epsteinok - basal cell carcinomas
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The fox knows many pathways, but the hedgehogknows how to cause basal cell carcinomas.(With apoogies to Ahiohus, 7th entuy bc.)
Basa e ainomas (BCCs) ae keatinoyte tumousthat ae so named eause of thei histoogia esem-ane to the es aong the asement memane the asa aye of the epidemis (FIG. 1). They ae themost ommony diagnosed human ane, at eastamong pesons of Euopean anesty1. Appoximatey750,000 BCCs ae teated eah yea in the UnitedStates aone. Despite this high fequeny, the deathate fom BCCs is extaodinaiy ow, a efetionpehaps of the exeent ae povided y physiiansand the fat that these tumous metastasize onyextemey aey. Nonetheess, they an ause signifi-ant tissue destution y oa invasion. In tota, theost of ae fo non-meanoma skin anes (NMSCs)suh as BCCs is the fifth highest fo a anes in
the Medicare popuation in the United States2. Ouundestanding of thei moeua pathogenesis hasadvaned onsideay in the past deade, and indeedthese tumous now seem to have eome the found-ing meme of an expanding goup of human anesin whih deeguated Hedgehog (HH) signaing is of
vita impotane. I eview hee ou uent undestand-ing of BCCs, inuding the envionmenta and genetifatos that ontiute to thei deveopment, theimoeua pathogenesis, the most ovious unansweedquestions aout them, and how new undestandingmight e tansated into moe effetive peventionand teatment.
Clinical aspects of BCCs
BCCs assiay appea as sow-gowing, tansuent,eevated esions on the sun-exposed skin of pesons offai ompexion3(FIG. 2). BCCs ou moe ommonyin men than in women, and they tend to ou aftethe age of 50. Howeve, younge peope may e deve-oping moe BCCs, pehaps oeated with the use ofutavioet (UV) ight suneds fo osmeti tanningpuposes, espeiay among younge women4,199. BCCsae often gouped togethe with skin squamous e a-inomas (SCCs; see FIG. 1b) and with sevea othe essommon tumous as NMSCs. SCCs ae onsideaymoe ikey to metastasize than ae BCCs. Unike SCCs,whih ae usuay peeded y ainoma in situ typeesions, BCCs have no detetae peuso esion. Oneindividuas have deveoped a BCC, they have a muhhighe isk of deveoping additiona BCCs: one estimateased on meta-anaysis gives a 44% isk of a seondBCC deveoping within 3 yeas in patients who have
deveoped thei fist suh tumou5. Usuay, howeve,individua patients deveop ony one o a few BCCs. Theinidene of deveopment of new NMSCs is aso high inthose with utaneous SCCs, and the seond NMSC tendsto e of the same type as the f ist6.
BCCs ou fa moe ommony in pesons ofEuopean anesty and in those who have had moe sunexposue. Thus, in Kauai, the egion of the United Stateswith the highest inidene of skin anes, the inideneof BCCs is 14-fod highe in pesons of Euopean anes-ty than in those of Japanese anesty7 and 34-fod highethan in those of Fiipino anesty8. Among pesons ofEuopean anesty, those of Ceti desent ae espeiay
Childrens Hospital Oakland
Research Institute, 5700
Martin Luther King Jr Way,
Oakland, California 94609,
USA.
e-mail: [email protected]
doi:10.1038/nrc2503
Medicare
The US federal government
medical insurance programme
that covers all citizens over the
age of 65.
Basal cell carcinomas:attack of the hedgehogErvin H. Epstein
Abstract | Basal cell carcinomas (BCCs) were essentially a molecular black box until
some 12 years ago, when identification of a genetic flaw in a rare subset of patients
who have a great propensity to develop BCCs pointed to aberrant Hedgehog
signalling as the pivotal defect leading to formation of these tumours. This discovery
has facilitated a remarkable increase in our understanding of BCC carcinogenesisand has highlighted the carcinogenic role of this developmental pathway when
aberrantly activated in adulthood. Importantly, a phase 1 first-in-human trial of a
Hedgehog inhibitor has shown real progress in halting and even reversing the growth
of these tumours.
NATUrE rEVIEWS |cancer VOlUME 8 | OCTOBEr 2008 |743
REVIEWS
http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=46515http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=46261http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=46595mailto:[email protected]:[email protected]://www.cancer.gov/Templates/db_alpha.aspx?CdrID=46595http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=46261http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=46515 -
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pone to deveoping NMSCs. Patients with ainism, inwhih onstitutiona mutations pevent meanin foma-tion, ae highy suseptie to the deveopment of BCCsas we as of SCCs and meanoma. By ontast, those ofAfian o South Asian desent with dak skin oouae highy esistant to thei deveopment. Inteestingy,this maked ethni diffeene in suseptiiity pesistsfoowing ogan tanspantation, when patients eomehighy suseptie to the deveopment of skin anes.Thus, the inidene of BCCs may e tenfod highe inogan-tanspant eipients of Euopean anesty thanin pesons of simia sun exposue who have not had anogan tanspant. Howeve, patients of East Asian anes-ty have an extemey ow inidene of these tumouseven afte ogan tanspant9.
As suggested y the invese oeation of inidenewith skin pigmentation, sunight is an envionmentafato that is impotant in BCC deveopment. Howeve,the exat eationship is ompex appaenty fa moeso than fo the deveopment of SCCs. Thus, the ini-dene of SCCs ises with the tota nume of hous ofsun exposue, espeiay when that amount appoahesa umuative 100,000 hous. To attain this muh sunexposue, one must spend muh of the day outdoos. Byontast, the inidene of BCCs peaks at appoximateytwofod at 10,00035,000 hous tota sun exposue anddoes not inease with futhe exposue10,11. Simiay,
the eative inidene of SCC:BCC ises with ineas-ing sun exposue this atio is onsideay highe inthe southen pats of the United States than in nothenpats. In addition, the use of sunseens and othe sun-potetive measues has not yet een found to oeatewith edued BCC isk, unike the edution of SCCsassoiated with sun potetion1214. Some have postuatedthat BCC deveopment, ike that of meanomas, may o-eate ette with intemittent sunight exposue, suh asthat sustained y eseah onoogists who jog o yeon weekends15. Additiona envionmenta insuts thateay oeate with BCC deveopment ae ionizingadiation and aseni exposue1618.
Molecular genetics
BCCs and basal-cell nevus syndrome. The vast majo-ity of BCCs ou spoadiay, ut thee is one aeheitae disode in whih patients have a makedsuseptiiity to deveoping BCCs. This is asa-enevus syndome (BCNS, aso known as Goin syn-dome o nevoid asa-e ainoma syndome; seeBOX 1).
