Decorin: A Growth Factor Antagonist for Tumor Growth Inhibition

Re iew A icle Deco in: A G ow h Fac o An agonis o Tumo G ow h Inhibi ion Te o A. H. Jä inen1,2 and S ua P ince1 1Schoolo Medicine,Uni e si yo Tampe e,33014Tampe e,Finland 2Depa men o O hopedics & T auma ology, Tampe e Uni e si y Hospi al, 33521 Tampe e, Finland Co espondence should be add essed o Te o A. H. J¨ a inen; bl [email p o ec ed] Recei ed 27 July 2015; Accep ed 21 Oc obe 2015 Academic Edi o : Jean Claude Dussaule Copy igh © 2015 T. A. H. J¨ a inen and S. P ince. This is an open access a icle dis ibu ed unde he C ea i e Commons A ibu ion License, which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed. Deco in (DCN) is he bes cha ac e ized membe o he ex acellula small leucine- ich p o eoglycan amily p esen in connec i e issues, ypically in associa ion wi h o “deco a ing” collagen ib ils. I has subs an ial in e es o clinical medicine owing o i s an i ib o ic, an i-in lamma o y, and an icance e ec s. S udies on DCN knockou mice ha e es ablished ha a lack o DCN is pe missi e o umo de elopmen and i is ega ded as a umo supp esso gene. A educed exp ession o a o al disappea ance o DCN has been epo ed o ake place in a ious o ms o human cance s du ing umo p og ession. Fu he mo e, when used as a he apeu ic molecule, DCN has been shown o inhibi umo p og ession and me as ases in expe imen al cance models. DCN a ec s he biology o a ious ypes o cance by a ge ing a numbe o c ucial signaling molecules in ol ed in cell g ow h, su i al, me as asis, and angiogenesis. The ac i e si es o he neu aliza ion o di e en g ow h ac o s all eside in di e en pa s o he DCN molecule. An eme ging concep ha mul iple p o eases, especially hose p oduced by in lamma o y cells, a e capable o clea ing DCN sugges s ha na i e DCN could be inac i a ed in a numbe o pa hological in lamma o y condi ions. In his pape , we e iew he ole o DCN in cance . 1. In oduc ion Deco in (DCN) is he bes cha ac e ized membe o he small leucine- ich p o eoglycan (SLRP) amily o ex acel- lula ma ix (ECM) p o eins. Due o i s close in e ac ions wi h collagen ibe s in he ECM— ha is, DCN “deco a es” collagen ibe s— he p o eoglycan was named deco in ea ly on [1]. DCN was ini ially cloned in 1986 and hough a he ime o be a s uc u al cons i uen o he ECM [1]. Howe e , soon i was es ablished ha DCN had a ole beyond jus a s uc u al componen o he ECM, as i became e iden ha i in luenced cellula unc ions such as p oli e a ion, sp eading, mig a ion, and di e en ia ion, as well as being a physiological egula o o in lamma ion [2–5]. Some o hese ea ly indings we e de i ed om umo cells [2–5], whe e i was shown ha DCN inhibi ed cance cell p oli e a ion and sp eading. These s udies spa ked a wo-decade-long ques ha es ablished DCN as a p omising an i umo agen o ea human cance pa ien s [6]. Mammalian DCN con ains a monome ic p o ein co e o 42 kDa and a single chond oi in/de ma an sul a e gly- cosaminoglycan (GAG) chain, a ached o a se ine esidue nea he N e minus [1, 7] (Figu es 1 and 2). DCN exis s as a dime in physiological solu ions [8, 9] and as a monome whenbound ocollagen[10](Figu es1and2)andis he bes cha ac e ized membe o he g owing amily o SLRPs [8, 9]. S uc u ally, i has a domain o andem leucine- ich epea s (LRRs, al oge he 12 LRRs), lanked on bo h sides by wo cys eine- ich egions [8, 9] (Figu