Integrins in Cancer. Nature Reviews

7/31/2019 Integrins in Cancer. Nature Reviews

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Mch f the caic iteratre regardig cacer aditegri ha impicated thi fami f adhei receptr i tmr ce priferati, migrati ad ria(BOX 1). The re f itegri i ce migrati ad iai i e f their mt tdied fcti i tmrbig ad ha recet bee reieed eehere1,2.Itegri direct bid cmpet f the extracearmatrix (ECM) ad pride the tracti ecear frce mtiit ad iai. ECM remdeig i a ctred b itegri, hich regate the caizati adactiit f prteae. I additi t their eetabihedre i migrati ad iai, itegri ca regatepriferati3. Athgh adheidepedet ctrf priferati i deregated i tmr ce, itegrictie t regate ce grth i me tmr4,5.Recet tdie hae hed e ight the crcia, adfte ctradictr, re itegri hae i regatig tmr ce ria. I additi t their igati

depedet effect, it i becmig cear that i mecae igated itegri ca pitie r egatieifece tmr ce ria, thereb affectig tmrgrth ad metatai. H itegri affect tmr ceria bth i the igated ad igated tate cd be acrcia determiat f the efficac f itegri atagiti cacer.

I additi t their re i tmr ce, itegri the rface f tmraciated ht ce caprfd ifece the maigat ptetia f atmr. The tmr micreirmet i cmpried f ma ht ce tpe, icdig edtheiace, periacar ce, fibrbat ad ifammatr

ce, hich ctribte t tmr prgrei bmediatig agigeei, mphagigeei, demoplaiaad ifammati. The iemet f itegri iagigeei i e decribed, ad recet tdie haedemtrated that the a ifece ma ther htce repe t cacer. Therefre, itegri atagit targetig the tmr micreirmet mightigificat crtai tmr prgrei.

Itegri pa the ipid biaer f ce ad prmteitracear igaig, tpica i the ctext f acti

ated ctkie receptr r grth factr receptr.Ceqet, tmr grth ad iai prbabdeped itegri crtak ith grth factr receptr r cgee i bth tmr ce ad tmraciated ce. Recet tdie hae demtrated thatme grth factr ad cgee reqire pecificitegri fr tmr iitiati ad prgrei. Theetdie highight the imprtace f dertadig cr

tak mechaim, a the cd ifece the tmrrepe t ihibitr f grth factr r itegriigaig.

I recet ear, great prgre ha bee made tardtargetig itegri i cacer. Preciica a e a ciicatdie ith ari itegri atagit hae demtrated their effectiee i bckig tmr prgrei. Phae II ciica tria ith cilengitide (deepedb Merck KGaA), a 3 ad 5 itegri atagit, hae h ciica actiit ad fe ide effect ipatiet ith glioblatoma. Thee pitie ciica fidig hae ed t the iitiati f the firt Phae III ciicatria ith a itegri atagit. The adace f itegri

Department of Pathology,

Moores University of

California at San Diego

Cancer Center,

3855 Health Sciences Drive,

Room 2344, La Jolla, CA

92093-0803, United States.

Correspondence to D.A.C.

e-mail:

[email protected]

doi:10.1038/nrc2748

Desmoplasia

The growth of fibrou or

connective tiue.

Cilengitide

An RGD-containing cyclicpentapeptide that inhibit

ligand binding to v integrin.

Glioblastoma

The mot common human

brain tumour, it originate from

glial cell and ha no known

cure.

Integrins in cancer:biological implications andtherapeutic opportunities

Jay S. Desgrosellier and David A. Cheresh

Abstract | The integrin family of cell adhesion receptors regulates a diverse array of cellular

functions crucial to the initiation, progression and metastasis of solid tumours. The

importance of integrins in several cell types that affect tumour progression has made theman appealing target for cancer therapy. Integrin antagonists, including the v3 and v5inhibitor cilengitide, have shown encouraging activity in Phase II clinical trials and cilengitideis currently being tested in a Phase III trial in patients with glioblastoma. These exciting

clinical developments emphasize the need to identify how integrin antagonists influence the

tumour and its microenvironment.

REVIEWS

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Focal adhesions

Dynamic, macromolecular

protein complexe that link the

ECM to the actin cytokeleton

through integrin.

atagit it the ciic highight the imprtace fctied reearch t determie the re itegri haei tmr prgrei ad t idetif the factr thatifece the effectiee f thee ihibitr.

Integrin biology

The integrin family of cell adhesion receptors. Itegriare heterdimeric ce rface receptr that mediateadhei t the ECM ad immgbi perfamimece. At eat 24 ditict itegri heterdimerare frmed b the cmbiati f 18 bit ad8 bit. specific itegri heterdimer preferetia bid t ditict ECM prtei. The repertire f

itegri preet a gie ce dictate the extet thich that ce i adhere t ad migrate differetmatrice. itegri ad itegri 51 recgize theRGD eqece their repectie igad. I fact, theeitegri ere firt idetified the bai f their abiit t recgize the RGD eqece6. other adheieeqece i ECM prtei hae a bee bered,icdig the EIlDv ad REDv eqece that arerecgized b itegri 41 i a ateratie picedfrm f fibrecti. o igati t the ECM, itegricter i the pae f the membrae ad recrit ari igaig ad adaptr prtei t frm trctrek a focal adheion. The cmpiti f thee

adhei differ depedig hether the ctactccr i tdimeia r threedimeia cditi7. Athgh itegri ack kiae actiit, bcterig the recrit ad actiate kiae, ch afca adhei kiae (FAK) ad src fami kiae(sFK), i additi t caffdig mece, ch ap130 CRKaciated btrate (p130CAs; a ka BCAR1). Itegri a cpe the ECM t the actictkeet b recritig prtei, icdig tai,paxii, actii, tei ad ici. Additia, aterar cmpex citig f a itegriiked kiae,PInCH (a k a lIMs1), ad pari regatema caffdig ad igaig fcti reqired fritegrimediated effect ce migrati ad r

ia8. Frthermre, itegri recritmet t membraemicrdmai b tetrapai might crcia regateitegri fcti i tmr ce9. Regati f therecritmet ad actiati f thee ad ther fca adhei prtei ifece ce adhei ad migrati the ECM. I fact, ma f thee mece are themeebeig ietigated a pibe target fr cacer therap.

I me cae, the fcti f a itegri i reated tit igad affiit. Icreaed affiit r actiati ca beidced b either igadmediated itegri cterig the ce rface r icreaed itracear igaig thrgh mece, ch a the GTPae RAP1A10.

Therefre, igaig that i idced b cgeer grth factr receptr ma tard ifeceitegri affiit ad fcti.

Integrin expression in cancer. A ide ariet fitegri ctribte t tmr prgrei. A maid tmr rigiate frm epitheia ce, theitegri expreed b epitheia ce (icdig64,61, 5, 21 ad 31) are geera retaied ithe tmr, thgh exprei ee ma be atered.Thee itegri tpica mediate epitheia ce adhei t the baemet membrae, bt might ctribtet migrati, priferati ad ria i tmr ce.Heer, itegri exprei ca a ar ciderab betee rma ad tmr tie. Mt tab,itegri 3, 51 ad 6, are a expreedat r detectabe ee i mt adt epitheia btca be high pregated i me tmr. Expreiee f me itegri, ch a 21, decreae itmr ce, ptetia icreaig tmr ce diemiati11. I fact, reexprei f 21 i breatcacer ce reered me f the maigat prper

tie f the ce, ggetig that 21 cd fctia a tmr pprer 12. stdie crreatig itegriexprei ee i hma tmr ith pathgica tcme, ch a patiet ria ad metatai, hae idetified eera itegri that might haea imprtat re i cacer prgrei. Tmr ceexprei f the itegri 3, 5, 51, 64,41 ad 6 i crreated ith dieae prgreii ari tmr tpe (TABLE 1), therefre, thee arethe mt tdied itegri i cacer. Heer, thi i b mea a cmpete it ad ther itegri certaictribte t cacer prgrei, particar mef the ht ce tpe i the primar tmr.

