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Squamouscellcarcinomasimilaritiesanddifferencesamonganatomicalsites

AmJCancerRes.20111(3):275300.
Publishedonline2010Jan1.

PMCID:PMC3175764
NIHMSID:NIHMS322111

Squamouscellcarcinomasimilaritiesanddifferencesamonganatomicalsites
WushengYan, 1IgnacioIWistuba, 2MichaelREmmertBuck, 1andHeidiSErickson3
1
PathogeneticsUnit,LaboratoryofPathology,CenterforCancerResearch,NationalCancerInstitute,NationalInstitutesofHealth,Bethesda,MD20892,
USA
2
ThoracicMolecularPathologyLab,DepartmentsofPathologyandThoracic/Head&NeckMedicalOncology,UniversityofTexasMDAndersonCancer
Center,Houston,TX77030,USA
3
ThoracicMolecularPathologyLab,DepartmentofThoracic/Head&NeckMedicalOncology,UniversityofTexasMDAndersonCancerCenter,Houston,
TX77030,USA
Pleaseaddresscorrespondenceto:Dr.HeidiS.Erickson,DepartmentofThoracic/Head&NeckMedicalOncology,UTMDAndersonCancer
Center,Houston,Texas77030,USA.Email:HSErickson@mdanderson.org:Dr.MichaelR.EmmertBuck,PathogeneticsUnit,LaboratoryofPathology,
CenterforCancerResearch,NationalCancerInstitute,NationalInstitutesofHealth,Bethesda,Maryland20892,USA.Email:mbuck@helix.nih.gov
Received2010Dec20Accepted2010Dec31.
AJCRCopyright2011

ThisarticlehasbeencitedbyotherarticlesinPMC.

Abstract

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Squamouscellcarcinoma(SCC)isanepithelialmalignancyinvolvingmanyanatomicalsitesandisthemost
commoncancercapableofmetastaticspread.Developmentofearlydiagnosismethodsandnoveltherapeuticsare
importantforpreventionandmortalityreduction.Inthiseffort,numerousmolecularalterationshavebeendescribed
inSCCs.SCCssharemanyphenotypicandmolecularcharacteristics,buttheyhavenotbeenextensively
compared.ThisarticlereviewsSCCasadisease,including:epidemiology,pathology,riskfactors,molecular
characteristics,prognosticmarkers,targetedtherapy,andanewapproachtostudyingSCCs.Throughthis
comparison,severalthemesareapparent.Forexample,HPVinfectionisacommonriskfactoramongthefour
majorSCCs(NMSC,HNSC,ESCC,andNSCLC)andmolecularabnormalitiesincellcycleregulationandsignal
transductionpredominate.Thesedatarevealthatthemolecularinsights,newmarkers,anddrugtargetsdiscovered
inindividualSCCsmayshedlightonthistypeofcancerasawhole.
Keywords:Squamouscellcarcinoma(SCC),nonmelanomaskincancer(NMSC),headandnecksquamouscell
carcinomas(HNSCC),esophagealsquamouscellcarcinoma(ESCC),nonsmallcelllungcancer(NSCLC),
epidemiology,riskfactors,molecularcharacteristics,prognosticmarkers,targetedtherapy
Introduction

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Squamouscellcarcinoma(SCC)isanepithelialmalignancythatoccursinorgansthatarenormallycoveredwith
squamousepitheliumwhichincludesseveraldifferentanatomicsites,includingtheskin,lips,mouth,esophagus,
urinarytract,prostate,lungs,vagina,andcervix.Oftheseanatomicsites,therearefourwhichmakeupthemajority
ofSCCcases:nonmelanomaskincancer,headandneckcancer,esophagealcancer,andnonsmallcelllung
cancer.Giventherangeoftissuesinwhichitarises,SCCrepresentsthemostcommoncancercapableofmetastatic
spreadintheUSandworldwide[1].Despiteadvancesindiagnosticmethodsandcombinedtreatmentmodalities,
thesurvivalratehasnotimprovedsignificantlyoverthelast30years[2]dueinparttoalackofreliableearly
diagnosticbiomarkersandalimitednumberofmolecularlytargetedtherapeuticstrategies.
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NumerousgeneticalterationshavebeendescribedinSCCsubtypes,althoughthemolecularmechanisms
contributingtotumorinitiationandprogressionarestillpoorlyunderstood.SCCssharemanyphenotypicand
molecularcharacteristicswitheachother[35],thusmolecularinsights,newmarkers,ordrugtargetsdiscoveredin
individualSCCsmayshedlightonthistypeofcancerasawhole.InthisarticlewewillreviewSCCasadisease
bydescribingthemostcommonanatomictypesofSCCwithregardtotheirepidemiology,pathology,andrisk
factors.Wewillalsoreviewthecurrentunderstandingofthemolecularcharacteristicsandprognosticmarkers.And
finally,wewillfocusontargetedtherapyandnewapproachestostudyingSCC.
Epidemiologyandpathology

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Nonmelanomaskincancer

Nonmelanomaskincancer(NMSC)isthemostcommoncancerinhumans[6],whichincludesSCCandbasalcell
carcinoma(BCC),andhasshownadramaticincreaseinCaucasiansinthelastfewdecades.AlthoughBCCis
mostprevalent,SCChasthehighermortalityduetometastasesandhighincidence[7].Thenumberofskincancers
diagnosedintheUnitedStatesoutnumbersallothercancerscombined,anditisestimatedthatoneinfive
Americanswilldevelopskincanceratsomepointintheirlife[8].MostskinSCCsshowrelativelybenignbehavior
andcanbecuredbylocalsurgicalanddermatologicmethods.However,someoftheselesionscanhavealocally
invasiveandaggressivecourse.Therateofmetastasisis0.3%to3.7%,withanoverall5yearsurvivalrateofless
than30%whensystemicdiseasedevelops[9].
Headandnecksquamouscellcarcinomas

Headandnecksquamouscellcarcinomas(HNSCC)makeupthevastmajority(morethan90%)ofheadandneck
cancersandrankasthesixthmostcommoncancerworldwide[10],with45,660newcasesofHNSCCdiagnosed
in2007and35,720newcasesreportedintheUSduring2009[11].Theyareagroupoftumorentitiesthatarise
fromsquamousmucosalsurfaces,includingnasalcavities,paranasalsinuses,oralcavity,nasopharynx,oropharynx,
hypopharynx,andlarynx.IncontrasttothedecliningoverallincidenceofHNSCC,whichismainlydueto
smokingpreventionandcessation[12],oropharynxcarcinomashowsarisingincidence,particularlyamong
individualslessthan45yearsofage,suggestingsomenontraditionalbehavioralandenvironmentalfactorsplaya
keyroleinitsepidemiology.HNSCChasa75%overall5yearsurvivalrateifdetectedearly[13].Despite
advancesindetectionandtreatmentsoverrecentdecades,mostpatientspresentwithmetastaticdiseaseatthetime
ofdiagnosis,reducingtheoverall5yearsurvivalrateto35%[14].Latediagnosis,formationofadditionalprimary
tumors,andmetastaseslargelycontributetothispoorsurvivalrate[15].
Esophagealsquamouscellcarcinoma