Using famiy-ased inkage studies of kindeds withBCNS, the ous aying the ausative mutant genewas mapped to human homosome 9q22 (REF.19) andthen to the pathed 1 (PTCH1) gene2022. This find-ing was espeiay instutive fo sevea easons.Fist, thee was peviousy ony minima insight intothe moeua undepinnings of this ane p53mutation in a sizae fation of spoadi BCCs wasessentiay the ony peviousy known moeuaanomaity23, and p53 mutations ae ommon innon-aneous skin of BCC patients as we24. Thisak of knowedge was due, at east in pat, to the dif-fiuty of gowing human BCCs in tissue utue o
as xenogafts and to the ak of a satisfatoy animamode. Mie teated with UV o ionizing adiation,o with hemia ainogens, deveop papiomas andainomas of the squamous ut not asa e ine-age. rats teated with ionizing adiation do deveopBCCs ut they aso deveop othe skin anes ingeate aundane. Seond, the funtion of PTCH1was oady ea its sequene identified it as thehomoogue of an aeady we-studied inhiito ofthe HH signaing pathway that was known to e uiafo deveopment in Drosophila melanogaster, and wasfound susequenty to oupy a simiay uia oein mammaian deveopment. Hene, it was staight-fowad to pedit and demonstate that its iaeiinativation podued onstitutive upeguation ofHH signaing. Thus, PTCH1 funtions as a assitumou suppesso gene. Thid, not ony was HH sig-naing found to e upeguated in a studied spoadiBCCs, ut aso this upeguation is fequenty aom-panied y, and at east in pat ased on, mutations inPTCH1. Cuenty, it is thought that upeguation ofHH signaing is the pivota anomaity in a BCCs,and indeed thee is some evidene that itte moethan HH upeguation is equied fo BCC aino-genesis25,26. Appoximatey 90% of spoadi BCCs haveidentifiae mutations in at east one aee ofPTCH1(often oss of the potion of homosome 9q haou-
ing PTCH1), and an additiona 10% have ativatingmutations in the downsteam smoothened (SMO)potein, whih pesumay ende SMO esistantto inhiition y PTCH1 (REFS 2730).
Hedgehog signalling. Athough a ompete desiptionof the intiaies of HH signaing is outside the fous ofthis review (see REFS 3133 fo eviews), some ak-gound infomation is neessay (FIG. 3). The HHsignaing pathway is named afte the famiy of exta-eua HH igands, of whih thee ae thee in mam-mas: soni hedgehog (SHH), Indian hedgehog (IHH)and deset hedgehog (DHH). PTCH1 is the eepto to
At a glance
Basalcellcarcinomas(BCCs)arekeratinocytetumoursthatresemblethebasallayer
oftheepidermis,andarethemostcommonlydiagnosedhumancanceramong
personsofEuropeanancestry.
Despitethishighfrequency,thedeathrateisextraordinarilylow,areflectionperhaps
oftheexcellentcareprovidedbyphysiciansandoftheirvanishinglyrarepropensity
tometastasize.
ThevastmajorityofBCCsoccursporadically,butpatientswiththerareheritable
disorderbasalcellnevussyndrome(BCNS)haveamarkedsusceptibilityto
developingBCCs.
FamilybasedlinkagestudiesofkindredswithBCNSidentifiedthepatched1( PTCH1)
gene,aninhibitorofthehedgehogsignallingpathway,asbeingmutatedinthese
patients.p53isalsomutatedinsomepatientswithsporadicBCCs.
DownstreamsignallingpathwaysthatarederegulatedinpatientswithBCCsare
currentlybeinginvestigated.
SurgeryiscurativeformostpatientswithBCCs.However,forthosefewthatdevelop
locallyadvancedormetastaticBCC,forwhichthereiscurrentlynoeffective
treatment,PhaseIclinicaltrialswithinhibitorsofthehedgehogsignallingpathway
haveproducedpromisingresults.
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http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=45135http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=109400http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=109400http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5727&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.uniprot.org/uniprot/P04637http://www.uniprot.org/uniprot/Q02936http://www.uniprot.org/uniprot/Q99835http://www.uniprot.org/uniprot/Q15465http://www.uniprot.org/uniprot/Q14623http://www.uniprot.org/uniprot/O43323http://www.uniprot.org/uniprot/O43323http://www.uniprot.org/uniprot/Q14623http://www.uniprot.org/uniprot/Q15465http://www.uniprot.org/uniprot/Q99835http://www.uniprot.org/uniprot/Q02936http://www.uniprot.org/uniprot/P04637http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5727&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=109400http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=109400http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=45135 -
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a
b
whih the HH igands ind, and suh inding eieves theinhiition of the pathway indued y unound PTCH1,speifiay though SMO in a non-stoihiometi man-ne. One eieved of inhiition, SMO sends signasthough a seies of inteating poteins, inuding sup-pesso of fused (SUFU), uminating in ativation of thedownsteam Gi famiy of tansiption fatos, GlI1,GlI2 and GlI3, the founding meme of whih wasidentified as a gene ampified in gioastoma34. Thesetansiption fato poteins exist in vaious foms, andGlI2 and GlI3 an e ativatos o suppessos of tan-siption; GlI1 seems to have ony ativato funtions.The staiity of these moeues is ontoed y phos-phoyation and uiquityationpoteoyti destu-tion, and poessing fom inative to ative suppessoo ativato foms is aompished, at east in pat, ypoteoysis3538.
The inteations of the omponents of the HH signa-ing mahiney an ou at the iium3942. SMO seemsto e exuded fom this stutue when inative, utesides within the iium when signaing is ativated43.
Taget genes whose expession is upeguated dietyy HH signaing in BCCs inude PTCH1, povidinga negative feedak that dampens of the pathway, GLI1,poviding a positive feedak fo the pathway, and HHIP,whih enodes a HH inding potein44,45. The expessionof mrNAs enoding these poteins is outiney ineasedin BCCs.
Somatic mutations in BCCs. In genea, BCCs seem tohave eativey stae genomes the few puished stud-ies suggest that they have owe eves of genomi insta-iity than do many extautaneous anes46. As notedaove, BCCs outiney ay mutations in PTCH1 andTP53 and, in 10% of instanes, in SMO47,48. Mutationsin sevea othe genes enoding omponents of HHsignaing have een sought ut few have een identi-fied, et aone onfimed47. The mutations identified inPTCH1 and TP53 ae fequenty of a type that is onsist-ent with thei having een podued y UV adiation.This is tue fo BCCs that aise spoadiay, and evenmoe so fo those age numes of BCCs that aise inpatients with xeodema pigmentosum (XP), suggest-ing that epai of UV-indued DNA damage nomaydoes edue BCC ainogenesis4951. Futhemoe, thissuggests that one eason fo the ineased inidene ofBCCs in ode peope might e the epoted edutionof DNA epai with ageing52.