At a glance

Integinsignallingegulatesdivesefunctionsintumoucells,includingmigation,

invasion,polifeationandsuvival.Insevealtumoutypes,theexpessionof

paticulainteginscoelateswithinceaseddiseasepogessionanddeceased

patientsuvival.

Inadditiontotumoucells,integinsaealsofoundontumou-associatedhostcells,

suchasthevasculaendothelium,peivasculacells,fiboblasts,bone

maow-deivedcellsandplatelets.Integinsignallingcuciallyegulatesthecontibutionofthesecelltypestocancepogession.Theefoe,integinantagonists

mayinhibittumoupogessionbyblockingcucialsignallingeventsinboththe

tumoumicoenvionmentandthetumoucellsthemselves.

Integinshaveapofoundinfluenceontumoucells,bothintheligatedandunligated

states,inwhichtheyegulatetumoucellsuvivalandmalignancy.

Althoughinteginsaloneaenotoncogenic,ecentdatahavefoundthatsome

oncogenesmayequieinteginsignallingfotheiabilitytoinitiatetumougowth

andinvasion.Theseeffectsmaybeduetotheimpotantcontibutionofintegin

signallinginmaintainingthecancestemcellpopulationinagiventumou.

Cosstalkbetweeninteginsandgowthfactoocytokineeceptosonbothtumou

andhostcelltypesisvitalfomanyaspectsoftumoupogession.Mechanismsof

cosstalkincludebothdiectandindiectassociationofinteginswithgowthfacto

ocytokineeceptos,whichaffectstheexpession,ligandaffinityandsignallingof

theeceptos.Theimpotantcontibutionofinteginstothebiologyofbothtumoucellsand

tumou-associatedcelltypeshasmadethemappealingtagetsfothedesignof

specifictheapeutics.Ofpaticulainteest,theinteginvinhibitocilengitideisnowinaPhaseIIIclinicaltialinglioblastoma,andbecausethisisthefistintegin

antagonisttoachievethismilestoneitplacesanti-integintheapyonthedoostepof

clinicalavailability.

Inadditiontotheiuseastheapeutictagets,integinscanbeimagingbiomakes

foassessingtheefficacyofanti-angiogenicandanti-tumouagents.

Integin-tagetednanopaticleswithadiveseaayofanti-tumoupayloadsalso

epesentapaticulalypomisingaeaofeseachthatmaydeceasethetoxicities

associatedwithsystemicdeliveyofadiationochemotheapy.

R E V I E W S

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Integrin

Tumour cell

Survival

Migration and invasion

Proliferation

Integrin regulation of cell survival and apoptosis

Depedig eirmeta ce, itegri hae theabiit t either ehace ce ria r iitiate appti(FIG. 1). Itegri ctat iterrgate their eirmet thrgh their capacit t iteract ith the ECM.ligated itegri rea ria iga, ad igateditegri ca prmte prappttic cacade. The baace f thee iga ret i ce ria r appti baed the abiit f the ce t iteract ith therrdig ECM. I thi a, itegri maitaithe itegrit f differet rga ad tie b preetigce frm riig i a imprper eirmet.

Itegri igati ehace ce ria thrgh eeramechaim, icdig icreaed exprei fBCl-2(REFs 13,14) r FlIP (a k a CFlAR)15, actiati f the PI3KAKT patha16 r cear factrB(nFB) igaig17,18, ad/r p53 iactiati19. Theece ria patha are differetia regated b pecific itegrigrth factr receptr pair. Fr exampe,i edtheia ce itegri 3 crtak ith fibrbat grth factr receptr (FGFR) preet appti

thrgh the intrinic apoptoi patha, ad 5 ad theacar edtheia grth factr receptr 2 (vEGFR2)fcti tgether t ihibit extrinic apoptoi20,21.

Athgh itegri atagit directed t 3 ad 5prmted edtheia ce death, hich ed t decreaedagigeei, geetic deeti fIgb3 (hich ecdeitegri 3) r deeti f bth Igb3 ad Igb5 i micedid t ihibit agigeei. Heer, mice deficieti thee itegri hed icreaed vEGFmediatedagigeei22, refectig a cmpeatr icreae ivEGFR2 i thee mice23. Iteretig, Igb3/ micedid h abrma cardiac edtheia ce mrphg aciated ith icreaed vEGF igaig24. Theeret highight crcia differece betee tdieiig geetic deeti f a itegri drig eardeepmet ad tdie i hich itegri atagitere ed t ppre itegri fcti i adt aima. The a itrate the imprtat re cmpeati cd hae i the iterpretati f ch kckttdie i mice.

Recet tdie hae highighted the re itegri haei mdatig appti. Ear rk hited at a pibeda re fr itegri i bth prmtig ce ria adidcig ce death. stdie hae h that athgh

me itegri, ch a 3 ad 64, ehace tmrprgrei25, paradxica, ther ch a 51 ihibitcgeeidced trafrmati26,27. Frther experimet hed that the prtmrigeic itegri 3cd ihibit tmr prgrei i me me mdef gibatma28 ad meama29. Thi apparet dicrepac might be expaied b the dicer that igateditegri ca idce appti30,31. I a prce termedintegrin-mediated death (IMD), igated itegri adheret ce recrit ad actiate capae 8, retig iappttic ce death30. IMD i ditict frm aiki, hichi appti that ccr i repe t cear detachmet frm the ECM32. Frther tdie demtrated thatthe f capae 8 i e mechaim b hich tmrce ca aid IMD, aig icreaed metatatic diemiati33. It i ti cear hat part IMD pa i thetherapetic effect f itegri atagit. Heer, it ithght that b ihibitig adhei t the ECM, itegriatagit ca idce IMD ad therefre hae a greatereffect i IMDeitie tmr.

I recet rk, e hae h that i IMDreitattmr ce the igated itegri 3 btatiaicreae achrageidepedet tmr ce riai viro ad metatai i vivo34(FIG. 2). Thee effectpecifica reqired itegri 3 recritmet adthe actiati f the receptr trie kiae sRC,hich ead t a FAKidepedet ria patha.

Thi achrageidepedet itegri 3sRC igaig mde might expai the aciati beteeitegri 3 ad tmr prgrei, a bered i

ari ciica tdie3541, ad cd hae imprtatciica ramificati. Firt, it gget that 3 atagit that fcti b bckig igad bidig t tmrce might be ieffectie i treatig me 3pitietmr. Heer, it remai pibe that ch atagit cd ti fcti a atiagigeic aget.secd, r td h that itegri 3expreigtmr that recrit ad actiate sRC i thi maerma be particar eitie t sFK ihibitr ch adaatinib.

Box 1 | Integrins in tumour cells

Integinsexpessedintumou

cellscontibutetotumou

pogessionandmetastasisby

inceasingtumoucell

migation,invasion,

polifeationandsuvival(see

thefigue).Integinadhesion

totheextacellulamatix(ECM)povidesthetaction

equiedfotumoucell

invasion.Integinsalsocontibutetotumoucellinvasionbyegulatingthelocalization

andactivityofmatix-degadingpoteases,suchasmatixmetallopotease2

(MMP2)anduokinase-typeplasminogenactivato(uPA).Integin-mediatedmigation

geneallyequiesfocaladhesionkinase(FAK)Scfamilykinase(SFK)signalling.