Esophagealcancer(EC)ranksastheeighthmostcommoncancer,withthesixthhighestmortalityintheworld[16,
17].Asthepredominanthistologicalsubtypeofesophagealcancer,esophagealsquamouscellcarcinoma(ESCC)
contributed80%ofallesophagealcancersworldwide.ESCCischaracterizedbyextremediversityingeographical
distributionandhighmortality.TheAsianesophagealcancerbeltregionshowsmuchhigherincidencethanother
areasoftheworld.Forexample,LinxianandsurroundingcountiesinChina[18].Despiteadvancesindiagnostic
methodsandcombinedtreatmentmodalities,themajorityoftumorsarediagnosedatadvancedstagesandthe
overall5yearsurvivalrateisonly40%[19].AlthoughrelativelylesscommonintheUnitedStatesthaninother
countries,therewerestill15,560newcasesand13.940deathsreportedin2007,whichwasthesixthleadingcause
ofdeathfromcancersamongAmericanmenthatyear[20].IntheUS,ESCCoccursmorecommonlyinAfrican
AmericanthanCaucasianpatientsandmorecommonlyinmenthanwomen,althoughtheprevalenceinwomenhas
beenincreasingsteadily[21].ThemajorityofESCCpatientspresentwithadvancedmetastaticdisease,withthe
overall5yearsurvivalofthesepatientsbeing<10%[22]
Nonsmallcelllungcarcinomas
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LungcanceristheleadingcauseofcancerdeathintheUnitedStatesandmostothercountries[23],with
approximately30%beingSCC[24].Lungcancersaredividedintosmallcell(SCLC)andnonsmallcelllung
carcinomas(NSCLC)basedontheirhistologyandcellularorigin.Nonsmallcelllungcancer(NSCLC)accounts
forapproximately8085%ofallcasesoflungcancerandisthemostcommoncauseofdeathinmenandsecond
onlytobreastcancerinwoman[25].NSCLCareclassifiedintofourhistologicsubtypes:squamouscellcarcinoma
(SCC),adenocarcinoma(ADC),largecellcarcinoma,andsarcomatoidcarcinoma.Anatomically,about70%of
SCCpresentascentrallungtumors[26],whereasadenocarcinomasgenerallypresentasperipherallungtumors
[24].Arecentlarge,randomizedphaseIIItrialshowedthatplatinumbasedchemotherapycombinationsyielda
mediansurvivaltimeofonly811months,a1yearsurvivalrateof3045%,anda2yearsurvivalrateof1020%
[27,28].Theoverall5yearsurvivalrateforlungcancerislessthan14%[29].
Overallcomparison

Overall5yearsurvivalratesforthefourmajorSCCsareamongthelowestofthemajorcancers.NMSChasan
advantageovertheotherSCCs,asitispresentedontheskinsurfaceandnotaninternalorgantherefore,the
chanceofearlydetectionismuchgreateranditisoftencuredbydermatologicandlocalsurgicalmethods.Forall
ofthemajorSCCs,includingNMSC,acommonthemeoflatediagnosis,formationofadditionalprimarytumors
andmetastasesareassociatedwiththepoorsurvivalratespresentedabove.Regionalrecurrenceaftersurgical
resectionisalsoacontributingfactorasisseenmorecommonlyinNSCLCSCCthanotherhistologicsubtypes
becauseSCCisabletospreadbyextendingthroughperiobronchialtubeswhichallowthemtodirectlyinvade
mediastinallymphnodesandothermediastinalstructures[26,30].EventhoughNMSChasanearlydetection
advantageovertheotherSCCS,repeatedexposuretoriskfactorswillinfluenceseverityofdiseaseprogressionand
recurrenceasequallyasobservedintheothermajorSCCs.
Riskfactors

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TheincidenceofSCCshowsmarkedvariationinitsdistribution,suggestingthatpersonalhabits,environmental
exposures,infections,andethnicityallplayaroleintheetiologyofSCC(Table1),withseveraloftheserisk
factorsinfluencingprognosis(Table2).
Table1
RiskfactorsofSCC

Table2
PrognosticindicatorsandmarkersofSCC

Nonmelanomaskincancer

Unlikeothertypesofsquamouscellcarcinoma,NMSCisprimarilycausedbychroniclongtermUVsolar
radiationexposure[31],inconjunctionwiththepatient'sskintype.Fairskinnedindividualswhoalwaysburnand
nevertanareatamuchhigherriskfordevelopingskinSCCthanthosewithdarkerskin[32],andithasbeen
demonstratedthatbothsunexposureearlierinlifeandintensesunexposureappeartoheavilypredisposethe
populationstoskincancer[32].Furthermore,humanpapillomaviruses(HPV)maybeinvolvedinthemultistep
processofskincarcinogenesisasacofactorwithUVradiation[33],especiallyinpatientswithpoorimmunestatus
suchasorgantransplantrecipients[34].And,smokingtobaccomaydoubletheriskofskincancer[35],thus
althoughtheeffectisnotasgreatasinotherSCCs,smokingplaysaroleinthedevelopmentofNMSC.

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Headandnecksquamouscellcarcinomas

ContrarytoNMSC,alcoholandtobaccousearethemostcommonriskfactorsforHNSCCintheUS,although
theyhavenotbeenassociatedwithsurvival[36].Moreover,alcoholandtobaccoarelikelysynergisticincausing
canceroftheheadandneck[37].Cigarettesmokershavealifetimeincreasedriskforheadandneckcancerswhich
is5to25foldincreasedoverthegeneralpopulation[38],andsmokingcessationdoesnoteliminatetheriskof
cancerdevelopment[39].Inaddition,environmentalexposuretotobaccosmokealsoincreasestheriskof
developingHNSCC,evenforindividualswhohaveneveractivelysmoked[40].Heavyalcoholconsumptionis
alsoanindependentriskfactorforHNSCC,particularlyforcancersofthehypopharynx[41].Moreover,smokers
andalcoholdrinkersareatriskforthedevelopmentofsecondprimaryoralcancers[42].Interestingly,eveninthe
presenceofalcoholconsumptionortobaccouse,ahighintakeoffruitandvegetablesmaypreventthedevelopment
ofaquarterofHNSCCandpossiblyonehalfoforalandoralphyrengealSCC[43].Causationhasbeenshown
withviralinfectionforHNSCCandtheassociationvariesbasedonthesiteofthetumor.Forexample,human
papillomavirus(HPV),inparticularHPV16,showsthehighestdistributioninthetonsils[44],whileEpsteinBarr
virus(EBV)infectionisassociatedwithnasopharyngealcancer.HPVisassociatedwith2025%ofHNSCC,and
individualswithHPVpositivetumorshaveabetteroverallsurvivalcomparedtothosewithHPVnegativetumors
[45,46].Specifically,thepresenceofHPV16isnowrecognizedasahighlyfavorableprognosticindicatorfor
patientswithHNSCC[45].Betelquidchewing,acommonhabitinsomeregionsofAsiaandsomeAsian
communitiesinthewesternworldisconsideredaregionalriskfactorforcancerswithapoorerprognosis[36].In
addition,oralhealth,acidrefluxdiseaseandenvironmentalexposures(nickelrefining,textilefibers,and
woodworking)arealsorelatedtoHNSCCtumorigenesis.
Esophagealsquamouscellcarcinoma