es 1 and 2). SLRPs ha e been g ouped in o h ee di e en classes on he basis o gene o ganiza ion, amino acid sequence simila i y, numbe o LRRs, and he spacing o cys eine esidues in he N- e minal segmen [8]. DCN belongs o class I SLRPs wi h biglycan (BGN) and aspo in [8, 11]. The s uc u al simila i ies be ween di e en SLRPs p o ide an explana ion as o why hey sha e some o hei biological unc ions [11–13]. DCN has been implica ed o play a ole in he de elopmen and p og ession o cance and a subs an ial amoun o wo k has Hindawi Publishing Co po a ion BioMed Resea ch In e na ional Volume 2015, A icle ID 654765, 11 pages h p://dx.doi.o g/10.1155/2015/654765 2BioMed Resea ch In e na ional Figu e 1: S uc u e o deco in: mammalian deco in (DCN) con ains a monome ic p o ein co e o 42 kDa and a single chond oi in/de ma an sul a e glycosaminoglycan (GAG) chain. DCN exis s as a dime in physiological solu ions and is he bes cha ac e ized membe o he g owing amily o SLRPs. S uc u ally, i has a domain o andem leucine- ich epea s (LRRs, al oge he 12 LRRs), lanked on bo h sides by wo cys eine- ich egions. Deco in dime s uc u e ( om PDB 1XKU). Images p epa ed wi h JMOL p og am. The N- e minus is in he “middle” o he an ipa allel homodime . Col Col GAG chain S P MyoS EGFR CTGF FN Thbs Thbs TGF-𝛽 LRR N-linked oligos FN Cys eine esidues Cys eine esidues Ma u e deco in (DCN) p o ein Signal and p opep ide I Amino e minus II Co e p o ein III Ca boxyl e minus IV PDGF C-MET Figu e 2: Deco in in e ac s wi h mul iple g ow h ac o signaling pa hways c ucial o cance g ow h. Schema ic d awing o he molecula s uc u e o deco in (DCN). All ou domains, I–IV, o deco in co e p o ein a e indica ed. DCN has a monome ic p o ein co e and a single chond oi in/de ma an sul a e glycosaminoglycan (GAG) chain. S uc u ally, i has a domain o andem leucine- ich epea s (LRRs), lanked on bo h sides by wo cys eine- ich egions. DCN in e ac s wi h a wide se o di e en signaling molecules; among hem a e di e en iso o ms o ans o ming g ow h ac o -𝛽(TGF-𝛽), pla ele -de i ed g ow h ac o (PDGF), epide mal g ow h ac o ecep o (EGFR), and E bB1–4 ecep o y osine kinases, myos a in (MyoS), connec i e issue g ow h ac o /CCN2 (CTGF), h ombospondin (Thbs), collagen (Col), and ib onec in (FN), implica ed in cance p og ession. The ac i e/binding si es o DCN o TGF-𝛽, CCN2, c-Me , and EGFR neu aliza ion/binding all eside in di e en pa s o he DCN molecule. Thus, in heo y, a single DCN molecule could simul aneously seques e mul iple impo an media o s o umo g ow h and an agonize mul iple signaling pa hways c ucial o umo g ow h and p og ession. Thus, owing o his mul i unc ionali y, DCN may exe i s an icance e ec s h ough mul iple molecula app oaches ha all con ibu e o a ying deg ee o i s biological e ec s on cance cells and umo en i onmen . BioMed Resea ch In e na ional 3 been published on i s he apeu ic an icance e ec s. We will e iew he ole o DCN in cance de elopmen and highligh i s as he apeu ic an icance po en ial in his e iew a icle. 2. Loss o DCN Leads o Spon aneous Tumo De elopmen DCNknock-ou (KO)micea e e ileandshownoob ious mal o ma ions in hei issues [14]. Thei skin and endons a e mechanically agileowing o heDCN unc iono egula ing collagen ib illogenesis [14]. When a double KO o DCN and ano he closely ela ed SLRP, BGN, was gene a ed, he pheno ype in he double-KO