Howeve,integin-specificmechanismsdoexistinthesignallingpathwaysthatesult

incellmotility.Foexample,inneuoblastomacellsalthoughtheintegin51usestheexpectedFAK-mediatedactivationofSrC,integin41activatesSrCthoughaFAK-independentmechanism 168.Someinteginsinhibittumoucellmotility,as

integin1(Itgb1)deletioninceasedtumoucelldisseminationinamousemodelofspontaneouspanceaticisletcance11.regulationofinteginecyclingisalsocucial

fotumoucellinvasion.rabGTPasesdiectinteginstotheleadingedgeofinvading

tumoucells79andcoodinatelyegulateinteginandgowthfactoeceptoecycling,

esultinginenhancedgowthfactosignalling79

.Diffeencesintheecyclingpathwaysmediatedbypaticulainteginsalsoinfluenceandomathethanpesistentcell

migation169.Inadditiontotheiwell-establishedoleinmigationandinvasion,

integinsalsoegulatepolifeation.Integinligationcontolstheexpessionof

keycellcyclepoteins,includingcyclinD1 (REF. 170)andthecyclin-dependent

kinaseinhibitofamily,whichegulateentyintotheSphaseofthecellcycle171.

Adhesion-dependentcontolofcellpolifeationisdeegulatedintumoucells,as

anchoage-independentgowthisahallmakofmalignanttansfomation.Howeve,

integinsalsohaveanimpotantoleintumougowth4,5.Futheeseachisneededto

deteminethemechanismsbywhichinteginscontinuetoegulatepolifeationin

tumoucells.Integinsalsocontoltumoucellsuvival.Ligatedinteginspevent

po-apoptoticsignallingcascadesinitiatedbyanoikisointegin-mediateddeathand

inceasesuvivalsignalling.Howeve,ecentevidencealsopointstoaolefounligated

integinsinegulatingtumoucellsuvivalandmalignancy.

Intrinsic apoptosis

Cell death initiated by cell

tre or DNA damage and

induced by mitochondrial

releae of cytochrome c and

activation of pro-apoptotic

capae.

Extrinsic apoptosis

Cell death induced by ligand

binding to tranmembrane

death receptor and the

activation of capae,

including capae 8.

Integrin-mediated death

(IMD). Apoptotic cell death

reulting from the recruitment

and activation of capae 8 by

unligated integrin on

otherwie adherent cell.

Dasatinib

A dual ABL1 and sFK inhibitor

manufactured by

Britol-Meyer squibb andapproved for treatment of

patient with chronic

myelogenou leukaemia.

R E V I E W S


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Integrin regulation of cancer stem cells

Cacer tem ce repreet a high tmrigeic bet f ce i the primar tmr. Recet eideceha impicated itegri a marker f bth rmaprgeitr ad tem ce ppati ad cacertem ce. I particar, the itegri 3 repreeta marker f mia prgeitr ce i the mammardcta epitheim42. I a me mde f ptae mammar tmrigeei, exprei f theprtcgee wnt1 caed the expai fthe mia prgeitr ce ppati, amg hich themia marker itegri 3 (a k a CD61)repreeted a high tmrigeic cacer tem ceppati43. Itegri 3 exprei idetified cacer tem ce i ard 50% ftrp53+/ tmr, btiteretig a itegri 3pitie cacer tem ceppati a t fd i the mre hmgeeERBB2 (a k a ne)pitie tmr43. Thifidig ma expai the ack f a bered effecthe ERBB2 a ed t drie tmr iitiati iIgb3/ mice44. Itegri igaig eem t maitaithe cacer tem ce ppati i tmr, a abati fPk2 (hich ecde FAK) decreaed the pf cacer tem ce i ptae frmig memammar tmr45. Additia, itegri ma regate the exprei f cacer tem ce marker, cha CD44 (REF. 46). A cacer tem ce are thght trepreet the mt tmrigeic ad aggreie b

et f a particar tmr, it i temptig t pecatethat the exprei f pecific itegri cd ehacecacer tem ce prpertie thrgh cperatiith tmriitiatig cgee r grth factrreceptr.

The host cellular response to cancer

I additi t their re i tmr ce, itegri area imprtat fr the ht cear repe t cacer.Edtheia ce, fibrbat, pericte, be marrderied ce, ifammatr ce ad pateet a eitegri fr ari fcti, icdig agigeei, dempaia ad the imme repe (FIG. 3).

I additi t itegri expreed tmr ce,

itegri preet ma f thee ce tpe might beptetia therapetic target.

Angiogenesis.The ctribti f agigeei t tmrprgrei i e etabihed ad the re f itegriha recet bee reieed47. Tmraciated bd

ee are trctra ad bigica ditict frm qiecet ee, ad accrdig t Hard Drak tmrmake bad bd ee (REF. 48). Their trt adeak characteritic cmprmie bd f, impairdrg deier, prmte fibri ad faciitate tmr ceitraaati eadig t haematge r mphaticmetatai. we hae etabihed that, ike qiecetedtheim, tmraciated ee expre itegri3 (REF. 49). It i pibe that icreaed exprei fitegri 3 ad 5 a agigeic edtheiace t bid priia matrix prtei ch a itrecti, fibrige, wiebrad factr, tepti adfibrecti that are depited i the tmr micreirmet. I additi, prtezed, bt t atie, cage i a igad fr itegri 3 ig t the expre fRGD ite made aaiabe b prtei50. Thee adheieiteracti cd pride ria ce ad/r tractifr iadig edtheia ce.

Thrgh geetic deeti, r treatmet ith itegriatagit, eera additia itegri hae bee idetified a crcia fr agigeei, icdig 11, 21,

41, 51, 61, 91 ad 64 (REF. 47). Itegricperati ith particar grth factr receptreem t cfer repiee t pecific agigeicgrth factr that are high expreed i tmr.Fr exampe, 3 ad FGFR iteracti idce agigeei dtream f FGF bidig, ad 5 advEGFR2 prmte vEGFidced agigeei51. Thedeepmet fciegitide a a atitmr ad atiagigeic aget directed t bth itegri 3 ad5 a part baed thee fidig. Thee ditictpatha f agigeei highight the fact that itegrica itegrate ce frm the ECM ad grth factr tdrie pecific itracear igaig eet.

Table 1 |Integrins in cancer progression

Tumu ty Itgis xss asscit tys

Melanoma vb3 and5b1 Vertical growth phase 35,172174 and lymph node metastasis173,175

Breast 6b4 andvb3 Increased tumour size and grade176, and decreased survival177(6b4). Increased bone metastasis3638,64 (vb3)

Prostate vb3 Increased bone metastasis39

Pancreatic vb3 Lymph node metastasis40

Ovarian 4b1 andvb3 Increased peritoneal metastasis178 (4b1) and tumourproliferation179 (vb3)

Cervical vb3 andvb6 Decreased patient survival41,180

Glioblastoma vb3 andvb5 Both are expressed at the tumournormal tissue margin andhave a possible role in invasion181

Non-small-cell lung carcinoma 5b1 Decreased survival in patients with lymph node-negativetumours182

Colon vb6 Reduced patient survival109

R E V I E W S


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_ ` _ ` _ ` _ `ECM

RTK

Ligatedintegrin

Ligatedintegrin

Unligatedintegrin

Unligatedintegrin

IMD Anoikis

Adherent cells Non-adherent cell

Raf Caspase 8

Intrinsicpathway

Extrinsicpathway

ERK

P PP P

S338 Y341S339 Y340

PI3KAKT activity NF-B activity p53 activity

Survival Apoptosis

BCL2

CFLAR

Nucleus

Vascular normalizationThe proce of retoring the

integrity and function of

the vaculature through

pruning immature veel

and increaing pericyte and

baement membrane coverage

of the remaining veel.