SimilartoHNSCC,smokingandalcoholingestionaremajoretiologicfactorsforthedevelopmentofESCC[47].
StudieshaveshownthatESCCriskisincreasedapproximatelythreetosevenfoldincurrentsmokers[4850]and
threetofivefoldinheavyalcoholusers[5053],withadditionalassociationsbetweenesophagealirritantssuchas
lyeingestion,rapidlyconsumedhighstarchdietswithoutfruitsandvegetables,andradiationtherapy[47].There
alsomaybeacausalrelationshipbetweenESCCandpreviousdiseasessuchasachalasia,headandneckcancer,
andPlummerVinsonsyndrome[54].Pickledvegetableintakeandmicronutrientdeficiency(suchaszinc)may
contributetoESCCformationinsomepartsofChina,especiallyinlightoflaboratoryexperimentsdemonstrating
thathightissuezincconcentrationisstronglyassociatedwithareducedriskofdevelopingESCCinexperimental
animals[55,56].TherearealsootherpotentialbutasyetunsubstantiatedriskfactorslikePAHsandacetaldehyde
relatedtoESCCinChina[57],withHVP16andHPV18reportedtoberiskfactors[55,58].IntheUS,ESCC
incidenceishighestinAfricanAmericansandmales.Interestingly,onecohortstudyofESCCandesophageal
adenocarcinoma(EA)founddecreasedriskofESCC,butnotEA,wasassociatedwithhigherintakeofbothfruit
andvegetables[59].
Nonsmallcelllungcarcinomas

Thecausalrelationshipbetweensmokingandlungcanceriswellestablishedwitha10to20foldincreasedriskof
lungcancerinsmokerscomparedwithneversmokers[60]andisthemajorriskfactorforthedevelopmentof
NSCLCSCC[61,62].IntheUS,smokingisestimatedtoaccountfor87%oflungcancercases(90%inmenand
85%inwomen)[63].Thelifetimeriskofdevelopinglungcancerisapproximately17.2%formalesmokersand
11.6%forfemalesmokers,andthisriskissignificantlylowerinnonsmokers:1.3%inmenand1.4%inwomen
[64].Healthyexsmokershavebeenshowntohaveasimilargeneexpressionpatterninnormalbronchial
epitheliumasnonsmokers,indicatingthatmostsmokinginducedgeneexpressionchangesreverttonormallevels
aftersmokingcessation[65].Asidefromsmoking,NSCLCisalsorelatedtogeneticfactors[66],radongas[67],
asbestos[68],andairpollution[69]withRadonexposurereportedasthesecondmajorcauseoflungcancerafter
smoking[67].Thereisasynergisticeffectbetweentobaccosmokingandasbestosexposureintheformationof
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lungcancer[68],andmorerecentlyHPV[70],JCvirus[71]andcytomegalovirus[72]havebeenreportedas
additionalpotentialriskfactorsforNSCLC.
Overallcomparison

TobaccosmokingandHPVinfectionappeartobecarcinogeniccausesforallfoursubtypes.Inaddition,several
riskfactorsaresharedamongthemajorSCCtypes.HNSCCandESCCsharethemostfactors,consistentwith
theirhistologicalrelationship,includingalcoholconsumptiondietaryfactors,andethnicity.UnliketheotherSCCs,
UVexposureisthemajorriskfactorforNMSC.AlthoughnumerousetiologicfactorsforSCCareknown,the
exactrolesandmolecularmechanismsofactionhavenotbeenfullyelucidated.
Molecularcharacteristicsandprognosticmarkers

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ThedevelopmentofclinicallyevidentSCCisamultistepprocessinvolvingtheaccumulationofmultiplegenetic
alterationsmodulatedbygeneticpredisposition,knownriskfactors,andotherunknownenvironmentalinfluences.
Thealterationsaretypicallyoncogeneactivation,includingrecessiveoncogenes[73]andtumorsuppressorgene
(TSG)inactivationviamutations,lossofheterozygosity,deletions,orothermechanisms(e.g.methylationand
miRNAmodulationofgeneexpression)[74].Molecularprofilingstudiesthatbeganwithsingleorrelativelysmall
groupsofgenesorproteinshavenowprogressedtolargescaleandhighthroughputmethodsusingDNA,RNA,
andproteinbasedapproaches.Theselargescalemethodsanalyzethousandsofgenesatonetimeandhaveledtoa
betterunderstandingofthecomplexityofgeneabnormalitypatternsofSCCandhaveacceleratedthediscoveryof
novelgenesinvolvedinSCCpathogenesis.Inadditiontoconventionalprognosticfactors[75],thesemolecular
characteristicsarebecomingincreasinglyvaluableasbiomarkersinadjunctprognostictools.Therearenumerous
molecularmarkersthathavebeenidentifiedinSCC,andinthissectionwecompareandcontrastthemajor
molecularabnormalitiesandtheirprognosticvalueamongthefourmajorSCCs.
MolecularmarkerscommontoNMSC,HNSCC,ESCC,andNSCLC

DifferentpatternsofmolecularchangesandtheirroleinprognosishavebeenshownbetweenthefourmajorSCCs
however,severalkeysimilaritiesarepresentincludingabnormalitiesinTP53,p63,Ki67,CCND1,EGFR,and
COX2(Table2,Table3).
Table3
MolecularabnormalitiesinSCC

TP53 TP53isoneofthemostimportanttumorsuppressorgenesinhumans[76]andfunctionsasatranscriptional

regulatorthatcontrolstheexpressionofgenesinvolvedinthecellcycle,DNArepair,apoptosis,andsenescence.
Understressconditions,p53isactivatedandtriggersavarietyofcellularresponsesneededtomaintaintheintegrity
ofthegenome,thustheproteinhasbeendesignatedaguardianofthegenome.p53mutationscanleadto
inactivationofp53andhavebeenfoundinabroadspectrumofhumancancers[77],includingNMSC,HNSCC,
ESCC,andNSCLC.Inactivationofp53isconsideredacriticalstepinthedevelopmentofNMSC[78]however,
TP53mutationhasnotbeencorrelatedwithaggressivenessofSCC,indicatingtheinvolvementofsubsequent
moleculareventsthatdeterminetumorbehavior[79].TP53alterationsanditslossoffunctionisacharacteristic
earlychangeinHNSCC[80].InHNSCC,ithasbeenobservedthatTP53mutationsthatoccurwithinthecore
domaincompletelyblockingDNAbindingarelinkedtoacceleratedtumorprogression,reducedtherapeutic
responsiveness,anddecreasedpatientsurvivalcomparedtotumorsthatharborlessdisruptiveTP53mutations[81,
82].InESCC,p53mutationhasbeenfrequentlyidentified[83,84]anditsfunctionpositivelycorrelatedwith
MDM2andp14(ARF)expression[85].Overexpressionp53hasalsobeensignificantlycorrelatedwithpoorer
prognosisforESCC[86].InNSCLCs,TP53mutationshavebeendetectedin4090%ofresectedtumors[8789],
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withdisruptionoftheTP53pathwayfrequentlyobservedinSCC[73].TP533mutationscanproduce
chemotherapyresistance[90]however,thespecifictypeofmutationandsensitivitytochemotherapyagentshas
notbeenidentified[88,91].Asdescribed,TP53/p53abnormalitiesarepresentinallfourmajorSCCs,buttodateis
onlyconsideredaprognosticfactorforHNSCCandESCC.
p63 p63,amemberofthep53family,iscriticalforthedevelopmentofstratifiedepithelialtissuessuchasepidermis