Predisposing constitutional genetic variants. Beause UViadiation is a signifiant isk fato fo BCC deveop-ment, genes that onto the extent of UV-indued DNAdamage and those whose potein poduts effet epaiof that damage ae pime andidates fo isk-modifyinggenes.
Vaiation in onstitutive pigment and aiity totan seem to e oeated invesey with BCC deve-opment. Hene, it is not supising that studies haveeen undetaken of the meanootin 1 eeptogene (MC1R), the majo known geneti vaiant on-tiuting to the degee of skin pigmentation.MC1R
enodes the eepto of-meanoyte-stimuatinghomone (MSH), a poteoyti podut of the agepotein enoded y the po-opiomeanootin gene(POMC).MC1R is highy poymophi among nomaindividuas and is a pime ontiuto in detemin-ing whethe the skin podues ownak pigment(eumeanin) o edyeow pigment (pheomeanin).
Non-funtiona MC1r vaiants esut in the podu-tion of pheomeanin and, in patiua, the pheno-type of ed hai53. Beause peope with ed hai andfai pigment have an ineased isk of skin anes,those with vaiantMC1R aees ae at ineased iskoth of meanomas and of BCCs, and the ineasedisk is dose-dependent, that is, highe in aies oftwo vaiant aees than in aies of a singe vaiantaee5457. Howeve, in oth BCCs and SCCs of theskin, the assoiation of vaiant aees and ineasedisk pesists even when oeted fo skin pigmenta-tion, thus suggesting a oe foMC1R in suseptiiityto skin anes that is mediated y mehanisms othe
Figure 1 | Htg t b m
qumu m th . | Basal cell
carcinomas (BCCs) are keratinocyte tumours that are so
named because of their histological resemblance to the
cells along the basement membrane the basal layerof the epidermis. b | Often BCCs are grouped as
non-malignant skin cancer together with squamous cell
carcinomas of the skin (shown) and several other less
common tumours.
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Linkage disequilibrium
When alleles at two or more
genetic loci occur more
frequently in the population
than expected given the known
allele frequencies and
recombination fraction
between the two loci. This
indicates that the loci are
tightly linked; that is,
sufficiently close together on
the same chromosome to be
co-inherited more than 50% of
the time.
than onto of pigmentation. Simiay,MC1R vai-
ants seem to ontiute to suseptiiity to meanomay mehanisms eyond thei effets on skin pigmenta-tion5860. Indeed, some have suggested that MSH andiety moduate keatinoyte poifeation and dif-feentiation61. Futhemoe, UV iadiation of keati-noytes an enhane POMC and MSH podution,whih suggests a possie paaine oe fo this ho-mone6264. Vaiation in BCC inidene is aso assoi-ated with vaiants in the genes enoding tyosinase,the ate-imiting enzyme in meanin fomation, andagouti signaing potein, whih inhiits the intea-tion ofMSH and MC1r. As with MC1r vaiants,thei effets on pigmentation do not seem to expaina of thei effets on BCC suseptiiity65.
Patients with XP have onstitutiona inativatingmutations in oth aees of etain genes that enodeDNA epai poteins, in patiua those invoved innueotide exision epai, a poess that is of uiaimpotane fo emoving UV-indued photopod-uts fom keatinoyte DNA. In patients with XP, thismoeua impotane is attested to iniay y thehuge inease in eative isk of deveoping BCCs andothe skin anes and the onset of these anes onaveage 50 yeas eaie than in those without suhgeneti impaiment66.
This finding aises the question of whethe moeommon vaiants in genes enoding poteins invoved
in DNA epai might ontiute to the eative isk ofdeveoping BCCs in patients without XP. Numeousstudies have investigated the epai apaities of esfom patients with BCC and onto patients, as weas the effets of ommon oding vaiants (pedomi-nantysinge nueotide poymophisms) on BCCeative isk. In genea, studies in patients with vai-ous anes indiate some edution of DNA epai67.One goup has puished sevea studies that favou aedued DNA-epai apaity (using the host e ea-tivation assay) in ymphoytes fom patients with BCCas opposed to ontos68, athough thei findings weenot onfimed in a sma independent study69.
Simiay, a eent sma study found edued in vivoeaane of UV-indued photopoduts fom DNAextated fom the skin of patients with BCC ompaedwith DNA extated fom a onto goup without skinane70. Howeve, the oveap etween individuas in thetwo goups was age, so vaiations in DNA epai, at eastas aptued y the assay used, annot aount fo a agepopotion of any diffeentia suseptiiity to BCC in theFinnish popuation studied.
Assoiations etween DNA epai gene vaiants andBCC eative isk that eah (o at east osey appoah)statistia signifiane have een epoted fo seveaDNA epai genes. Pehaps the most studied of these isthe gene poymophism that undeies the T241M su-stitution inXRCC3. Some studies7173 ut not a74,75 havefound that this sustitution is assoiated with a eduedeative isk fo BCCs. Counteintuitivey, this sustitu-tion is aso assoiated with an ineased isk fo eastane71 and it does not seem to hange DNA epaiapaity, at east y the assay used. The usua expanationfo suh findings is that the identified poymophism is
not ausative, ut is simpy oated nea (is in linkage dis-equilibrium with) the ausative mutation, o it oud ethat the epoted assoiation esuts ae spuious.
Studies of poymophisms in othe DNA epai geneshave aso suggested assoiations with the eative isk ofdeveoping BCCs,ut othe studies have faied to find thesame assoiation. Ceay, the eationships etween iden-tified assoiations and hanges in DNA epai ae onfus-ing (BOX 2). Suh unetainties ague fo the potentia ofuniased, genome-wide assoiation studies to identifypoymophisms that onfe a eative suseptiiity toBCC fomation, and to unove geate undestandingof the mehanisms undeying BCC deveopment.