Tumour stroma

The fibroblat, immune cell,

pericyte, endothelial cell and

inflammatory cell that

urround a tumour and have a

major role in tumour growth

and progreion.

Perivascular cells.Agigeei t deped the iadig edtheim bt a reqire periacar ce, ch a pericte ad acar mth mcece, hich aciate ith the deepig edthe

im ad prmte bd ee matrati. Tmrtpica expre immatre bd ee ith redcedperiacar cerage52. Thi ead t trt adeak ee that acct fr mch f the hpxia adpr perfi tpica bered i tmr. Itegriregate the iteracti betee edtheia ce adthe acar baemet membrae, ad recet tdiegget that the edtheia ce itegri 41 i ecear fr a iteracti ith acar ce adhei mece 1 (vCAM1) pericte, retig i edtheiacepericte iteracti ad ee tabiizati53.Recet tdie hae decribed a imprtat re frbd ee recritmet f pericte i regatig

bd ee brachig ad patec i tmr thrghvacular normalization54, the maipati f hich maimpre the deier f chemtherapetic. Accrdigt jai ad ceage54, rmaizig the tmr acatre ith aget ch a beacizmab r ther vEGFpatha ihibitr hd make it pibe t icreaedrg deier t the tmr ad gai a impred therapetic idex fr a ide rage f atitmr aget.I fact, crtak betee grth factr receptr, cha vEGFR2 ad pateetderied grth factr receptr(PDGFR), regate pericte recritmet t tmraciated bd ee55. Itegri cperati iththee grth factr receptr ma be ita fr regatigbd ee rmaizati i tmr.

Desmoplasia.Abdat cage depiti i a hamark f the dempatic reacti i bth primartmr ad their metatae. Thrgh itegri igaig, the depited cage icreae tmr cepriferati, ria ad chemreitace, pibctribtig t the etabihmet ad prgrei f

metatatic ei56. Itegri that are expreed trma fibrbat a ctribte t ehaced tmrgrth. Itegri11 i cmm erexpreed i trma fibrbat that are aciated ith mace gcarcima (nsClC). Exprei f 111 fibrbaticreaed tmr grth b timatig the reeae fiiike grth factr 2 (IGF2)57. Thi td highight the imprtace f the regati f grth factr igaig b itegri fr the tmrprmtigeffect f the ht trma. Targetig the tumour tromaith itegri atagit cd repreet a e aeefr tmr therap.

Bone marrow-derived cells.Circatig be marrderied ce are recrited t id tmr, i hichthe ca ppre tmr grth ad a ecretepragigeic grth factr ad ctkie thatctribte t tmr prgrei. Imme ce,icdig macrphage ad atra kier ce, arecrcia fr tmr pprei. Fr exampe, macrphage tmr ifitrati i decreaed i Igb3-/- micead ctribte t icreaed tmr brde, demtratig that the exprei f itegri 3 macrphage i imprtat fr their tmr ppreie fcti58. Ateratie, the tmrhmig fbe marrderied ce ca ret i icreaedtmr prgrei b icreaig agigeei.

Be marr ce expreig a fctia iactieitegri 3 mtat faied t be recrited t ite feacarizati, retig i decreaed pathgicaagigeei59. Hmig f edtheia ad mcte precrr t tmr a reqire itegri41 (REF. 60). Exprei f itegri 41 bemarrderied ce prmte adhei t thetmraciated edtheim, ad bckade fitegri 41 redced bd ee deit60,61. It it cear hether bckig tmr hmig f bemarrderied ce repreet a iabe therapetictrateg a their tmrppreie effect mightteigh their pragigeic ptetia.

Figure 1 | Itgi-mit sui sus ttic twys. Integrins can

paradoxically initiate pro-survival as well as pro-apoptotic signals. Which pathway is

more active depends on the ligation status of the surface integrins expressed by a given

cell. In a cell in which most of the integrins are ligated, a pro-survival pathway is initiated

through increased nuclear factor-B (NF-B) or PI3KAKT activity, decreased p53activation and increased expression of the pro-survival molecules BCL-2 and FLIP (also

known as CFLAR). Cooperative signalling between growth factor receptors and integrins

also differentially activates Raf leading to distinct mechanisms of cell survival. Signalling

through integrin v3 and the fibroblast growth factor receptor promotesphosphorylation of Ser338 and Ser339 of Raf, protecting cells from the intrinsic pathway

of apoptosis, and integrin v5 and vascular endothelial growth factor receptor 2phosphorylate Tyr340 and Tyr341 of Raf, preventing apoptosis through the extrinsic

pathway. In adherent cells in which many of the integrins are unligated, the unligated

integrins initiate cleavage of caspase 8, triggering apoptosis through integrin-mediated

death (IMD). On complete loss of adhesion, cell death is initiated through a process

termed anoikis. Apoptosis induced by anoikis may proceed through either the intrinsic or

extrinsic pathways. ECM, extracellular matrix; RTK, receptor tyrosine kinase.

R E V I E W S


http://www.cancer.gov/drugdictionary/?CdrID=43234http://www.uniprot.org/uniprot/Q9UKX5http://www.uniprot.org/uniprot/Q9UKX5http://www.uniprot.org/uniprot/Q9UKX5http://www.cancer.gov/drugdictionary/?CdrID=43234


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v3

Survival or anchorageindependence

SRC

FAKp130CAS

x1

Apoptosis

Anchorage-dependentinvasion, proliferationand survival

FAK

SRC

FAK

SRC

ECM

v3

v3-negative tumour v3-positive tumour

x1

p130CASp130CAS

Polyoma middle T

Derived from the polyomaviru,

the middle T antigen i

commonly ued to induce

pontaneou tumorigenei in

moue mammary epithelial

cell a a model of breat

cancer.

Platelets.Mtipe tdie hae iked tmr cepateetiteracti ith icreaed tmr metatai. The ECMprtei fibrige fcti a a bridge betee itegriIIb3 pateet ad 3 tmr ce. Thi iteracti faciitate tmr ce arret i the acatre,eadig t metatai t ari ite, icdig the bemarr6264. Cmbied bckade f bth tmr itegri3 ad pateet itegri IIb3 icreaed the atiagigeic ad atitmr effect cmpared ith bckigtmr itegri 3 ae65, ggetig that atagitthat target bth itegri pateet ad edtheia cecd hae greater ciica efficac i patiet.

Integrin cooperation with oncogenes

Athgh itegri ack the abiit t trafrm ce, adtherefre d t fcti a cgee, eera itegricperate ith cgee r receptr trie kiae tehace tmrigeei. I ptae me mdef tmrigeei, itegri ch a 64 cperateith ERBB2 t icreae breat tmr et ad iai66. Itegri 1 mediate breat cacer that i drie

b the polyoma middle T cprtei67, ad itegri 1i reqired fr KRAs-G12Didced tmr i theg68. There eem t be me pecificit t the abiitf itegri t crtak ith particar cgee, aitegri igaig thrgh FAK i reqired fr cgeei thrgh Ra ad PI3K69,70, herea tmrigeei idced b ERBB2 reqired itegri 64 (REF. 70).I ather exampe, i viro ad i vivo experimethed that itegri 3 ergize ith the SRccgee t icreae tmrigeic ptetia71. Iteretig,

thi effect ehaced the cgeic effect f sRC,ad t mrphgica trafrmati72. Thee tdiegget that me cgee are depedet itegriigaig, a prpert that cd ptetia be expitedtherapetica.