[92]andisusuallylimitedtotheproliferative(basallayer)compartmentoftheepithelium[93].p63expressionhas
beenreportedtobeastrongpredictorofpoorlydifferentiatedNMSC[94].Whereas,expressionofp63is
frequently(>95%)observedinHNSCCandassociatedwithincreasedsurvival[9598].Hence,p63maybe
involvedinsquamouscellcarcinomaformationthroughvariouspaths.p63alterationisalsoseeninESCCand
reducedexpressionofp63hasprognosticimplicationsforpatients[99].InNSCLCSCC,p63isusedto
differentiateSCCfromadenocarcinomabecauseadiffusestrongp63andCK5/6immunoexpressionisessentially
restrictedtoSCC[24].Interestingly,inNSCLChighexpressionofCCND1[100]andCD24[101]areassociated
withaworseclinicaloutcome,whileexpressionofp63[102]andBCL2[103]haveapositiveprognosticvalue.In
contrasttoTP53,p63abnormalitiesinthefourmajorSCCsareconsideredprognosticforSCC.
Ki67(MKI67) Ki67isacellproliferationindexmarkertypicallyincreasedintumorsandfoundrelatedtorapid

growthandrecurrenceinNMSC[104].InHNSCC,coexpressionofp21/Ki67isastrongnegativeprognostic
factor[105].InpatientswithstageIIandIIIadvancedESCC,asignificantcorrelationhasbeenidentifiedbetween
Ser392phosphorylationofp53andhighlevelsofKi67,lymphaticinvasion,andpoorerprognosis[106].
Similarly,onecohortstudyfound97%ofNSCLCsamplesexpressedKi67andoverexpressionwasassociated
withsignificantlyshortersurvival[107].Similartop63,Ki67abnormalitiesareprognosticforthefourmajor
SCCs.Butincontrasttop63,Ki67abnormalitiesallappeartobeindicativeofpoorprognosisinallfourmajor
SCCs.
CCND1 CCND1,acellcycleregulator,actsbyphosphorylatingandinactivatingtheretinoblastomaprotein[108].In

NMSC,CCND1isinvolvedintheearlydevelopmentofSCCviaabnormaltissueorganizationanddifferentiation
[109],withoverexpressionfrequentlyseeninkeratinocytecarcinogenesis[110112].Interestingly,CCND1
overexpressioncoupledwithTP53mutationhasbeencorrelatedwithpoorerprognosisinNMSC[110112].In
HNSCC,CCND1polymorphism(GG)inexon4hasbeenshowntobeanindependentprognosticindicatorof
diseasefreeinterval[113].InESCC,CCND1isoverexpressedin23to73%oftumorsamples[55,114]andis
significantlycorrelatedwithpoorerprognosis[115,116].ContrarytoCCND1inESCC,theabsenceofCCND1
immunoexpressioninNSCLCisassociatedwithworseprognosis[117].Similarlytop63,CCND1isassociated
withpoorerprognosisinNMSC,ESCC,andNSCLC,butisconverselyassociatedwithimprovedprognosisin
HNSCC.
EGFR EGFRispresentinthecellmembraneasamonomerandisactivatedbyligandbindingtotheextracellular

domain[118].MutationsthatleadtoEGFRoverexpressionhavebeenassociatedwithanumberofcancers.For
example,somestudiesidentifiedEGFRoverexpressioninmetastaticSCCoftheskin[119121].EGFRwasalso
showntobeupregulated/overexpressedin90%ofHNSCCsandassociatedwithlocalrecurrenceandpoor
survival[122,123].OverexpressionofEGFR[124,125],issignificantlycorrelatedwithpoorerprognosisfor
ESCC.SCCsdemonstratemostofthegeneticabnormalitiescommonlypresentinNSCLCs,exceptforKRASand
EGFRgenemutations,whicharemorefrequentinadenocarcinomas[73,126].OverexpressionofEGFR,p53
[127129]andHer2[130,131]hasshownconflictingresultsinNSCLCandtheiruseasprognosticmarkers
requirefurtherstudy[132136].However,twoprognosticproteinsinNSCLChavebeenidentifiedandareused
together.NSCLCshavingbothIGFR1andEGFRpositiveimmunoreactivityrepresentasubpopulationcapable
ofdevelopingaggressiveclinicalbehavior[137].Again,similarlytop63,EGFRisassociatedwithpoorer
prognosisinNSCM,HNSCCandESCC.Butduetoconflictingreports,theuseofp63asprognosticmarkerin
NSCLCneedstobeinvestigatedfurther.
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COX2 COX2(PTGS2)isanenzymethatfunctionsinproteinmetabolismbyincreasingprostaglandinsynthesisand

playsaroleintumorigenesis.TheexpressionofCOX2isupregulatedinmanycancersanditsproduct,PGH2,is
convertedbyprostaglandinE2synthesesintoPGE2whichinturncanstimulatecancerprogression[138].For
example,inNMSC,highexpressionofCOX2hasbeenfoundinAK,SCCandBCC[139]andCOX2
expressionincreasesduringprogressionfromAKtoSCC[140].OverexpressionofCOX2hasalsobeenshownin
HNSCC,andsomeexvivostudieshavedemonstratedthatCOX2isoverexpressedinESCCandpremalignant
lesions[141,142].StatisticallysignificantCOX2overexpressionhasalsobeenfoundin28.9%ofNSCLCSCC
[143].OverexpressionofCOX2andupregulationoftheprostaglandinpathwayplaysasignificantroleinSCC
andblockadeoftheprocesshasstrongpotentialforcancerpreventionandtherapy.However,todate,COX2has
notbeenidentifiedasaprognosticmarkerofSCCs.
OtherkeymolecularmarkerssharedinseveralSCCs