A ommon vaiant in TP53 ous at odon 72, andthe two aees enode eithe aginine o poine (Po).Taken togethe, at east some of the puished studiesimpy that the Po aee enhanes suseptiiity to BCC,ut pehaps ony in peope who ae eativey moe esist-ant to deveoping these tumous those with dake skinpigmentation and a ak of vaiantMC1Raees76,77. Theeae simia puished esuts fo an assoiation etweenthis vaiant and suseptiiity to utaneous meanomas78.Again, as with othe studied poymophisms, onfitingdata aguing fo no assoiation have aso een puished79.A futhe ompiation of the anaysis is an assoiation ofthe Po aee with esistane to hidhood sunun. Thus,TP53 aees may onto not ony suseptiiity to skin
ane ut aso to sunun, and the effets of one aeemay e opposite on these two phenotypes and in ounte-intuitive dietions. A ioogiay ative poymophism in
MDM2, whih infuenes p53 potein staiity, was foundnot to e assoiated with BCC eative isk in one studythat assessed moe than 1,000 sujets80.
One ommon poymophism at exon 23 ofPTCH1enodes eithe Po o euine at odon 1315. In patientswith moe sevee BCCs (mutipe tumous, eay onset),two studies have found an assoiation with the geno-type enoding Po/Po55,81. Howeve, in one study thatwas not estited to patients with geate BCC seveity,the individua singe nueotide poymophism was not
Figure 2 | Th utu b
m. BCCs classically appear as slow-growing,
translucent, elevated lesions on the sun-exposed skin of
persons with fair skin and occur more commonly in men
than in women.
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assoiated with BCC eative isk, athough one hapo-type that inuded this poymophism was so assoiated.Possie assoiations with the many othe genes enod-ing memes of the HH pathway and/o genes enodingontos of this pathway emain to e studied. Finay,Bamain and oeagues epoted the supising findingthat a Ptch1 poymophism in the mouse is an impotantontoing fato in the suseptiiity to mutant HrAS-indued skin tumous of the squamous ineage. Theysuggest that suh poymophisms may onto the eativesuseptiiity to fomation of SCCs vesus BCCs82.
Moeua anayses ae theefoe onsistent with theidea of geneti onto of suseptiiity vesus esistaneto BCC ainogenesis. In patiua, suh anayses aeonsistent with the idea that esistane is assoiated withette potetion against mutagenesisand with etteepai of whateve DNA damage does ou. Howeve,we have yet to identify onviningy the geneti undepin-nings eneath the wide ange of inia outomes in somepeope of nothen Euopean anesty with pae ompex-ions who sunathe: some get many BCCs, some get many
SCCs, some get fewe tumous, some get ony peane-ous ainomas in situ, some get ony winkes and somesustain no iniay appaent skin damage at a.
Pathway interactions and expression changes
Sevea goups have assessed genome-wide expession inkeatinoytes in whih HH signaing has een ativatedexpeimentay83 and diety in BCCs. A question withthe atte is the hoie of onto es against whih theBCC expession esuts ae ompaed. Puished stud-ies have ompaed expession pattens of whoe tumouwith those of whoe noma skin8486 o of es at thepeiphey of BCC nests with those of es of the asaaye of the intefoiua epidemis87. Ovea, pehaps
as expeted, many diffeenes in expession have eenfound, ut so fa the fied has not pogessed suffiientyto enae fim onusions to e dawn aout whihfindings ae epoduie aoss diffeent patfomsand investigatos, and whih hanges ae uia to theaeant ehaviou of the BCC ane es.
Cuenty, the est-studied downsteam mediatosemain those on whih investigatos have hosen to fousas andidate tagets. Among these ae upeguated pateet-deived gowth fato eepto- (PDGFr)88, the upeg-uated apoptosis inhiitos BCl2(REFS 89,90) and CASP8and FADD-ike apoptosis eguato (CFlAr)91 and thedowneguated apoptosis indues CD95 (FAS)92,93 andBMI1(REFS 94,95). The wiing downsteam of HH sig-naing ativation seems to diffe in vaious tissues. Thus,inhiition of mitogen-ativated potein kinase signa-ing inhiits the gowth of HH pathway-stimuated BCCes ut not that of eeea ganue peuso es88,96.But, in tuth, we have ony a imited undestanding ofwhih downsteam expession hanges ae atuay u-ia fo HH-indued BCC ainogenesis. Moe data have
een puished duing the past few yeas indiating thatothe signaing pathways may have pofound effets onHH signaing in anes (see eow and BOX 3), athoughmost of these studies did not addess BCCs speifiay.
PI3KAkt. Inteations of the HH signaing pathwayand the phosphoinositide 3-kinase (PI3K)Akt path-way ae suggested y modes in whih HH-induedtumoigenesis is enhaned y onomitant PI3KAktsignaing ativation97 o esponses to HH igands aeenhaned y onomitant insuin-ike gowth fato(IGF) igand. Indeed, Ptch1+/Igf2/ mie fai to deveophadomyosaomas98, ut no data aout the depend-ene of BCC fomation on Akt signaing have eenpuished. These two assia pathways may inteatat sevea eves. Fist, ativation of HH signaing insome systems an affet PI3KAkt signaing99102.Seond, PI3KAkt signaing an affet HH signaing:ativated PI3KAkt an staiize GlI2 though inhii-tion of potein kinase A (PKA)-mediated phopsho-yation that nomay esuts in uiquitin-tageting anddegadation103.