Integrin crosstalk with growth factor cytokines

Grig eidece pprt a cetra re fr cperatieigaig betee itegri, grth factr receptr adctkie receptr i ma apect f tmr prgrei (FIG. 4). Itegri crtak t regate tmrce adhei, migrati, iai ad ria, bt aaffect ma apect f the ht repe t cacer,particar i the agigeic edtheim. Heer,t a crtak i prtmrigeic, a me itegrica ihibit tmrigeei that i idced b certaicgee73. Frm the mer exampe f crtakthat hae bee decribed, eera theme hae emergedregardig the derig mechaim ied. I meitace cperatie igaig, pib mediated bthe frmati f a itegrigrth factr receptr cm

pex7477, ptetiate actiati f dtream kiaech a MAPK78 r AKT79 ad therefre ehace cemigrati ad ria. I ther exampe, itegri adgrth factr r ctkie receptr reciprca regatethe rface exprei f e ather8089, r the reeaef their repectie igad90,91. I additi t thee geera mechaim, recet tdie hae ecidated thermde f crtak (decribed be) that cd haeimprtat impicati fr tmr metatai ad theacqiiti f drg reitace.

EGF and its receptors.Member f the epiderma grthfactr (EGF) receptr fami, icdig EGFRadERBB2, ctribte t tmr frmati ad metataii ma tmr tpe, icdig breat ad pacreaticcacer. Icreaed exprei ad hperactiati f EGFreceptr ccr i ma cacer, ad erexpreif ERBB2 i cgeic. I tmr ce, cperatibetee itegri ad member f the EGF receptr fami affect ma apect f tmr prgrei,icdig tmr iitiati, priferati, migrati adiai. The itegri 64 ma be particar ita ttmr frmati i the bet f patiet ith breatcacer that expre high ee f ERBB2 a it cperate ith itegri 64 t idce ptae mammar tmr frmati ad tmr ce iai66.Thi cperatie effect cd be de t the frmati

f a itegri 64ERBB2 cmpex that ehace theactiati f iga tradcer ad actiatr f tracripti 3 (sTAT3) ad jun, eadig t the f ce parit ad hperpriferati, repectie66. Frthermre,thee tdie fd that the deeti fIgb4 icreaedthe efficac f targeted ERBB2pecific therap66,highightig the ptetia imprtace f cmbiatitherap ig atagit targetig itegri ad EGFreceptr fami member.

I pacreatic cacer, the EGF patha i fte hperactiated, hich ptetiate the tmr ce migrati ad metatai f thi high aggreie dieae.EGF timate pacreatic tmr ce migrati

Figure 2 | a itgi 3SrC cgic uit mts cg ic.In tumour cells, both b1 integrins (that is, xb1) and integrin vb3 induce adhesion-

dependent activation of focal adhesion kinase (FAK) and SRC, in addition to

phosphorylation of the adaptor protein p130 CRK-associated substrate (p130CAS).

These signalling events result in invasion, proliferation and survival of tumour cells bound

to the extracellular matrix (ECM). In suspended tumour cells unligated integrin vb3

signals directly through SRC and p130CAS to increase cell survival independently of FAK.

This effect occurs in tumour cells that are already resistant to integrin-mediated death.

R E V I E W S


http://www.uniprot.org/uniprot/P0851http://www.uniprot.org/uniprot/P00533http://www.uniprot.org/uniprot/P00533http://www.uniprot.org/uniprot/P0851


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v3

41

41

v3

IIb3

111

v5

xx

51

v3

Endothelial cell

Tumour cells

Pericyte

VCAM1

Platelets

Angiogenicsprout

Fibroblasts

Blood vessel

Fibrinogen

6

1

2

3

4

5

Monocyte

Myeloid cell

GFs andcytokines

GFs and cytokines

Collagen

Trastuzumab

A humanized monoclonal

antibody that bind ERBB2 on

tumour cell and prevent

uncontrolled proliferation

caued by aberrant ERBB2

ignalling.

itrecti i viro9294 ad metatai i vivo93,94, adthee effect reqire itegri 5 (REF. 94). Iteretig,

befre actiati i timated ce itegri 5 iabe t cter ad frm fca adhei it 95,hich ma be a prereqiite fr itegrimediatedce migrati. Itead, 5 reqire EGFdepedetactiati f sRC fr it abiit t mediate ce migrati94. Frther tdie reeaed a reqiremet fr sRCphphrati f the p130CAs btrate dmai adbeqet actiati f the GTPae RAP1A (REF. 94),a k mediatr f itegri actiati. EGFitegricrtak i t imited t pacreatic cacer, ad it aicreae the migrati f c cacer ce thrghitegri 31 ad 64 (REF. 96), ad hepatcearcarcima thrgh itegri 11 ad 21 (REF. 97).

Therefre, EGF igaig i tmr ce ma icreaethe abiit f particar itegri t mediate ce migrati ad ria, retig i icreaed metataticptetia.

other tdie hae demtrated that itegri igati itef regate EGF igaig, crcia ifecigtmr ce ceptibiit t treatmet. I fact, itegriigati ca idce EGFR phphrati idepedetf EGF, retig i icreaed MAPK actiati, tmrce priferati ad ria98 thrgh a sRCp130CAspatha99. The abiit f itegri t icreae EGFRigaig ma be particar imprtat i breat cacer expreig high ee f ERBB2. A recet tdfd that itegri igaig icreaed EGF ecretiad ERBB2 cterig i breat cacer ce, retigi reitace t the ERBB2 ihibitr tratuzumab90.Ihibiti f itegri igaig reered tratzmabreitace, ggetig that thi cmbied apprach mapre therapetica efficaci i ERBB2expreigbreat cacer.

HGF and receptors.The hepatcte grth factr (HGF)receptrMET i impicated i tmr iitiati ad themetatai f ari cacer, ad itegri cperatiith MET ret i ehaced tmr prgrei. Iparticar, itegri 4 ergize ith MET t ehacethe trafrmati f fibrbat ad icreae tmrigeic ptetia100. I breat cacer ce, HGF bidigt MET icreae achrageidepedet grth bidcig phphrati f itegri 4, retig ithe recritmet f prtei ch a sHP2 (a ka PTPn11) ad the beqet actiati f sRC adERK101. Cmpex frmati betee MET ad itegri64 ehace HGFidced iga, icdig tmrce iai77. Thi effect ma be de t the ptetiati f HGFidced Ra ad PI3K igaig b 64mediated recritmet f prtei ch a sHC1 adPI3K77. Heer, itegri 4 i t reqired fr HGFidced tmr ce iai102. Additia, METcperate ith ther itegri, a itegri 5 ctribte t MET igaig b ctrig the expreif HGFidced gee reqired fr ce migrati103.ItegriMET crtak i a idirect regated bther mece. Fr exampe, the tetrapai KAI1 (ak a CD82) ppree itegrimediated actiati f MET retig i redced tmr ce iai104.Therefre, the re f MET i cacer eem t deped crtak ith tmr ceaciated itegri.

