high aldehyde dehydro
genase (ALDH) activity are, in fact, melanoma stem
cells.Luoandcolleaguesinvestigatedhumanmelanoma
cells that fulfill the criteria for CSCs, namely self
renewal and differentiation, by serial xenotransplanta
tionintoNOD/SCIDmice.ThesecellspossesshighALDH
activity and are more tumorigenic than ALDHnegative
cellsinmurinemodels.Thegenesignaturesofthemel
anoma CSCs include retinoic aciddriven genes and
thoseimplicatedinstem cellfunction[50].Santiniand
colleaguesusednonadherentspheresand ALDHenzy
maticactivitytoenrichforCSCsinacollectionofhuman
melanomas. They found that melanospheres express
highlevelsofHedgehogpathwaycomponentsandem
bryonic pluripotent stem cell factors. Pharmacological
inhibition of Hedgehog signaling by the SMOOTHENED
(SMO) antagonist cyclopamine, and the GLI antagonist
GANT61, and targeting either SMO or GLI1 by shRNA
resultedinasignificantdecreaseinmelanomastemcell
selfrenewalinvitroaccompaniedbyareductioninthe
numberofALDHhighmelanomastemcells[51].
The Rhodamine 123 (Rh123) exclusion assay has
been used to identify stemlike cells in metastatic hu
manmelanomasandmelanomacelllines.Asmallsub
setofRh123lowcellswasenrichedforstemcelllikeac
tivities, including the ability to selfrenew and produce
nonstemRh123highprogenyfrommelanospheres,reca
pitulatingthephenotypicprofileoftheparentaltumor.
Inhibition of the PI3K/AKT pathway caused specific re
version of a subset of Rh123high cells to the Rh123low
phenotype that were less quiescent and displayed a
significantincreaseinmelanosphereformationforming
ability[52].
Anaka and colleagues analyzed the growth proper
ties, transcriptional profile and genotype of melanoma
cellsgrowndenovoinstemcellmedia(SCM)andfound
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a neural lineage gene expression profile that was not

representative of matched patient tissue specimens.
They concluded that SCM culture of melanoma results
in a neural bias that could potentially confound target
identification[53].

Prostatecancer
Stemcelllikeprostatecancercellsarecapablenotonly
oftumorinitiationandmaintenanceinprostatecancer
(PC), but also of tumor reinitiation in castration
resistant PC (CRPC). Germann and colleagues reported
the identification of the human counterpart of murine
castrationresistant cells (CARNs), which express the
putative prostate tumor suppressor Nkx31, luminal
markers such as cytokeratin 18 and the androgen re
ceptor, and possess stem celllike properties. These
humanPCSC/CARNlikecellsmayrepresentthecellof
originoftumorreinitiationinCRPCandhavepotential
lyimportantclinicalimplications[54].
Taylor et al. used prostatic basal cells enriched
basedinitiallyon21integrin(hi)expressionandsub
sequently for stem cells by CD133. Unexpectedly the
tumorigenic potential did not reside in the CD133(+)
populationbutwasconsistentlyfoundintheCD133()
population, confirming that benign human basal cells
includecellsoforiginofprostatecancerandreinforcing
theirimportanceastherapeutictargets[55].
The TRAMP (transgenic adenocarcinoma of the
mouse prostate) model is well characterized. TRAMP
miceconsistentlydevelopaprogressivelesionknownas
prostatic intraepithelial neoplasia that develops into
adenocarcinoma between 24 and 30 weeks of age.
Gallis group established longterm selfrenewing PCSC
lines from the different stages of TRAMP progression
usingthetumor(orfloating)sphereassay.Thesestage
specificprostatecelllineshadCSCpropertieswithwell
definedgenesignaturescorrespondingtodistinctstag
esofhumantumorprogression.Theyshouldprovidea
valuable preclinical model for elucidating the
pathogenetic mechanisms in prostate adenocarcinoma
andfortheidentificationofpossibletherapeutictargets
[56].

Sarcoma
Soft tissue sarcomas (STSs) may arise from mesenchy
mal stem cells (MSCs). The expression pattern of MSC
markers in sarcoma cell lines, primary tumor samples
and fibroblasts has been examined by flow cytometry
usingarecentlyassembledpanelofantibodies.Expres
sionofW5C5,W8B2(alsoknownastissuenonspecific
alkalinephosphatase,TNAP),CD344andCD271marked
subpopulations with increased proliferation potential,
but the bona fide progenitor cell markers CD117 and
CD133 were not expressed. Overall the data implied a
hierarchicalcytoarchitectureofthemostcommonadult
type sarcomas and establish W5C5, TNAP, CD344 and
CD271 as potential sarcoma progenitor cell markers
[57].