FOXM1.FOXM1, whih enodes a meme of thefokhead ox of tansiption fatos, is expessed inBCCs at highe eves than in noma keatinoytes 104.This gene is moe geneay expessed in a poifeating
es, its expession is highe in tansfomed e inesand its oveexpession ontiutes to ainogenesis andto moe maignant ehaviou in vaious ane mod-es105109. Its tansiptiona ativity an e ativated yDNA damage though CHK2 phosphoyation and on-sequent potein staiization and, in tun, its expessionstimuates the expession of the DNA epai enzymesXrCC1 and BrCA2(REF. 110). FOXM1 is a HH tagetgene, and its oss esues enty into mitosis in esspeifiay diven y HH signaing111. Expession ofFOXM1 is uia fo noma mitosis, and its oss anause homosoma instaiity, mitoti atastophe andonsequent e death112. FOXM1 tansiptiona ativity
Box 1 | Gorlin syndrome
Patientswiththissyndrome,alsoknownasbasalcellnevussyndrome(BCNS),hadbeen
describedpreviouslyonnumerousoccasionsbutitwasthedentistRobertGorlinwho
realizedmostclearlyhalfacenturyagothatmultipleabnormalitiesoccurredinthesame
patients,thusjustifyingthesyndromedesignation.Thisconditionisinheritedasan
autosomaldominantafflictionandcanproducemany,variedphenotypical
abnormalities165,mostprominentamongwhicharethedevelopmentoftens,hundreds
oreventhousandsofbasalcellcarcinomas(BCCs)startinginadolescenceoroccasionally
eveninchildhood.PatientswithBCNSalsocharacteristicallydevelopodontogenic
keratocysts,theencroachmentofwhichintothejawsoftenbeingtheaspectthatismost
troublesometothepatient.Othertumourstowhichtheyareparticularlyproneare
medulloblastomas.Approximately12%ofpatientswithmedulloblastomashaveBCNS
andapproximately35%ofpatientswithBCNSdevelopmedulloblastomas,mostly
duringchildhood166.Ovarianfibromascanalsooccur,sometimesinearlychildhoodor
eveninfancy167.MorerarelyoccurringinBCNSpatients,butprobablyatanincidence
greaterthaninnon-BCNSindividuals,aremeningiomas,rhabdomyosarcomas,cardiac
fibromasandmesentericcysts.ThelifespanofpatientswithBCNS,barring
medulloblastomas,seemstobeclosetonormal,butnocompilationoftheiragesor
causesofdeathhasbeenpublished.Thus,wedonotknowwhetherornotthesepatients
haveanysmallincreaseinincidenceofanyofthemorecommonlyfatalcancers,
includingthoseinwhichaberrantHedgehogsignallinghasbeendescribed.Amongthe
moreintriguingphenotypicalabnormalitiesinthesepatientsisastrongpropensityto
developBCCsaftertherapeuticionizingradiation,whethergivenfortreatmentofBCCs
orofmedulloblastomas.BCNSismostoftendiagnosedonthebasisofclinicalfindings,
andmajorandminorphenotypicalcriteriafordiagnosishavebeenproposed168.
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PTCH1
SMO
a Normal
SUFU
Target genes
b BCC
PTCH1
SUFU
Target genes
Gli
Gli
Gli
Gli
|
Skin pigmentation,DNA damage repair,P13KAkt and Wntpathways, and FOXM1
Activatingmutations
Loss ormutation
SMO
HH
an e inhiited y ArF113, and phamaoogia inhii-tion of FOXM1 with a e-penetating ArF peptide114 owith a sma moeue115 has an antiane effet in modesystems. We do not yet know the degee of dependeneof BCCs on FOXM1 expession.
In addition, anothe FOX famiy meme, FOXE1,is expessed in human epidemis and at a highe evein human BCCs116. Its oss is assoiated with anomadeveopment of the hai foie in a patten onsist-ent with it eing a HH taget gene and with it mediat-ing downsteam effets of HH signaing117. Again, itsdownsteam taget genes and the oe it has in BCCainogenesis ae unknown.
Wnt signalling. Athough pevious studies have dawnonfiting onusions egading the oe of Wnt signa-ing in BCC ainogenesis, a eent study pesents on-
vining evidene fo the equiement fo ativated Wnt
signaing to e downsteam of HH signaing in thesetumous, in oth mie and humans118. These findingssuggest yet anothe taget fo theapeuti intevention.
In summay, we sti have ony a dim idea of the fatosthat onto BCC keatinoyte HH signaing, othe thandive mutations, and of the wiing downsteam of thispathway. Often impessive esuts in mode systems sug-gest that suh knowedge oud point to potentia tagetsfo theapies, whih oud pehaps e usefu in omina-tion with the speifi HH inhiitos now unde deve-opment, espeiay eause moduatos of these othepathways ae aso unde deveopment. Hene, a goaassessment of these in BCCs emains a high pioity.
Mouse models of BCC carcinogenesis
As disussed eaie, assia mouse skin ainogen-esis modes eadiy podue tumous of the squamousineage ut none of the BCC ineage. The identifiationof the pivota oe of HH signaing in BCC aino-genesis stimuated the engineeing of sevea modesin whih HH signaing oud e manipuated andBCCs oud e podued, some of whih ay inati-
vating mutations in genes enoding inhiitos of HHsignaing, and some of whih ay ativated mutantso oveexpessed wid-type positive eguatos of thispathway(TABLE 1). These modes have aowed stud-ies of inteventions hemopevention and hemo-theapy as we as moe asi investigations intoBCC tumoigenesis.
The fist esson deived fom the modes is thatdeeguated HH signaing is indeed uia to BCCainogenesis. Thus, eithe onstitutive o onditiona
oveexpession of GlI1 (REF. 119) o of GlI2 (REF. 120)in keatinoytes an podue BCC-ike poifeations inthe skin. Simiay, expession of SMO aying the ati-
vating mutations identified in human BCCs aso anpodue muine BCCs29. Futhemoe, Ptch1+/ miedeveop BCCs, and those BCCs often have deetion ofthe wid-type opy of Pth1 as we as upeguation ofHH signaing121. Simiay, mie aying one inati-
vated, mutant aee of the HH suppesso Sufu ae asosuseptie to BCC deveopment122. Thus, mie ayingmutations in genes that enode at east fou diffeentomponents of the HH signaing mahiney deveopBCCs, o at east skin tumous eseming BCCs.
Figure 3 | a b hmt th Hghg (HH) gg thwy. | The family of extracellular HH ligands, of
which there are three in mammals (sonic hedgehog (SHH), Indian hedgehog (IHH) and desert hedgehog (DHH)) bind to the
patched 1 (PTCH1) receptor. This relieves the inhibition of smoothened (SMO) by PTCH1, and SMO sends signals througha series of interacting proteins, including suppressor of fused (SUFU), resulting in activation of the downstream Gli family
of transcription factors: GLI1, GLI2 and GLI3. b | Loss ofPTCH1 in patients with basal cell nevus syndrome predisposes
them to basal cell carcinoma (BCC) development. Sporadic BCCs routinely carry mutations in PTCH1andTP53, consistent
with their having been produced by ultraviolet radiation and, in 10% of instances, in SMO. Other mutations have been
implicated in BCC development, including genes that regulate skin colour, DNA damage repair genes, members of the
phosphoinositide 3-kinase (PI3K)Akt and the Wnt pathways and FOXM1.
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Parenteral
Administration of a drug by
injection, such as
subcutaneous, intramuscular
or intravenous, rather than
administration through the
alimentary canal.
The seond esson is that it seems that the degeeof ativation of HH signaing is oeated with thehistoogia appeaane the stonge the ativation,the moe the tumous eseme human BCCs123. With
weake ativation, the tumous moe osey esemehuman tumous that ae moe hai-foie-ike.