TGF and receptors.Athgh geera k fr itatipriferatie effect, trafrmig grth factr(TGF) i a echaracterized idcer f epitheiameechma trafrmati (EMT) i tmr ce,retig i ehaced ce migrati ad iai.Itegri are itrmeta i the actiati f TGFigaig. TGF igad are ecreted a iactie cmpexe ith a atecaciated peptide (lAP). TheTGF1 lAP a firt idetified a a igad fr itegri6, ad exprei f itegri 6 regate TGF1actiati105. It i k that mtipe itegrica bid the RGD mtif i the lAP f TGF1, bt

Figure 3 | Itgis i t st ss t cc. Integrins expressed in many

tumour-associated cell types have crucial roles in increasing tumour progression

and metastasis. In endothelial cells, integrins regulate the migration, proliferation and

survival necessary for angiogenesis (step 1). The interaction between pericytes

and endothelial cells is crucial for the stabilization of newly formed vessels during

angiogenesis. Binding of integrin 41 on endothelial cells to vascular cell adhesionmolecule 1 (VCAM1) on pericytes plays an important part in pericyte recruitment to

the neovasculature (step 2). Myeloid cells and monocytes in primary tumours

contribute to disease progression by secreting cytokines andgrowth factors (GFs)that initiate angiogenesis and tumour cell migration (step 3). Several studies have

shown that integrins have an essential role in the homing of myeloid cells and

monocytes to tumours. Fibroblast infiltration into the primary tumour, known as

desmoplasia, also contributes to tumour progression through increased growth factor

secretion (step 4). In addition, the invading fibroblasts deposit large amounts of

collagen that might result in resistance to therapy in some tumours (step 5). A recent

study showed that integrins, such as 111, are crucial regulators of growth factorsecretion by these fibroblasts. Platelet expression of aIIb3 may be important forinteracting with tumour cells through a fibrinogen bridge, possibly aiding in

metastatic dissemination (step 6).

R E V I E W S


http://www.cancer.gov/drugdictionary/?CdrID=42265http://www.uniprot.org/uniprot/P08581http://www.uniprot.org/uniprot/P08581http://www.uniprot.org/uniprot/P01137http://www.uniprot.org/uniprot/P01137http://www.uniprot.org/uniprot/P08581http://www.cancer.gov/drugdictionary/?CdrID=42265


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_ `

ECMEGF SDF1

RTK CXCR4Integrin

RasERK FAKSRCp130CAS

Enhanced signalling Migration and invasion Metastasis

Nucleus

Growth factors Chemokines

Regulation of integrinexpression levels

Autocrineor paracrine

Autocrineor paracrine

bidig f itegri 6 ad 8 ret i TGF1actiati106. I cacer ch a baa ce carcima,icreaed itegri 6 exprei crreate ith aggreie dieae, pib ig t icreaed TGF1 actiati frmig a dee tmr trma107. Frther tdiehae h that itegri 6 actiate TGF1i vivo,ctribtig t tmr grth108, ad that pregatif itegri 6 i tmr ce i aciated ith EMT,TGF1actiati ad icreaed migrati109.

Itegri igaig ca a direct mdate TGFrepe. Itegri 3 ad sRC cperate ith TGF tidce EMT f mammar epitheia ce110, ad thi reqiresRCdepedet phphrati f TGF receptrtpe 2 (TGFBR2)111. Additia, TGF timatiidce phphrati f the ctpamic dmai fitegri 1, retig i itegri actiati ad tmrce iai112. A TGFi predmiat ecreted btmr trma ce, crtak betee itegri adTGF ma hae a imprtat re i the ctribtif the tmr trma t cacer prgrei.

VEGF, FGF and their receptors.Itegrigrth factrcrtak t ccr tmr ce, bt a haa re i ari ht ce tpe, icdig edtheiace, i hich it ctribte t tmr agigeei.Drig agigeei, bth itegri ad grth factrare ita t edtheia ce migrati, priferati ad

ria. Therefre, ciderabe effrt ha ge itidetifig pecific fctia iteracti beteeidiida itegri ad grth factr receptr. Ifact, ditict itegrigrth factr pair hae beedecribed that ctribte t agigeei thrghdifferet igaig patha.

Drig tmr agigeei edtheia ce i thetmr micreirmet mt reit ce death that iidced b tree ch a hpxia ad triet depriati (itriic appti) r ifammatr mediatr (extriic appti). we hae prei decribedditict patha f agigeei that are mediated bpecific itegrigrth factr receptr pair49. Theepatha iga t prtect edtheia ce frm ditict appttic timi thrgh differetia actiati fRaf19,20(FIG. 2). FGFR cperate ith itegri 3 ticreae the phphrati f Raf ser338 ad ser339thrgh PAK19,20, retig i RafAsK1 (a ka MAP3K5) cmpex frmati i the mitchdria, ihibitig the itriic patha f appti113.B ctrat, vEGFR2 cperate ith itegri 5,

eadig t sRCdepedet phphrati f RafTr340 ad Tr341 ad reitace t extriic appti that i idced b ifammatr mediatr cha tmr ecri factr (TnF)19,20. Thi dercrethe imprtace f Raf drig tmr agigeei addcmet h ditict itegrigrth factr pairca differetia ifece dtream edtheiaria patha. A cetra re fr Raf i agigeei a etabihed b targetig mtatia iactieRaf t the tmr acatre, hich ptet ihibitedagigeei ad tmr grth i mice114.

Additia exampe f crtak betee vEGFR2ad itegri hae a bee decribed i acaredtheia ce. Fr exampe, sRC recritmet tvEGFR2 prmte crtak ith itegri 3 adsRCdepedet trie phphrati f the ctpamic dmai f itegri 3 (REF.113). Thi ma bereated t the icreaed ee f vEGFR2 i Igb3/

mice eadig t a cmpeatr icreae i agigeei22. Ather mechaim b hich vEGF ifeceitegri 3 igaig i thrgh regatig the affiit tate, r actiati f the itegri115. Actiati fitegri 3 ca i tr icreae tmr ce ecretif vEGF, pridig a feedback p retig i icreaedtmr grth91. specific itegrigrth factr pairhae a bee idetified i FGFmediated agigeei.Itegri 4 ctribte t FGFmediated agige

ei, a a targeted deeti f the igaig prtif the ctpamic dmai f itegri 4 reted idecreaed FGFidced agigeei ad redcedtmr ize116. Therefre, igaig thrgh ditictitegrigrth factr receptr pair ha crcia rei tmr agigeei.

CXCR4.Athgh bet characterized fr it re ithe recritmet f haematpietic ce t ite fir r ifecti, the chemkie receptr CXCR4 ia expreed tmr ce ad ari tmraciated ce tpe. Bidig f CXCR4 t it cgate igad trma cederied factr 1 (sDF1; a

Figure 4 | Itgigwt ct itgicyti ct csst.Cooperation between integrin and growth factor signalling or integrin and cytokine

signalling is crucial to tumour progression. Several crosstalk mechanisms have so far

been elucidated. Integrin ligation may lead directly to the increased secretion of growth

factors and/or cytokines, which can then bind to their receptors in an autocrine or

paracrine manner to further induce signalling. In addition, signalling induced by either

integrin ligation or growth factor binding may activate common downstream pathways

resulting in enhanced signalling overall compared with the activation of either receptor

alone. This signalling seems to most commonly converge on kinases such as Src family

kinases (SFKs), scaffolding proteins such as p130 CRK-associated substrate (p130CAS),

and GTPases, such as the Ras family. Alternatively, both chemokine and growth factor

signalling may regulate integrin function by directly controlling integrin expression

levels. ECM, extracellular matrix; EGF, epidermal growth factor; FAK, focal adhesion

kinase; SDF1, stromal cell-derived factor 1; RTK, receptor tyrosine kinase.