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Sarcomas characterized by the presence of tumor
specific fusion oncogenes as a result of chromosomal
translocations have been modeled in mice. Rodriguez
and colleagues describe the first model of sarcoma
basedontheexpressionofasarcomaassociatedfusion
proteinFUSCHOPinhumanMSCs,whichshouldenable
insightsintothemechanismsofcellulartransformation
insarcomaandtestingforpotentialtherapeutictargets
[58].

Ovariancancer
Factors affecting intratumoral heterogeneity, invasion
andmigrationofovariancancercellshavebeenreport
ed. By examining clonal subpopulations from a single
ovarianclearcellcarcinomainahumanembryonicstem
cell (hESC)derived cellular microenvironment in mice,
Abelson and colleagues demonstrated marked
intratumoral phenotypic heterogeneity. Moreover, the
derived cells displayed microenvironmentdependent
plasticity with the capacity to switch from CD44+
/ALDH+selfrenewingcellsthatsustaintumorgrowthto
differentiatedCD44/ALDHcells,leadingtheauthorsto
propose that a paradigm shift is required in the ap
proachtoanticancertherapy[59].

Signalingpathways,transcriptionfactors,and
othermolecules

Angiogenicfactors
Theangiogenicpropertiesoftumorinitiatingcells(TICs)
havebeenexaminedinarangeoftumortypesincluding
breast (MCF7), glioblastoma (U87MG), colon (HT29),
nonsmallcell lung (A549) and pancreatic (PAN1) can
cers.Longtermculturesgrownasmonolayers(TIClow)
orasnonadherenttumorspheres(TIChigh)weregen
erated. TICs from U87MG and HT29 but not from
MCF7, A549 and PANC1 possess increased angiogenic
activity. Differential angiogenic activity and sensitivity
to antiangiogenic therapy were found in the same tu
mortype,suggestingthattheefficacyofantiangiogenic
drugs,suchasVEGFAneutralizingantibody,isdepend
entontheangiogenicpropertiesoftheTICs[60].
Examination of the biological effects of MSCs on
tumor cells showed that they inhibited the growth of
human glioma cell lines and patientderived primary
gliomacellsinvitro[61].CoadministrationofMSCsand
gliomacellscausedasignificantreductionintumorvol
ume and vascular density. Endothelial progenitor cell
(EPC)recruitmentandthecapacitytoformendothelial
tubes was also significantly impaired in conditioned
media derived from MSC/glioma coculture, suggesting
that MSCs suppress tumor angiogenesis through the
releaseofantiangiogenicfactors.Decreasedexpression
of platelet derived growth factor (PDGF)BB in
MSC/gliomacocultureimpliesthattheantitumoreffect
of MSCs may be mediated through the PDGF/PDGFR
axiswhichhasanestablishedroleingliomaangiogene
sis.
www.StemCells.com

MSCs have considerable potential as tumor

targetingvehiclesduetotheirinnatetumortropichom
ingproperties.Keungandcolleagues[62]reviewrecent
progress in novel cellbased cancer therapies utilizing
geneticallyengineeredMSCs,inparticulartheirapplica
tiontotargetingangiogenesisandtumorstromaingas
trointestinalmalignancies,suchashepatocellularcarci
nomaandpancreaticadenocarcinoma.
In a comprehensive proteomic analysis of human
glioblastoma stem cells (GSCs) and neural stem cells,
hepatomaderivedgrowthfactor(HDGF)hasbeeniden
tified as a novel angiogenic secreted factor [63]. GSC
conditionedmediuminducedmigrationofhumancere
bral endothelial cells that could be blocked with anti
HDGF antibodies in vitro, and neoangiogenesis, which
couldbeabrogatedbyHDGFtargetedsiRNAsinvivo.