A thid stiking finding is that p53 oss makedyenhanes HH-diven tumoigenesis. This was shownfist y the deveopment of meduoastomas inamost 100% ofPtch1+/;Trp53/ mie as opposed to aninidene of ess than 10% in Ptch1+/ mie that havewid-type p53 (REF. 124). Simiay, we have found thatPtch1+/ mie in whih p53 is deeted onditionay inK14-expessing keatinoytes have a maked enhane-ment of BCC ainogenesis. Theefoe, the high ini-dene of p53 mutations in human BCCs is poay notsimpy aused y the fat that BCCs usuay aise in sun-exposed skin, ut athe efets the aiity of p53 ossto ontiute to the deveopment of BCCs and pehaps tothat of othe HH-diven tumous as we.
Finay, esuts of phamaoogia inteventions inthe Ptch1+/ mouse seem so fa to oeate we withesuts of the same inteventions in humans. Fo exam-pe, topia appiation of the etinoid tazaotene, aetinoi aid eepto-/ igand that is widey used foteatment of ane, (see ate) inhiits BCC deveopmentin the Ptch1+/ mouse and has ea anti-BCC effiay inhumans. Simiay, we have found that systemi non-steoida anti-infammatoy dugs, suh as eeoxi,weaky inhiit BCC ainogenesis in oth human andmouse PTCH1+/ individuas (J. Tang et al., unpuished
osevations).
Interventions
Prevention. Athough the use of sunseens has not sofa een assoiated with a edution in BCCs, thee ishope that thei use eaie in hidhood might edueate BCC ainogenesis. Cinia tias addessing thishypothesis wi not e ompeted in the nea futue, andso ounseing of sun avoidane must uenty ey onest guesses. One atenative to sun-potetion measuesis that of atifiia tanning y systemi administationofMSH125, and indeed tanned skin is ess susepti-e to UV-indued DNA damage126. As ompaed with
UV-indued tanning, MSH-indued tanning woudseem to have the advantages of eing non-mutageni,non-pomoting and non-immunosuppessive, ut itsinia patiaity has yet to e demonstated, and
uent deveopment effots invove parenteral dugs, aoute of administation that is not ikey to gain univesaaeptane fo UV potetion.
Oigonueotides that mimi the fee ends of teo-mees enhane DNA epai, stimuate tanning127 andhave antiane effiay in vaious ane modes,inuding UV-teated Ptch1+/ mie128. Anothe stategyto enhane DNA epai apaities is to appy exta op-ies of DNA epai enzymes. Supisingy, suh poteinsappied in iposomes an penetate skin and aumuatein the nueus of UV-damaged es in an appaentyataytiay ative fom suh that signifiant edutionin UV-indued skin hanges, inuding expeimentaainogenesis, an e seen129. Suh topia appiationsove one yea signifianty edued the deveopment ofnew skin anes in patients with XP130.
Systemi etinoids have een epoted to e effe-tive against new BCC deveopment in patients withBCNS131,132 o XP133, ut have shown no potetive effetin tias in patients who ae at high isk of deveopingspoadi BCCs134,135. Supisingy, poonged topiaappiation of tazaotene an ue 2550% of spoadihuman BCCs136138. Topia tazaotene effetivey pe-
vents BCC ainogenesis in the Ptch1+/ mouse139,140,and we (D. Bikes and E.H.E.) ae now onduting amutiente inia tia of its effiay in patients withBCNS. Finay, one inia tia of dietay intevention
in patients who wee at high isk of deveoping newspoadi skin anes found that a ow-fat diet (20%of aoies as fat as opposed to the usua 3540%) wasassoiated with a edution in the nume of newBCCs141.
Treatment narrowing the hedgehogs powers. Sugiaexision of BCCs is uenty y fa the most ommonyused teatment, and onto appoahes 100%. Howeve,this high ue ate is aompanied y the inevitae dis-omfot and saing of sugey, and the high fequenyof BCCs makes them an expensive effot fo those whofoot the i. As PDGFr has een epoted to mediate
Box 2 | Defects in DNA repair genes that might affect development of basal cell carcinomas
StudiesinvestigatingapossiblelinkbetweendefectsinDNArepairgenesandbasalcellcarcinomas(BCCs)haveyielded
conflictingresults.Forexample,asinglenucleotidepolymorphismin XPAreportedtobeassociatedwithincreased
relativeriskofBCCsisalsoassociatedwithincreased,notdecreased,DNArepaircapacity 169;XRCC1polymorphisms
havebeenreportedtobeassociated 170ornottobeassociated 171withBCCrelativerisk;andstudiesofassociationsof
BCCrelativeriskwithXPD(alsoknownas ERCC2)polymorphismsareinconflict 172175.Thesedisparateresultssuggest
thattheeffectsofanysinglegenepolymorphismmaybeweakbuttheydonotexcludethepossibilityofstrongereffects
ofcombinationsofpolymorphisms,andremindusofourlackofknowledgeabouthowtheefficiencyofDNArepairiscontrolledinnormalindividuals.Suchcontrolsseemtoincludenotjustpolymorphismsinthegenesencodingtheseand
otherDNArepairgenes(forexample,DNApolymerase-176),butalsopotentiallypolymorphismsingenesencodingother
proteinsthataffectthelevelofDNArepair,suchasinterleukin12,whichenhancesthisprocessandcanapparentlyaffect
susceptibilitytoultraviolet(UV)-inducedskincancers177.Inaddition,wehaveonlyapartialunderstandingofthe
mechanismsbywhichUVinducesskincancers.ThesemechanismsprobablyincludenotonlydirectDNAdamagebut
alsoindirectDNAdamagethroughtheproductionoffreeradicalsandUV-inducedimmunosuppression 178,whichmay
impairputativeimmunedefencesagainstskincancerdevelopment 161.
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Cyclopamine
The teratogenic component of
corn lilies that is responsible
for the cyclopean (one-eyed)
phenotype of lambs born of
dams eating this plant.
some of the downsteam effets of HH signaing inBCCs, use of appoved agents that inhiit this eeptokinase woud e sensie88. These inude soafeni andimatini (Geeve) ut no study of thei effiay in BCChas een puished. One systemi hemotheapy epotedto have some effiay fo oay unontoae BCCsis the omination ofpaitaxe andaopatin142. Withthe evidene fo HH ativation in many types of viseaanes, the ationae fo deveopment of HH inhiitos(HHIs) has eome ompeing. Consequenty, at easthaf a dozen phamaeutia ompanies have emakedon HHI deveopment, and BCCs that ae not ontoaey oa theapies ae potentia tagets fo tias of HHIs.