Inadditiontothesharedcellcycleregulation(TP53,p63,Ki67,andCCND1),signaltransduction(EGFR),and
proteinmetabolism(COX2)molecularabnormalities,severalothermolecularabnormalitiesofgeneexpression,
proteinexpression,genemutation,andepigeneticregulationandtheirrespectiveprognosticvalueshavebeen
characterizedinSCCs(Table2,Table3).KeymarkerssharedintwoorthreeofthemajorSCCsinvolveseveral
classesofgenesincludingsignaltransduction(VEGF),transcriptionfactor(SOX2),celladhesion(CDH1),and
extracellularmatrixdegradation(MMPs).AdditionalmarkersaffectingonlyoneoftheSCCscanbefoundin
Table2andTable3.
VEGFisanimportantsignaltransductionproteininvolvedinbothvasculogenesisandangiogenesis.Four
subtypeshavebeendescribed(A,B,C,andD).VEGFalterationisinvolvedinHNSCCandESCC.InoralSCC,
itwasreportedthatoverexpressionasmeasuredbyimmunohistochemistryofsubtypesAandBwerecorrelated
withtumorangiogenesisandsubtypesCandDwithmetastasesandpoorprognosis[144].InESCC,VEGF
(VEGFA)expressionhashistoricallyrangedbetween2493%[145],andrecentlyelevatedimmunoexpressionhas
beenreportedin55%ofESSCtissues(n=108)[146].OverexpressionofVEGFhasbeensignificantlycorrelated
withpoorerprognosisofESCC[145].
VEGF

SOX2 Arecentlydiscoveredlineagesurvivaloncogene,SOX2,hasbeenshowntobeimportantinHNSCC,

ESCC,andNSCLC.Lineagesurvivaloncogenesareactivatedbysomaticmutationsandthusmayplayan
importantroleincarcinogenesis.ThegenomicamplificationoftheSOX2embryonicstemcelltranscriptionfactor
locatedonchromosome3q26.33wasfirstreportedinESCCandNSCLC[147].SOX2hasbeenassociatedwith
poorprognosisinESCC[148],butitsuseasaprognosticmarkerinNSCLChasnotyetbeenelucidated.In
HNSCC(oral),highproteinexpressionofSOX2hasbeenfoundtocorrespondtocopynumbergainin52%of
oralSCCtumors[149].miR145isinvolvedinregulatingSOX2[150]however,itsroleasaprognosticfactorin
SCCsisstillunknown.
OurgrouphasrecentlycharacterizedSOX2proteinexpressionrelatedtothepathogenesisofNSCLCSCC[151].
ByassessingSOX2mRNAexpressioninvariouspublisheddatasetsagainstthepreviouslycharacterized
OCT4/SOX2/NANOGsignature,wewereabletoeffectivelyseparateSCCsfromadenocarcinomas.Inthisstudy,
wefurthercharacterizedSOXimmunoexpressionofNSCLCtissuesandidentifiedSOX2proteinexpression
patterninSCCdevelopment(hyperplasia,dysplasia,andcarcinomainsitu)[151].
CDH1(Ecadherin) CDH1belongstothecadherinfamilyofCa2+dependentcellcelladhesionmoleculeswhich

induceandmaintainintercellularconnections.CDH1hasbeenimplicatedincarcinogenesisduetoreduced
expression[152]andpromoterhypermethylation[153].InNMSC,downregulationofCDH1islinkedto
increasedpotentialfortumorinvasivenessanddistantmetastasisandthefrequenciesofCDH1promoter
hypermethylationappeartobecorrelatedwithamoreadvancedstageofsquamouscarcinogenesisinskin[153].In
ESCC,tumorswithreducedCDH1expressioninvadedeeper,havemorelymphnodemetastasis,andhavemore
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lymphaticinvasionthantumorswithpreservedCDH1expression[154].DisorganizedCDH1expressionwasalso
reportedtobeafeatureofadvancedESCC[152].
MMPs Matrixmetalloproteinases(MMPs)areafamilyofzinccontainingendopeptidasesthatdegradevarious

componentsoftheextracellularmatrix,andhavebeenstronglyimplicatedinmultiplestagesofcancerprogression
includingtheacquisitionofinvasiveandmetastaticproperties.MMPsarealteredinNMSC,HNSCCandESCC.
InNMSC,MMP2andMMP9immunoexpressionisassociatedwithNMSCpathogenesisandisanindicatorof
cutaneouscancerinvasionandprogression[155].ExpressionofMMPshasbeenidentifiedinboththeepithelial
andstromalelementsofHNSCC[156],withMMP2andMMP9showedanassociationwithinvasivepotential
[157,158]andpooroutcome[159].Guetal.evaluatedtheexpressionofMMP1,MMP7,MMP9,andMMP13in
ESCCtissuesfrom208patientsandfoundthatMMP7,MMP9,andMMP13maybeinvolvedwithearlystage
ESCC,andtheircoexpressionpredictedpooroutcomeforESCCpatients[160].Thesedataareconsistentwiththe
previousfindingthatexpressionofMMP7andMMP9maybeagoodmarkerforthepresenceoflymphatic
metastasisinESCC[161].Moreover,ourgroupidentifiedMMP3andMMP10aspotentialearlydiagnosis
biomarkersforESCC.Bothenzymesshowedatumorincreaseatboththetranscriptionalandproteomiclevels
[162].
Genemutations GenemutationsotherthanthoseinTP53,EGFR,andCCND1havealsobeenshowntobe

importantinSCCs,withalargeproportionofmutationshavingbeenidentifiedinNSCLCandtoalessextent
HNSCC.Functionalinactivationofp16throughdeletionfrequentlyoccursinHNSCC[163].Chromosome3p
containsnumerousTSGs(e.g.ALS2CL,EPHA3andCMYA1)andthelossofheterozygosityinthisregionmay
contributetoSCCs,includingHNSCC[164]andNSCLC[165].ActivatingRASmutationsoccurin
approximately15%to20%ofNSCLC,withamajorityofthembeingKRAS[166],howeverthesemutationsare
rareinSCC[167].Also,cMET,TTF1,LKB1,BRAFandPIK3CAareoftenmutatedoramplifiedinNSCLC
[167].
TheepigeneticmechanismofmethylationhasbeenshowntomodulateofgeneexpressioninSCCs.
Sinceitsdiscoveryasacyclindependentkinaseinhibitorin1993,thetumorsuppressorp16(INK4A/MTS
1/CDKN2A)hasgainedwidespreadimportanceincancer[168].LikeNMSC,genemethylationhasalsobeen
identifiedinHNSCC,ESCC,andNSCLCtovaryingdegrees.p16inactivationoftenoccursviamethylationin
bothHNSCC[163]andESCC[169].Thissilencingofp16inESCChasbeenshowntoleadtoderegulationof
cellproliferationandconsequentgenomicinstability[169].Differentpatternsofgenemethylationhavebeenfound
inthemajorhistologicaltypesofNSCLCs,withLKB1andRASSF1beingthemostimportantinNSCLCSCC.
InactivationoftheTSGLKB1bymutationanddeletionisarelativelyfrequenteventinSCC(19%)ofthelung
[170].But,RASassociationdomainfamily1gene(RASSF1)isthemostfrequentlyhypermethylatedgenein
NSCLC.RASSF1AmethylationhasbeencorrelatedwithworseprognosisinsurgicallyresectedNSCLCpatients
andwasconfirmedasanindependentprognosticfactorbymultivariateanalysis[171].
Methylation

miRNAs miRNAsareaclassofsmall(1824mer)nucleicacidsthatnegativelyregulategeneexpression.