R E V I E W S


http://www.uniprot.org/uniprot/P26012http://www.uniprot.org/uniprot/P61073http://www.uniprot.org/uniprot/P48061http://www.uniprot.org/uniprot/P48061http://www.uniprot.org/uniprot/P61073http://www.uniprot.org/uniprot/P26012


9/14

k a CXCl12) idce tmr ce migrati adctribte t metatai. sDF1 timati f CXCR4 tmr ce icreae the exprei f itegri, cha 51 ad 3, icreaig ce adhei ad iaii viro87,88 ad experimeta metatai i vivo117. Iadditi t icreaig itegri rface exprei, sDF1ctr adhei b agmetig itegri actiati118. Iather exampe, itegri igati reciprca regateCXCR4 exprei ee89. Frther tdie are eeded tdetermie the reeace f itegriCXCR4 crtakt tmr grth ad ptae metatai.

Integrins as targets for cancer therapy

The exprei f itegri i ari ce tpe thatare ied i tmr prgrei ad their abiit t crtak ith grth factr receptr ha madethem appeaig therapetic target. Preciica tdiehed that itegri atagit ihibit tmr grthb affectig bth tmr ce ad tmraciatedht ce, mt tab the agigeic edtheim.Itegri atagit crret i ciica tria icde

mca atibdie ad RGD peptide mimetic(ee Araamide e al.47 fr a cmpete reie). yearf preciica tdie ad ear ciica tria hae cmiated i the iitiati f a Phae III ciica tria igibatma ith the RGD peptide mimetic ciegitide.I thi ecti, e dic the crret tat f itegriatagit i cacer therap, icdig the tdie pprtig the deig f the firt Phae III ciica tria f aitegri ihibitr i cacer.

Targeting v3 and v5.Itegri 3 i pregated ibth tmr ce ad agigeic edtheia ce, makig it a attractie therapetic target. Fctibckigmca atibdie, ch a lM609, ere amg thefirt itegri atagit deeped, ad hed ciderabe atiagigeic actiit i preciica mde119.A a ret f thee tdie, etaracizmab (MEDI522),a hmaized eri f lM609, a deeped. I additi t it atiagigeic effect, etaracizmab ihibited tmr grth b direct affectig tmr ce120,ad impaired be rerpti b ihibitig tecatattachmet, ggetig pibe efficac i redcigbe metatai121. A a ret f it efficac i preciica tdie, etaracizmab a e f the firt itegriatagit itrdced it ciica tria. Phae I triaith itaxi, the precrr f etaracizmab, hed atiagigeic actiit122, txicit ad dieae tabiiza

ti i me patiet ith adaced id tmr123 adrea ce cacer124. A Phae II td hed me efficac i metatatic meama125. The hma itegripecific mca atibdCnTo 95, hich targetbth 3 ad 5 itegri, a had atitmr adatiagigeic effect i xegraft tmr mde126,127.I a Phae I tria, CnTo 95 a txic128, caizedt tmr ad hed ig f atitmr actiit129.Bth CnTo 95 ad etaracizmab are beig frthereaated i additia ciica tria.

Ciegitide i a ihibitr f bth 3 ad 5itegri, ad it a eected i r abratr bcreeig a ibrar f ccic RGD peptide i a cefree

receptr aa fr their capacit t ihibit itegri3 ad 5 bt t b3 (REF. 130). Ciegitide icrret beig teted i Phae II tria i patiet ithg ad prtate cacer131, ad Phae II ad Phae IIItria are crret dera i gibatma. s far,ciegitide ha h igificat prmie i patietith atetage gibatma b extedig patiet r

ia ith miima ide effect (diced be)132135.neerthee, i me tdie, Red e al.22

fd that the cti ifi f er ccetrati f RGD peptide paradxica timate tmr grth ad agigeei b prmtigvEGFidced edtheia ce migrati22. Theeret are citet ith pbihed acct frmther grp hig that ccetrati fbe itegri atagit ca fcti a itegriagit i me cae136138. sch tdie mightbe reeat t recet tdie i hich ihibitr fvEGF icreaed tmr perfi retig iehaced tmr prgrei139,140. Heer, theicreaed tmr perfi aciated ith ati

agigeic therap might be expited t icreaethe deier f chemtherapetic aget, ptetiaexpaiig h atiagigeic aget ch a ciegitide are mt effectie he ed i cmbiatiith chemtherap. It i a imprtat t ciderthat ciegitide ad ther atiagigeic therapiemight target mtipe ce tpe i the tmr micreirmet, icdig the tmr ce themee,ad therefre their atitmr effect ma t beetire de t atiagigeic actiit.

Gibatma are aggreie, high acarized brai tmr fr hich patiet ria i margia icreaed b crret therapie.oce diaged, patiet tpica hae a hrt ifeexpectac f a fe mth. Ceqet, thedeepmet f therapetic pti that ctr thidieae i crcia. Thee high acarized tmrexpre itegri 3 agigeic bd ee, ae a the tmr ce themee, ggetig thatatagit t thi itegri might be therapeticabeeficia i patiet ith gibatma. I preciica tdie, ciegitide effectie ihibited agigeei ad the grth f rthtpic gibatma141,142.Imprtat, the brai micreirmet a a crcia determiat f the ceptibiit f thee tmrt ciegitide, a tmr that frmed i the fak fthee ame mice ere affected b treatmet ith

thi drg141. I additi, highgrade gibatmaabdat expre the ECM prtei itrecti,a itegri 3 igad, ad thi iteracti affecttmr ce ria14 ad iai143. Therefre, thereatie arge qatit f itrecti preet ithe brai micreirmet rrdig gibatma might expai h thee tmr are ceptibet ciegitide treatmet.

Thee prmiig preciica tdie ere the baifr ciica tria i patiet ith gibatma. Phae Itdie ith ciegitide i patiet ith recrret gibatma hed that it a e terated ad prdceddrabe repe that eemed t be reated t chage i

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reatie cerebra bd f132. Ather Phae I td ichidre ith refractr brai tmr determiedthat it a e terated ad prdced tabe dieae,ith a f repe i me patiet133. A Phae II tria ithciegitide hed atitmr efficac ad miimatxicit i patiet ith recrret gibatma134.A differet Phae I/II tria examied ciegitide ipatiet ith e diaged gibatma ad metit primar ed pit ith 69% f patiet prgreifree after 6 mth135. Imprtat, thi tria made theberati that patiet ith ered exprei fO6methgaieDnA methtraferae (MGMT),ig t prmter methati, exhibited a higher rate(91%) f prgreifree ria at 6 mth. TheMGMtprmter i a prgtic marker i patietith gibatma: tmr ith methatedMGMtprmter idicate a er prbabiit f patietria, a MGMT i thght t icreae reitacet drg ch a temzmide, hich i a crrettadard therap.

The farabe ret btaied frm thee ear

ciica tria prided the impet fr a Phae IIItria ith ciegitide that bega i octber 2008. TheCEnTRIC tria i er apprximate 500 patietad meare the effect f ciegitide the ria fpatiet ithMGMtprmter methati i cmbiati ith temzmide ad raditherap. Thi ithe firt Phae III cg tria carried t ith aitegri atagit. A a cmpai t the CEnTRICtria, the Phae II CoRE tria i ae the efficac fciegitide i a arge mber f patiet he tmrhae methatedMGMtprmter.

Targeting 1 integrins. strategie that target 1itegri, particar 51, hae a h efficaci redcig tmr brde i preciica mde. Aitegri 1 ihibitr atibd igificat affectedi viro ad i vivo grth f hma breat cacertmr ce144. vciximab, a fctibckigmca atibd agait itegri 51, ihibitagigeei ad impede tmr grth145,146. APhae I tria i patiet ith adaced id maigacie hed that ciximab a e teratedad ma hae ciica efficac147. vciximab i crret i Phae II ciica tria fr id tmr 148.ATn161 i a RGDbaed peptide ihibitr fitegri 51 that bck breat cacer grth admetatai i vivo149. I me mde f c ca

cer metatai t the ier, cmbiati therap ithATn161 ad frraci igificat redcedtmr brde ad ier metatae cmpared itheither treatmet ae150. ATn161 a teted ipatiet ith adaced id tmr ad a eterated ad prged tabe dieae i ethirdf the patiet151.