The fist we-studied HHI is the pant akaoidcyclopamine143. Indeed, one intepid goup appiedyopamine topiay and epoted egession of fouspoadi BCCs144. Cyopamine is a ompetitive inhiitoof SMO signaing, inding diety to the potein145147,and inhiits the gowth of maignant es diven y HHativation148. Infinity Phamaeutias in Camidge,Massahusetts, USA is deveoping yopamine deiva-tives with ette phamaoogia and inhiitoy pop-eties as potentia HHIs, and the ompany expets toaunh a phase 1 tia of one of these in 2008.
The fist HHI tested in phase 1 tias was a Cuis
Genenteh ompound (Cuis 61414), whih poduedneithe inia hanges in the tumous no edutions ofmrNA enoding the HH taget gene GLI1 when appiedtopiay to spoadi human BCCs (see Cuis wesite2006 pess eease in Futhe infomation). Howeve,GDC-0449, a seond CuisGenenteh HHI moeue,seemed to have minima toxiity and to ause iniaysignifiant enefit in eight out of nine patients withmetastati o oay advaned BCCs when administeedoay in a phase 1 tia149. Genenteh expets shoty toinitiate phase 2 tias of this moeue in patients withadvaned BCCs and in patients with advaned ooetaand ovaian anes.
The patia aies to the deveopment and use ofHHIs in oaized BCCs inude the high ue ate withsugey, despite the unattative aspets of suh po-edues desied eaie. If systemi deivey of HHIwee to e used, the agent woud have to e essentiay100% fee of advese extautaneous effets. One poten-tia on-taget advese effet might e on noma tissuestem es suh as those of the ain, the maintenaneof whih in mie is suppoted y HH150,151. loss of theseain stem es in mie has een epoted to give ogni-tive defets152. Indeed, the minimay annoying dysgeusia(distotion o oss of the sensation of taste) and aopeiaseen in the systemi HHI tia oud e aused y on-taget effets of inhiition of HH funtion nomayequied fo maintenane of the ofatoy u, tonguepapiae and hai foie150,153155. Suh theapy-induedoss ouing in humans with paneati ane mighte toeae; not so fo patients with the usua BCCs.HHIs aso an ause pematue osue of epiphyses156,a eminde that deveopment is not ompete at ithand a potentia ontaindiation to HHI teatment of
hidhood meduoastomas.
Unanswered questions
Why are BCCs so much more common than other humancancers?The answe to this question taditionay haseen that they aise in an ogan that is sujet to eno-mous mutageni insuts exogenousy and endogenousyas a ost of the ontinued ifeong high tunove of theepidemis. Viewed in moeua tems, it might aso ethe ase that, unike in the deveopment of many viseaanes, disuption of meey one antiane mehanism estaint of HH signaing seems to e enough toaow thei gowth. Howeve, viewed in anothe ontext(postate ane in the edey, fo exampe), pehapsthei fequeny is not so high afte a. Moeove, theappaenty high inidene might e, in pat, a podut ofthe fat that these esions ae ovious to the naked eye.Indeed, as we have een ae to examine intena tissuesmoe osey, the inidene of inidentaomas ises da-matiay, with the aompanying quanday of what isthe pope media intevention. If the diagnosis of BCCswee to depend on ogan dysfuntion athe than appea-ane, thei inidene might pummet to ess than that ofmany assia visea anes. In this ontext, the skinmay seve as a usefu mode fo how mediine wi eanto dea with the ineasing numes of inidentaomasthat ou impoving diagnosti aumen unoves.
Why does the incidence of BCCs not rise proportionally tothe amount of UV exposure as in SCCs?One possiiity fothis omes fom the osevation that sun exposue ati-
vates DNA epai mehanisms157: pehaps mutations ofPTCH1 ae moe suseptie to epai than mutationsin the genes that undeie SCCs. Howeve, no evidenefo suh diffeentia epai is avaiae. One atenativeis suggested y the osevation that vitamin D inhi-its HH signaing though inding to SMO potein 158.Thus, moe fequent UV exposue might maintaina eve of keatinoyte vitamin D that is suffiient toinhiit the gowth of BCCs ut not of SCCs. A potentia
Box 3 |Signalling pathways implicated in HH-induced tumours
Phorbolesters,whichactivateproteinkinaseC(PKC),arethemostextensively
studiedpromotersofsquamouscellcarcinogenesis,soitisnotsurprisingthat
membersofthePKCfamilyhavebeeninvestigatedinrelationtobasalcellcarcinomas
(BCCs).InitialreportsindicatedthatalthoughPKC isexpressedintheepidermaland
hairfolliclebasallayers,itisnotexpressedinBCCtumournests 179,180.Inmodelcell
systemsin vitro,PKCinhibitstheactivityoftheGlifamilyoftranscriptionfactors.
Bycontrast,PKCincreasesGliactivity,andsonichedgehog(SHH)activationofGliinatleastsomecontextsseemstorequirePKC activity181,182.TheeffectsofPKCseem
tobedownstreamofsuppressoroffused(SUFU)butupstreamofGLI1 (REF. 182).PKC
alsomayactthroughactivationoftheMAPKkinase(MEK) tocontrolGli
transcriptionalactivityitself.LikePKC,PKCseemsnottobeexpressedinBCC
tumournestsbutbothareexpressedinBCCstroma 180.Oneofthecancer-stimulatory
genesdownstreamofPKCisornithinedecarboxylase( ODC),andinthePtch1+/mouse
model,ODCinhibitorsreduceUV-inducedBCCcarcinogenesisandreduceexpression
ofhedgehogtargetgenes 183.However,ODCactivitycanbecontrolledbyother
pathwaysaswell184.
Epidermalgrowthfactorreceptor185190andtransforminggrowthfactorreceptor191196
pathwayscaninfluenceHHsignallingmarkedlyinmodelsystems,butthereislittle
evidencefortheirpossiblerolesinBCCcarcinogenesis.Surprisingly,becauseNotch
activationcandrivesomehumanleukaemias,NotchlossinmicecanactivateGLI2
expressionandproduceskintumours,includingBCCs197,198.