Chemokinereceptors
LongandcolleaguescomparedaCD133+specificpopu
lation of ovarian cancer cells (CSLCs) to CD133 non
CSLCs. In the former cell type CC type chemokine re
ceptor (CCR) 1, CCR3 and CCR5 were upregulated and
blocking of CCR5, CCR1 or CCR3 effectively inhibited
their invasive capacity, suggesting that activation of
CCR1, CCR3 or CCR5 may contribute to the metastatic
propertiesofovarianCLSCs[64].
A subpopulation of the renal carcinoma cell (RCC)
lineRCC53expressestheCXCtypechemokinereceptor
4(CXCR4).Whengrownasspheres,mostofcellswere
CXCR4positive, expressed stem cell associated tran
scriptionfactorgenesatelevatedlevelsandweremore
resistanttowardthetyrosinekinaseinhibitorssunitinib,
sorafenib and pazopanib. Interestingly, higher CXCR4
mRNA levels in primary RCC from patients with local
ized, but not disseminated, disease predicted shorter
survival. More effective treatments of metastatic RCC
may develop from combining standard treatment pro
tocols with blockade of the CXCR4 signaling pathway
[65].

Polycombgroupproteins
The polycomb group (PcG) proteins are composed of
twomultimericproteincomplexesthatfunctionasepi
geneticgenesilencersinmanyaspectsofdevelopment
and in cancer. Polycomb recessive complex 1 (PRC1)
includes the BMI1 polycomb ring finger, which pro
motes neural stem selfrenewal. The role of BMI1 in
recurrenceandresistanceincancerhasbeenreviewed
[66].TheinteractionofBMI1withFoxG1intheregula
tion of selfrenewal and tumorigenicity of
medulloblastomastemcellshasbeeninvestigated[67].
Both FoxG1 and BMI1 were significantly enriched in
nonShh/Wntmedulloblastomasofgroups3and4that
are characterized by metastatic progression, poor pa
tient outcome and the lack of a molecular pathway
phenotype.

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SOXtranscriptionfactors
TwomembersoftheSoxfamilyoftranscriptionfactors
have recently been implicated in CSCs. SOX2 is a self
renewalfactorinlungstemcellsandishighlyexpressed
inasubpopulationoflungcancercellsinwhichprolifer
ation, survival and chemoresistance are dependent on
SOX2 signaling. SOX2 elicits oncogenic EGFR and BCL1
signaling, and the expression of SOX2, EGFR and BCL1
levelsweresignificantlycorrelatedinlungtumors.SOX2
isassociatedwithpoorprognosisinlungcancerandhas
potential applications as a prognostic marker and as a
therapeutic target in the disease [68]. In the
CD44high/ESAhighsubpopulationofcellssortedfromhead
and neck cancers inhibition of GSK3b reduces the ex
pression of Sox2, Oct4 and Nanog and upregulates ex
pression of the differentiation markers Calgranulin B
andInvolucrin[69].
Investigationoftheepigeneticregulationofgenesin
the tumorinitiating population of pancreatic cancer
cellsrevealedthatSOX9,whichisdemethylatedinCSCs,
plays a critical role in the invasion process. The NFB
signaling pathway is activated in pancreatic CSCs and
inhibition of the pathway disrupted the stem celllike
propertiesofthecells.Thisstudyestablishesalinkbe
tween the canonical NFB signaling pathway and the
invasiveness of pancreatic CSCs and could lead to the
identification of novel molecules that function at the
epigeneticlevelandwhichmayformfuturetherapeutic
targets.[70].

HedgehogandNotchsignalingpathways
Aberrant activation of the Hedgehog and Notch path
ways via mutations or overexpression has been impli
cated in many tumor types through pathogenetic
mechanismsrangingfromtumorinitiationtoangiogen
esisandcancerstemcellmaintenance.Thepolypeptide
ligand Hedgehog (Hh) activates the signal transduction
pathwaythatbearsitname.TheHh pathwayisessen
tial for embryonic development, but is silenced in
adults. Evidence is accumulating that it plays an im
portantroleintissuerepairandcarcinogenesis.Promis
ingresultswereobtainedinearlyphaseclinicaltrialsof
Hh inhibitors as monotherapy for patients with basal
cell carcinoma and medulloblastoma, leading to the
realization that combination therapy regimes and the
developmentofcorrelativebiomarkersshouldbepriori
tizedinfutureresearch[71].
A close link has been found between the Notch 1
pathway and tumor vascularization of GBM cells [72].
ActivationofNotch1signalingreducedthegrowthrate
andmigrationofGBMcells,accompaniedbyamarked
reductionintheexpressionoftheneuralstemcelltran
scription factors ASCL1, OLIG2 and SOX2 and by
upregulation of HEY1/2, KLF9 and SNAI2. Following
terminationofNotch1stimulation,expressionofOLIG2
and growth were restored. In xenotransplantation ex
periments, Notch1stimulated GBM cells resulted in
poorly disseminated but highly vascularized tumors, in
contrast to control GBM stem cells, which gave rise to
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infiltrative and poorly vascularized grafts. Notch1

stimulated GBM cells expressed pericyte cell markers
andwerecloselyassociatedwithendothelialcells.