Throughtheirtargets,miRNAsareknowntoplayimportantrolesincelldifferentiation,proliferation,and
apoptosis,andalteredmiRNAlevelsresultintheaberrantexpressionofgeneproductsthatmaycontributeto
cancerbiology[172,173].AnemergingnumberofstudieshaveshownthatmiRNAscanactasoncogenes,as
tumorsuppressorgenes,orsometimesasboth[174].HighthroughputanalyseshavedemonstratedthatmiRNA
expressioniscommonlydysregulatedinhumancancer[173].However,considerabledisagreementremainswith
respecttothemiRNAsignatureforspecificcancercelltypes,whichappearstodependlargelyontheanalytical
platform[173].
DysregulationofmiRNAshavebeenidentifiedinHNSCC,ESCC,andNSCLCandnotNMSC.However,
Drosha,animportantenzymeinthemiRNAmachinery,hasbeenfoundtobeoverexpressedinNMSCthusgiving
strengthtothehypothesisofmiRNAinvolvevementinNMSCcarcinogenesis[175].InHNSCC,overexpression
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ofmiR211hasbeenassociatedwithinvasivepotential[176].InadditiontomiR211,miRNAprofilinghas
revealedfourupregulatedmiRNAs(miR21,31,18,and221)and13downregulatedmiRNAs(miRNA133a,
133b,125a,138,139,200c,26b,302b,302c,342,371,373,375)associatedwithHNSCC[177].
Moreover,theratioofmiR221:miR375showedahighdiscriminatorypotential,withasensitivityof92%and
specificityof93%indistinguishingtumorfromnormaltissue,suggestingthatthissimplemolecularmarkermay
holdsignificantclinicalpotentialasadiagnostictool[178].miR21hasalsobeenreportedinESCCandfoundto
inducecellproliferationandinvasion[179].OurgroupevaluatedESCCrelatedmiRNAsbycomparing
microdissectedcellsinvolvedinnormaldifferentiationandtumorigenesisandconfirmedthatmiR21was
overexpressedintumors(Zhu,etal,submitted).miRNAshavebeenshowntoregulateseveralimportantpathways
inNSCLCandhavebeencorrelatedwithdiseaseoutcomeinNSCLC[180182].Ofinterest,afivemiRNA
signature(let7a,miR221,miR137,miR372,andmiR182)hasbeenidentifiedinNSCLCthatpredictstreatment
outcome[182].Inthatstudy,patientswithhighriskscoresintheirmiRNAsignaturesshowedpooroveralland
diseasefreesurvivalscomparedwithpatientswithlowriskscores[182].LossofexpressionofmiRNA128b,
putativeregulatorofEGFR,correlatedwithresponsetotargetedEGFRinhibitioninprimaryNSCLC[183].
miRNAisanareaofveryactiveresearchthatwillhaveanimpactonpathogenesisandtherapyasmoreislearned
abouttheroleofmiRNAsinSCC.
Numerousmolecularabnormalitiesingeneexpression,proteinexpression,genemutation,andepigeneticregulation
havebeencharacterizedinSCC(Table3),withseveralofthesemarkersassociatedwithdiseaseprognosis(Table2
).CommonalitiesinmolecularchangespresentinthefourmajorSCCsarepredominantlyfoundincellcycle
regulationandsignaltransduction.Althoughnotallofthedescribedmolecularabnormalitiesaresharedinallfour
oftheSCCs,manyaresharedinatleasttwoorthreeoftheSCCs.Thecomparisonofmolecularcharacteristic
similaritiesanddifferencesinSCCprovideinsightnotonlyintotherelationshipsbetweenNMSC,HNSCC,
ESCC,andNSCLC,buttoSCCasawhole.AndthisinsightintoSCCcanputativelybetranslatedtoimproved
diseasecontrolandtreatment.Currently,drugstargetingseveralofthesegeneandpathwayabnormalitiesarebeing
usedinthetreatmentofSCC.
Targetedtherapy

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Targetedtherapyisatypeoftreatmentthatusesdrugsthatidentifyandattackspecificcancercellswithoutharming
normalcellsandhasbeenextensivelyinvestigatedinrecentdecades,bothasasinglemodalitytherapyandin
combinationwithcytotoxictreatmentssuchasradiotherapyorchemotherapy.Withthegrowingunderstandingof
moleculargeneticsofSCC,targetedtherapiesnowofferexpandedtreatmentoptionsforpatientsthathaveclinically
significantbenefits.ThetargetsthatarecurrentlyconsideredthemostrelevantinSCCsfallintooneofthe
followingcategories:cellcycleregulation,signaltransduction,growthfactorreceptors,angiogenesis,andprotein
degradation.
SimilartothefactthattherearefewprognosticmarkersforNMSC,therearecurrentlynotargeteddrugsdeveloped
forNMSC.Althoughnotdevelopedasatargetedtherapy,Diclofenac,adualinhibitorofCOX1andCOX2with
higherselectivityforCOX2,hasbeeninvestigatedandreportedtobeeffectiveforpatientswithAK,a
precanceroussyndromeofskin[184].
SeveraltargetedtherapiesarebeinginvestigatedforHNSC,ESCC,andNSCLCwithmanyofthemolecular
targetsbeingsharedamongthethreeSCCs(Table4).Targetedtherapieshavebeenextensivelyinvestigatedin
HNSCandNSCLC,especiallyEGFRTKIsandtheirmechanismsofresistance.
Table4
MoleculartargetsfortherapyinSCC

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Growthfactorreceptorantagonists
EGFR EGFRisamemberoftheERBBfamilyoftransmembranetyrosinekinasereceptors[132].EGFRandtheir

receptorsareinvolvedinsignaltransductionandtumorgrowth,thusblockadeofthesesystemsprovidesa
therapeuticapproach,throughneutralizingligands,inhibitingligandbinding,orblockingthetyrosinekinasesofthe
receptors.ExamplesofEGFRinhibitorsincludemonoclonalantibodiesagainsttheextracellulardomainofthe
receptor(e.g.,cetuximabandpanitumumab)andreceptortyrosinekinaseinhibitors(TKIs)thattargetthe
intracellulardomain(e.g.,gefitinibanderlotinib).EGFRinhibitorshavebeenappliedinHNSCC,ESCCand
extensivelyinNSCLCclinicaltrials.InHNSCC,patientswithlocallyadvanceddiseasehavebeenshownto
benefitfromtheadditionofEGFRinhibition(forexample,cetuximab)toradiotherapy[185].But,EGFRtargeted
therapytrialsconductedinHNSCCtodatestillshowvariousdisadvantagessuchaslowefficacyandsignificant
toxicity[186].InESCC,inhibitionofEGFRTKbyerlotinibispromisingthroughinducinggrowthinhibitionand
cellcyclearrestinhumanesophagealcancercellsandenhancingtheantineoplasticeffectsofothertargetedagents
[187].CetuximabandpanitumumabarecurrentlybeinginvestigatedinNSCLC.PhaseIItrialsshowedthat
cetuximabimprovedsurvivalinchemonavepatientswithadvancedcancer[188,189]andpanitumumabis
currentlyinphaseIItrial[190].
EGFRTKIsgefitinibanderlotinibwerethefirsttwotargetedagentsrecentlyapprovedforthetreatmentof
NSCLCintheUnitedStatesandseveralmarkershavebeenidentifiedthatpredictresponseinNSCLCpatients.
TheseEGFRTKIsproduceresponsesinapproximately10%ofNSCLCpatientshavingprogressedwithprior
chemotherapy[191193].Butinthosepatientswhobenefitfromgefitiniborerlotinibtheresponsescanbedramatic
andmaylastforlongerthanayear,withfavorableresponsebeingassociatedwithactivatingmutationsinthe
EGFRtyrosinekinasedomain(exons18to21),increasedgenecopynumber,andincreasedproteinexpression
[191194].EventhoughtargetingEGFRmutatedNSCLCswithgefitiniborerlotinibhasbeeneffective,mostof
thesepatientsacquireresistancetotheEGFRTKItherapy[195,196]inanaverageof612months[197].
Interestingly,smokerspresentingwithNSCLCsaregenerallyresistanttoEGFRTKIs[198,199],whichmayhave
implicationsinothertargetedtherapiesofthisclassbecauseSCCisthepredominanthistologicsubtypeassociated
withsmokers.InanefforttocounteractEGFRTKIresistancemechanisms,aninitialstudyhasshownTKIresistant
NSCLCcelllinescanbetreatedbyadministeringPI3KmTORandMEKsignalinginhibitorssimultaneouslywith
EGFRTKIs[200]but,todatethishasnotbeentestedinNSCLCpatientpopulations.
Othergrowthfactorreceptorantagonists IGFIactsthoughtheIGFreceptor1(IGFR1)topromotecellsurvival