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750 | OCTOBEr 2008 | VOlUME 8 www.tu.m/w/
http://www.cancer.gov/Templates/drugdictionary.aspx?CdrID=299013http://www.cancer.gov/Templates/drugdictionary.aspx?CdrID=37862http://www.cancer.gov/Templates/drugdictionary.aspx?CdrID=39762http://www.cancer.gov/Templates/drugdictionary.aspx?CdrID=39176http://www.cancer.gov/Templates/drugdictionary.aspx?CdrID=39176http://phx.corporate-ir.net/phoenix.zhtml?c=123198&p=irol-newsArticle&ID=881050&highlighthttp://phx.corporate-ir.net/phoenix.zhtml?c=123198&p=irol-newsArticle&ID=881050&highlighthttp://www.cancer.gov/Templates/db_alpha.aspx?CdrID=444983http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=445074http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=44201http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=44642http://www.uniprot.org/uniprot/P11926http://www.uniprot.org/uniprot/P11926http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=44642http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=44201http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=445074http://www.cancer.gov/Templates/db_alpha.aspx?CdrID=444983http://phx.corporate-ir.net/phoenix.zhtml?c=123198&p=irol-newsArticle&ID=881050&highlighthttp://phx.corporate-ir.net/phoenix.zhtml?c=123198&p=irol-newsArticle&ID=881050&highlighthttp://www.cancer.gov/Templates/drugdictionary.aspx?CdrID=39176http://www.cancer.gov/Templates/drugdictionary.aspx?CdrID=39762http://www.cancer.gov/Templates/drugdictionary.aspx?CdrID=37862http://www.cancer.gov/Templates/drugdictionary.aspx?CdrID=299013 -
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faw in this is that one study suggested that honi sunexposue fais to inease utaneous vitamin D eveseven whie ineasing intena eves159. Consistent withthis idea, howeve, is the finding that skin podution of7-dehydohoesteo, the peuso moeue that UVadiation onvets to vitamin D, wanes in the edey,and this paaes the ineasing inidene of BCCs withageing160. Moe geneay, the ineasingy studied and
disussed antiane effets of vitamin D stoes mightaso have some anti-BCC ainogenesis effet. Anothepossiiity might e that the photoimmunosuppessionthat ous with sun exposue affets SCCs moe thanBCCs; indeed, in immunosuppessed ogan tanspantpatients, the inidene of SCCs ineases onsideaymoe than the inidene of BCCs. Howeve, at eastin Ptch1+/ mie, anti-ejetion dugs an aow moeoust BCC ainogenesis161, and so the immunesystem odinaiy may povide at east some pote-tion against BCC as we as SCC ainogenesis. Betteundestanding might ome wee we ae to identifyiniay inappaent peuso esions.
Why do BCCs so rarely metastasize?Not ony do BCCsessentiay neve spead to distant egions, ut asothe imitation of thei gowth to that y oa exten-sion aows aefu, miosopiay ontoed su-gia exision to give a ue ate appoahing 100%.One possiiity might e that physiians emove BCCsefoe they gow to a size that aows the aumua-tion of the additiona mutations needed to metasta-size. Yet patients with BCNS may have hundeds ofBCCs; ommony, BCCs in these patients ae emovedony when they impinge on sensitive stutues suhas the eye, and most ae teated with a wait and seeappoah. Anothe possiiity woud e that ativated
HH signaing is inompatie with metastasis. Butpostate ane metastases have highe HH signa-ing ativity than do the pimaies fom whih theyaose162, suggesting that this might not e the answe.A thid possiiity might e that speiaized anomastoma is equied, and indeed thee is some evidenethat BCCs ae espeiay dependent on stoma, at eastfo thei expeimenta tanspantation to othe sites inhumans163. In addition, oss of speiaized stoma mighte one eason fo the maked downeguation of HHsignaing when expeimenta BCCs o meduoasto-mas ae tansfeed fom the host to tissue utue. Butin most patients with BCCs, thee woud seem to e
no ak of UV-damaged stoma avaiae as a soi foBCCs to f ind if this wee the main ause of thei ak ofmetastasis. Finay, BCCs tend to have eative genomistaiity, and pehaps it is this that povides the aieto futhe DNA anomaities that might onfe meta-stati potentia. But why do BCCs not aquie genomiinstaiity? Might suh instaiity e inompatie withthei suessfu oa gowth?
What can we learn about BCCs that may further informour knowledge of visceral cancers?If hedgehog ativa-tion at fist indues keatinoyte senesene, as has eensuggested in expeimenta modes of HH signaing ati-
vation164, why does senesene not ou with physi-oogia HH signaing duing deveopment, hai foieying and expeimenta modes with onditiona Gioveexpession?25 A geate undestanding of the HHpathway and the indution of senesene is needed toaddess this question. It is possie that the degee ofdeeguation of HH signaing found in human aneis enough to oveome indution of senesene. Indeed,
it wi e inteesting to detemine how muh HH signa-ing is equied to dive ane deveopment in diffe-ent tissues. Anaysis of tissues fom the eent phase 1inia tias of HHIs in patients with BCC wi asopovide impotant data on whethe a ompete aseneof HH signaing is equied fo a inia esponse owhethe a edution is a that is needed. late stagetias of HHIs in BCC wi aso e ae to addess whetheeapse o esistane ou in patients with advanedBCC. Finding mehanisms of esistane, shoud theyou, might hep the deveopment of HHIs fo otheanes suh as meduoastoma, in whih HH signa-ing is deeguated. As BCCs seem to have eativey ittegenomi instaiity, it is easonae to hope that muta-tions may not e as fequent a mehanism of esistaneas is the ase with moe genetiay unstae anes.Finay, it wi e impotant to estaish the signaingpathways downsteam of the Gi tansiption fatosthat dive ainogenesis. These might povide oppo-tunities fo deveopment of dugs with pehaps a ettetheapeuti index (fo exampe, spaing stem es that, ateast theoetiay, might e the taget of oatea dam-age with HH inhiition) than that of diet inhiitionof HH signaing.
Conclusions
In itte moe than one deade, thanks to the wok of
many investigatos, ou undestanding of the moeuapathogenesis of BCCs has gone fom ose to zeo toa faiy signifiant ody of infomation. Cetainy, westi have ony a udimentay knowedge of the genetiundepinnings that detemine whih peope deveopBCCs and whih do not, and of the wiing that diveskeatinoytes to BCC ainogenesis. But it does seemthat we aeady have enough infomation to have aeasonae hane of tansating ou moeua unde-standing to ea inia enefit. The suessfu moeu-ay tageted teatment of BCCs with HHI might eony the fist of the inia enefits that esut fom the
vanquishing of the evi hedgehog.
Table 1 | Occurrence of basal cell carcinoma (BCC) in mouse models
G Bcc ut x(tg)
Bcc ut ut
Shh Yes No
Ptch1 No Yes
Smo Yes No
Sufu No Yes
Gli1 Yes No
Gli2 Yes No
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