Transforminggrowthfactor1
Transforminggrowthfactor1(TGF1)isapleiotropic
cytokine that mediates tumor growth, metastasis and
cytokine production. The combined effects of TGF1
and a hypoxic environment significantly induced self
renewalcapacityinnonstemosteosarcomacells,lead
ing to increased chemoresistance, tumorigenicity,
neovasculogenesisandmetastaticpotential.Incontrast,
blocking the TGF1 signaling pathway inhibited the
differentiation and clonogenicity of osteosarcoma cells
and reduced CSC selfrenewal capacity and hypoxia
mediated dedifferentiation. Thus, stem cells and non
stem cells exist in a dynamic equilibrium in this osteo
sarcomacellpopulation,andCSCsappeartodevelopde
novo from differentiated cancer cells [73]. RUNX3 is a
mediator of TGF1 and acts as an antagonist of Wnt.
Loss of Runx3 in gastric epithelial cells results in spon
taneous epithelialmesenchymal transition (EMT) pro
ducing a stem celllike subpopulation that remarkably
expresses the gastric stem cell marker Lgr5. These re
sultssuggestthatRUNX3hasaprotectiveeffectagainst
abnormal growth factor signaling in gastric epithelial
cells [74]. Treatment of colon and breast cancer cells
with TGF1 triggered the EMT program and increased
theexpressionofthelargeintergenicnoncodingRNA,
Hotair.AblationofHotairexpressionpreventedTGF1
mediatedEMTandthecolonyformingcapacityofcolon
andbreasttumorcells[75].

Pluripotencyrelatedoncogenes
Developmentalpluripotencyassociated2(DPPA2)regu
lates chromatin structure and functions in the mainte
nance of pluripotency and proliferation of embryonic
stemcells.Anotherfamilymember,DPPA4isassociated
withactivechromatinandisinvolvedinthedifferentia
tionofEScellsintoaprimitiveectodermlineage.DPPA4
ishighlyexpressedinembryonalcarcinoma,pluripotent
germcelltumorsandothermalignancies.Interestingly,
anexpressionscreenforoncogenicfociinducinggenes
inahumanembryonicstemcellcDNAlibraryidentified
DPPA4andDPPA2asoncogenes[76].

CONCLUSION

The renaissance of interest in cancer stem cell biology

hasledtoanumberofmethodologicaladvancesforthe
study of CSCs. Mather has reviewed the selection of
subpopulations of existing tumor lines derived from
serumcontainingmedia,thecreationoflinesfromma
lignantornormalcellsbygeneticmanipulationandthe
direct selection of CSCs from tumors or sorted tumor
cells using defined serumfree conditions [77]. Label
retaining cells (LRCs) are thought to arise from either
slowcycling or asymmetric cell division and to repre
AlphaMedPress2014

sent adult tissue stem cells. Using a novel method for

andtreatmentofarangeofcancers.Itisrepresentative
the isolation of live LRCs Xin and colleagues demon
ofahuge amount of literature covering CSCsspanning
basic, translational and clinical research and should
strated labelretaining cancer cells (LRCCs) in several
provide a plethora of options for readers interested in
gastrointestinal (GI) cancers, including fresh surgical
current cuttingedge investigations in cancer and leu
specimens.Moreover,byrealtimeconfocalmicroscop
kemia.
ic cinematography they were able to track live LRCCs

undergoing asymmetric nonrandom chromosomal co

segregation LRC division. The authors concluded that
AUTHORCONTRIBUTIONS
LRCCmayrepresentanovelpopulationofGIstemlike

cancercells[78].
Both authors contributed equally in the writing of the
The collection of recent papers reviewed here co
articles.
versimportantaspectsoftheoccurrence,pathogenesis

19.YangJ,LiaoD,ChenC,LiuY,ChuangTH,
Gribben J, Lassailly F, Bonnet D (2014) A
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