andcellproliferation[201].Itplaysanimportantroleinnormalgrowthandhasanaboliceffectsinadultsnormally.
ButIGFIhasbeenimplicatedincancers[202]asitsantiapoptoticpropertiesallowcancerouscellstoresistthe
cytotoxiceffectsofchemotherapeuticdrugsorradiotherapy.Arecentclinicaltrialreportedthatcombiningthefully
humanizedantiIGFIRmonoclonalantibodyA12withradiationtotreatHNSCCresultedinmorepronounced
antitumoractivitythaneitheragentalone[203].InNSCLC,earlyclinicaltrialsshowedanacceptablesafetyprofile
togetherwithpharmacodynamicevidencethatIGFRIcanbesuccessfullytargeted[204].And,biomarkersofthe
IGFIRpathwaywereshowntobekeyelementsindevelopmentandmonitoringofantiIGFRItherapyinNSCLC
[205].Recently,phaseIIstudydatahassuggestedthatcoadministrationofanantiIGFIRantibodywith
chemotherapyimprovestheresponserateandprogressionfreesurvival[204].
HER3(ERBB3),ageneencodingamemberoftheepidermalgrowthfactorreceptor(EGFR)familyofreceptor
tyrosinekinaseshasemergedforHNSCCtargetedtherapywithinthepastfouryears[206,207].Several
laboratoriesaredesigningantibodiesthatwillblockHER3heterodimerizationwithEGFRorHER2toprevent
signalingtoPI3K/Akt[208].
Cellcycleregulation

AlthoughcellcycleregulationcontainsthemostmolecularabnormalitiesinSCC(Table3)andsubsequently
numerouspotentialtherapeuticbiomarkers,currentlyonlyonemarker,CCND1,hasbeenexploited.Mutations,
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amplificationandoverexpressionofCCND1arefrequentlyobservedinavarietyoftumors,includingSCCs,and
maycontributetotumorigenesis.Flavopiridol,thefirstcyclindependentkinaseinhibitorinhumanclinicaltrials,
wasreportedasatargetingdrugforHNSCC[209].FlavopiridolhasalsobeenshowntodecreaseCCND1
expressioninESCCcelllinesandwassubsequentlyfoundtoinduceradiosensitivity[210]andmayhave
applicationtotheotherSCCs.
Signaltransduction

SignaltransductionwasthesecondmostcommongroupofmolecularabnormalitiesinthefourmajorSCCs(
Table3).Ofwhich,bothofmTORandMEThavebeenidentifiedinHNSCCandNSCLCasmoleculartargets.
mTORisaserine/threonineproteinkinasethatregulatescellgrowth,cellproliferation,cellmotility,cellsurvival,
proteinsynthesis,andtranscription.ItisactivatedbyAktandblocksapoptosistoincreasetheproliferativepotential
ofcancercells.SeveralmTORinhibitorsarecurrentlyunderinvestigationinHNSCC[211].InanongoingphaseII
trial,combinedinhibitionofmTORwitheverolimusandgefitinibwasevaluatedinpatientswithstageIIIB/IV
NSCLC[212].Bortezomibisasmallmoleculeproteasomeinhibitorthathasshownencouragingresultsinaphase
IItrial,andaphaseIIItrialofgemcitabine/carboplatinbortezomibinadvancedstageNSCLCisinprogress
[213].
CMETisthecellsurfacereceptorforhepatocytegrowthfactor(HGF),alsoknownasscatterfactor[214].Binding
ofthereceptortoitsligand,hepatocytegrowthfactor,inducesreceptordimerizationthattriggersconformational
changesthatactivateMETtyrosinekinaseactivitywhichthenhaveprofoundeffectsoncellgrowth,survival,
motility,invasionandangiogenesis[215].DysregulationofMETsignallinghasbeenshowntocontributeto
tumorigenesisinanumberofmalignanciesandhencecanserveasapotentialdrugtarget.Zucali,etal.foundthat
activatedcMETappearedtobeamarkerofprimarygefitinibresistanceinNSCLCpatientsandsuggestedcMET
maybeatargetfortreatment[216].InNSCLC,severalphaseII/IIItiralwithPF02341066eitherasmonotherapy
orincombinationwithEGFRinhibitorsarecurrentlyunderway[217].
Inaddition,preliminarydatafromaphaseIItrialtestingofsorafenib,apotentinhibitoroftheRaf1,BRaf,
VEGFR23,andPDGFRBpathways,inmetastaticorrecurrentHNSCCwererecentlyreported[218].Sorafenib
treatmentforNSCLCisbeingevaluatedinseveralphaseIIIstudies[217].
Proteindegradation

Cox2hasbeenimplicatedinapoptosisresistance,angiogenesis,decreasedhostimmunityandenhancedinvasion
andmetastasis,and,thusisinvolvedincriticalaspectsofcarcinogenesis[219].COX2selectiveinhibitors,aform
ofnonsteroidalantiinflammatorydrug(NSAID)thatdirectlytargetsCOX2,hasbeenshowntoreducethe
occurrenceofcancersandprecancerousgrowths[220]andisinclinicaltrialsforbothESCCandNSCLC[219].
Histonedeacetylaseinhibitors(HDIs)havebeenshowntoblocktheactivationofCOX2transcription[221].In
recentyears,therehasbeenanefforttodevelopHDIsforcancertherapyandtheyhavedemonstratedactivityin
patientswithadvancedsolidtumorsinphaseItrialsaswellasinpatientswithrelapsedNSCLC[222].Since
COX2dysregulationwasalsoshowninallofthefourmajorSCCs,HDIsshouldbeinvestigatedforSCCasa
whole.
Angiogenesis