Additional integrin antagonists.seera additiaitegri atagit hae h efficac i preciica tdie, bt hae t et made it t the ciic. Ixegraft tmr mde, the itegri 3 mamece atagit s247 ihibited breat cacer be

metatae152, decreaed c cacer metatai adagigeei, ad icreaed ria153. A peptideatagit f itegri 3, PsK1404, ihibited breatad aria cacer be metatae itht affectigtecat actiit154. Admiitrati f the RGD peptidmimetic s137 ad s247 prdced atimetataticeffect155. Preciica tdie hed that atiee teither ItGAVr ItGB3 ppreed the grth f bctae iected hma hepatcear carcimace156. A mca atibd agait itegri 6,6.3G9, bcked the grth f hma phargea carcima ce bth i viro ad i vivo108. Iteretig,treatmet f ce ith thi atibd a ihibitedTGF igaig, ggetig that at eat me f itefficac might reqire crtak ith the TGF receptr. It i be iteretig t bere the perfrmacef thee e aget i ciica tria, ad td htheir efficac ma be ptimized i cmbiati ithadditia therapetic trategie.

Targets for cancer imaging and drug delivery

Imaging. Crret, there are aidated bimarkerfr ciica aeig the efficac f atiagigeictherapie, icdig ciegitide. Athgh cadidatemarker are beig ietigated, icdig erm ee f vEGF, FGF ad paceta grth factr, a ea the abdace f circatig edtheia ce adtheir precrr, thee marker hae t et citet predicted tmr repe. A a ret, better

acar imagig techiqe are beig deeped tmitr repiee t treatmet. I particar,ciderabe effrt ha bee expeded characterizig itegri atagit fr their abiit t pecificadeier diagtic aget t tmr ce ad aciated bd ee. Cpig f the itegri 3 atibd lM609 r ther atagit t a paramageticctrat aget157 r radicide158 ha aed thedetecti f agigeic ee i rabbit ad metmr mde. A itegri 3targeted mageticreace imagig apartice ha a bee ed tdetect the eacatre f mite id tmr ia xegraft tmr mde159. Additia, agigeic

ee ca be detected b ctrat ehaced trad ith micrbbbe targetig itegri160.RGD peptide abeed ith64C,18F ad tramaperparamagetic ir xide partice hae abee ed t detect itegri i xegraft mdef breat161, brai162 ad g cacer163, repectie.

sme f thee imagig aget hae recet derge eaati i cacer patiet. scitigraphicimagig ig a radiabeed itegri 3targetedpeptide (99mTcnC100692) detected a high prprtif maigacie i patiet ith breat cacer164,165. Iather td, deier f 18FgaactRGD i cmbiati ith pitr emii tmgraph (PET)prided iaie qatitatie aemet fitegri 3 exprei i hma tmr166. Theetdie gget that abeed itegri atagitcd pride imprtat diagtic t fr aeig the efficac f atiagigeic ad atitmrtherapie.

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Targeted delivery of therapy. Itegritargetedtherapetic hae recet pred beeficia i deierig chemtherapetic, ctic ire, prappttic peptide (ch a TnF ad TnFreatedapptiidcig igad (TRAIl)) ad radicetide t bth tmr ce ad the pprtig acatre (TABLE 2). The e f itegri targetig t deiertherapetic t the tmr acatre a f irt hb Hd e al.114, h ed a itegri 3targetedapartice t eectie deier a mtat RAf1gee t the tmr acatre, retig i appti f edtheia ce ad tmr regrei. Mrerecet tdie hed that deier f targeted apartice aded ith dxrbici t itegri 3pitie tmr acatre ihibited the grth fmetatae hie eimiatig the txicit ad eight aciated ith temic admiitrati f thi

drg167. Thi deier methd reted i a 15fdimpremet i tmr ad atimetatatic actiithe cmpared ith admiitrati f the free drg.The preferetia actiit f thee apartice metatae gget that grig metatatic tmrma hae a greater depedece agigeic ee ad cd be mre ceptibe t itegri3targeted therap.

Conclusions

Itegri expreed b tmr ad tmraciatedht ce mediate a diere arra f cear effect retig i tmr prgrei ad metatai. Imprtat

amg thee i the re itegri hae i determiigtmr ce ria. I the pat fe ear tdie haereeaed e re fr igated itegri i thi prce. uder me circmtace igated itegri caidce tmr ce appti thrgh IMD b recritig ad actiatig capae ceaage. Tmr ce thatare reitat t IMD gai the abiit t metataize. Ithi cae igated itegri ma prmte ce ria,retig i icreaed achrageidepedece admetatai. Thee effect f igated itegri ma beciica reeat ad prbab repreet imprtat factr i determiig tmr ce eitiit t itegriatagit.

Crtak ith grth factr receptr i reqiredfr ma f the cacerprmtig effect f itegri.Recet tdie hae h that certai grth factrreceptr ad cgee reqire pecific itegri fr

their effect tmrigeei ad metatai. Thi gget that it ma be paibe t tair the e f itegriatagit i idiida patiet he tmr arerepie t particar grth factr r cgee.Ateratie, the ECM cmpiti f the tmrmicreirmet ma hae a ita re i determiig the eitiit f a tmr t itegri atagit.Thi ma part expai the ciica repiee fpatiet ith gibatma treated ith ciegitide.Ftre tdie i hae t ecidate the factr repibe fr tmr ceptibiit t thee ihibitr adthee i timate ifece h effectie thee agetare a cacer therapetic.

Table 2 |Integrin targeting methods

Tutic gt Tgtig mity Tumu m(s) rsuts rs

MutantRAF1 Organicvb3ligand

Subcutaneous humanmelanoma cells

Regression of established primaryand metastatic tumours andapoptosis of the tumour-associatedvasculature

113

Nanoparticle

loaded withdoxorubicin

cRGD Orthotopic mouse

pancreatic tumour cells andhuman melanoma and renaltumour cells

Suppressed spontaneous metastases

by disrupting the associatedvasculature at very low doses

167

Nanoparticleloaded withfumagillin

cRGD Vx-2 rabbit adenocarcinoma Suppressed angiogenesis andtumour development at low doses

183

Oncolytic measlesvirus

cRGD Subcutaneous humanmyeloma cells

Targeted delivery of virus to tumourneovessels

184

TRAIL RGD Subcutaneous human coloncancer cells

Inhibited primary tumour burden to agreater extent than TRAIL alone

185

p53 RGDK-lipopeptide Orthotopic mousemelanoma cells

Targeted tumour vasculature andinhibited tumour volume

186

Radionucleotide cRGD Subcutaneous humanovarian cancer cells

Increased survival compared withuntreated mice

187,188

Radionucleotide Etaracizumab Orthotopic humanglioblastoma cells andsubcutaneous human coloncancer cells

Decreased angiogenesis andreduced tumour volume better thandelivery of the antibody alone

189

Cytotoxicimmunoconjugates

CNTO 95 Subcutaneous human colonand lung cancer cells

Reduced primary tumour burdenabove the level observed withantibody alone

190

cRGD, cyclic arginine-glycine-aspartic acid; RGDK, arginine-glycine-aspartic acid-lysine; TRAIL, tumour necrosis factor-relatedapoptosis-inducing ligand.

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