AlthoughVEGFalterationhasnotyetbeenshowntobedirectlyinvolvedinNMSCandNSCLC,VEGF
expressioningenerallyiscommonlyseenintumorsduetoitsinvolvementinvasculogenesisandangiogenesis.
Furthermore,VEGFmaycauseacelltosurvive,move,orfurtherdifferentiatethroughvariousmolecular
mechanisms,thusVEGFisapotentialtargetforthetreatmentofcancer,includingSCCs.AntiVEGFtherapies
havecapitalizeduponthispotentialandhaveproventobeimportantinthetreatmentofcertaincancersusing
monoclonalantibodies(bevacizumab)andorallyavailablesmallmoleculeVEGFTKIs(sorafenib).InSCC,
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sorafenibhasbeenusedinclinicaltrialsofHNSCCandNSCLC[223,224].Bevacizumab,thefirstcommercially
availableangiogenesisinhibitor,hasbeentestedinHNSCCandNSSCLC[225,226].Interestingly,improved
outcomehasbeenshownusingbevacizumabincombinationwiththecombinationchemotherapyofpaclitaxel
carboplatininpatientswithadvancedNSCLC,butiscontraindicatedforSCCduetosafetyrisks[226].This
contraindicationforSCCisduetograde5hemoptysisinSSCpatientsandidentificationviamultivariateanalysisof
SCCasanindividualsignificantriskfactor[226].Assuch,bevacizumabincombinationwithpaclitaxelcarboplatin
isnowonlyusedwithnonsquamousNSCLCs.
AdvancesinunderstandingthemolecularpathogenesisofSCChasprovidedauniqueopportunitytoattackSCC
bytargetedtherapy.Examinationofmolecularabnormalitiesintumorshasbecomeincreasinglyimportant.
Similarly,thedevelopmentofmolecularsignatures(e.g.mRNAexpressionprofiles)fromtumorsthatprovide
informationontheprognosisandpredicttheresponseofindividualpatient'stumorstospecifiedtherapywouldbea
majorstepforward.Foratargetedtherapytotrulybeeffective,wemustalsohavebiomarkerstopreciselypredict
ormonitortumorresponseorresistancetocytotoxicandtargetedagents[227].Unfortunately,todate,nogood
clinicalorbiologicalmarkerstopredictoutcomesoftargetedtherapyhavebeenidentified.
NewapproachtostudyingmolecularabnormalitiesinSCC

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InanefforttoadvancethemolecularprofilingandsubsequentunderstandingofSCCasawhole,new
methodologiesarebeingdevelopedusingspecificanatomicsiteSCCswiththegoalofapplyingthesenovel
approachestothecharacterizationofmolecularabnormalitiesinotherSCCs.Ourgrouputilizedamicrodissected
normalbasaltumorgeneexpressioncomparisontoidentifypathwaysandgenesthatcouldbeputativetherapeutic
targetsforESCC(Yanetal.submitted).Inotherwords,wecontrastedtheexpressionprofileofanormaldividing
cellpopulationagainstitscounterparttransformedcellpopulationinasearchforgrowthrelatedgenesthatare
uniquetocancerandnotpartofthestandardcellgrowthmachineryperse[228].Thedatashowedthatgene
expressioninnormaldifferentiatedcellswasmarkedlydifferentfromnormalbasalcellsandtumorwhereas,tumor
andnormalbasalcellsweremorecloselyrelated.Tumorcellsshowedageneraldecreaseindifferentiallyexpressed
genesrelativetonormalbasalcellsasopposedtodifferentiatedcellsthatexhibitedtheoppositetrend.Theresults
identifiedtwohighlydysregulatednetworksinnormaldifferentiationandtumorigenesisDNArepairpathways
wereinvolvedinnormalandpathologicalgrowthandsomeindividualcelldifferentiationrelatedpathwayand
geneswereuniquelyexpressedinbasalcellscomparedtodifferentiatedcells.Furthermore,usingourbiologic
filter,12geneswereidentifiedasbeinguniquetothenormalbasaltumorcomparisonandcouldpotentiallybe
therapeutictargetsfortreatingESCC.
Inaseparatestudy,wehavefocusedoncharacterizingtargetedtherapyrelatedmolecularbiomarkersfrom
NSCLCeversmokersversusneversmokers,usingmicrodissectedpairedtumor/normalcellsandanovelqRT
PCRwithpreamplificationmethoddevelopedbyourgroup(Yanetal.submitted).Thedataprovidedpotentially
usefulinformationinguidinganindividualtreatmentapproachforlungcancer.
AlthoughthesestrategieshavebeendevelopedinESCC,thesenovelmethodologiescanbeappliedtootherSCCs
toidentifypotentialtherapeutictargetsdirectlyrelatedtotumorigenesis.Wehopethatthesenewapproachesto
studyingSCCwillalsoelucidatemarkersforprognosisandleadtoeffectivetherapiesforSCCsofallanatomical
sites.
Conclusion

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Despiteimprovementsindiagnosisandtherapy,mortalityandmorbidityratesforsomeformsofSCCremainhigh.
Earlydiagnosisisofcourseimportantinpreventingthiscancerandreducingmortality,andinparalleltoimproving
screeninganddiagnosticefforts,thereisasignificantneedtodevelopnoveltherapeuticagentsforpatientswith
advanceddisease.SCCsdemonstrateawiderangeofepithelialtumorsthatvaryintheiranatomicsites.These
tumorsshowvaryingdegreesofrelationshiptoriskfactors,withHPVinfectionshowingthegreatestrelationship.
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Modernmoleculargeneticanalysisallowsustoprobebeneaththephenotypicsurfacetotheunderlyingetiologic
molecularabnormalitiesofSCCandanumberofmoleculesthatcontributetothecomplexeventsofcarcinogenesis
andcancerprogressioninthesecancershavebeenidentified.ThemolecularlesionsfoundinSCCtumorsshare
commonelementsandcharacteristicchanges,withmolecularabnormalitiesofcellcycleregulationandsignal
transductionpredominatingSCCsasawhole.
Encouragedbythedevelopmentofmethodologiesforisolationofcellsfromsmallhistologiclesions,suchaslaser
microdissection,combinedwithtechniquestoperformgenomicstudiesfromminuteamountofDNA,RNAand
protein,severalgroups,includingours,havemadesubstantialprogressonunveilingthemolecularandgenetic
abnormalitiesofSCCs.ThedevelopmentandapplicationofnewmoleculargeneticmethodsforanalysisofSCC
tissuespecimenswillhelpdelineatethesignificantmolecularabnormalitiesresponsibleforSCCdevelopmentand
progression.Additionalstudiesareneededtofurtherimproveourunderstandingofthesimilaritiesanddifferences
amongthevariousSCCs,towardimprovementsindiagnosis,prognosisandtherapy.
Acknowledgments

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ThisworkwassupportedbytheCohenReinauchBATTLE2FundandtheIntramuralProgramoftheCenterfor
CancerResearch,NationalCancerInstitute,NIH.
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