mice was mo e se e e han in he DCN KO mice [12]. The DCN-BGN double-KO pheno ype is eminiscen o a speci ic sub ype o Ehle s- Danlos synd ome (EDS), he p oge oid a ian , a clinically and gene ically he e ogeneous connec i e issue diso de cha ac e ized by skin hype ex ensibili y, join hype mobili y, and issue agili y [12, 15]. Taken al oge he , he p esence o BGN compensa es o he loss o DCN in he DCN KO. In his con ex , i is wo h no ing ha aspo in sha es he collagen binding si e wi h DCN [11]. Theo e ically, aspo in couldcompensa e o bo hDCNandBGNindouble-KO animalandalle ia e hepheno ypecausedby heabsenceo i s wo amily membe s. Despi e he compensa o y e ec o BGN (and he po en- ial compensa o y ole o aspo in) in he absence o DCN, 30% o DCN KO mice de eloped spon aneous in es inal umo s and a high- isk die en iched in a ampli ied and accele a ed he umo de elopmen and g ow h ini ia ed by DCN de iciency [16]. In e es ingly, E-cadhe in, a p o- ein ha egula es cell-cell adhesion, epi helial-mesenchymal ansi ion, and me as asis, was almos comple ely los om he DCN KO in es ine, and loss o DCN and E-cadhe in accele a ed colon cance cell g ow h and in asion [16]. DCN and p53 umo supp esso double-KO mice, in u n, ha e a signi ican ly as e a e o lymphoma de elopmen han p53 KO alone and succumb o hymic lymphomas mon hs ea lie hanp53KOmice[17].Mos ecen ly, heabsenceo DCN in KO mice has been shown o p omo e chemically induced hepa ic ca cinogenesis [18, 19]. Gene ic abla ion o DCN led o enhanced umo occu ence as compa ed o wild- ype animals in di e en models o hepa ic cance [18, 19]. Taken oge he , all o he da a gene a ed on DCN KO mice sugges ha DCN is a po en umo supp esso gene [6, 16–19]. The e ha e no been any mu a ions epo ed o DCN in human malignancies, whe eas such mu a ions cause human diseasecalledcongeni als omalco nealdys ophy(CSCD), hediseasecha ac e izedbyco nealopaci iesand ision impai men [20]. 3. Reduced Exp ession o DCN in Human Tumo s A la ge numbe o publica ions om di e en ypes o human cance s ha e shown ha DCN exp ession in umo s is signi - ican ly educed om he le els exp essed in no mal issues o e yo en o allylos om umo issue[21,22].The educed o o al absence o DCN exp ession has been epo ed o ake place in b eas , colon, p os a e, ascula , and bladde cance s, liposa comas, myelomas, and malignan pe iphe ial ne e shea h umo s [21–26]. In line wi h hese indings, he e is also e idence om human cance s ha DCN exp ession dec eases wi h he malignan ans o ma ion o umo cells, i s exp ession being los in he ans o ma ion om benign o malignan umo s o i s exp ession being lowes o o ally absen in hemos agg essi e umo s[21–25,27].Insuppo o hisconcep ,lowle elso DCNincance sa eassocia ed wi h signi ican ly poo e ou come and a sho e ime o p o- g ession han wi h pa ien s exp essing highe le els o DCN in b eas , lung, and so issue cance s as well as in myeloma [21–23, 28]. The educed exp ession o DCN is no es ic ed only o umo cells in cance p og ession; s omal exp ession o DCN is also dec eased by soluble ac o s sec e ed by umo cells [29–31]. Myeloma cells sec e e CCL3 chemokine ha supp esses DCN exp ession in he su ounding bone ma ow s oma [31] because s omal/os eoblas de i ed DCN isknown oinhibi myelomacellp oli e a ionandsu i al [29,31,32].B eas cance cells,in u n,sec e epe ios in ha seques e s DCN and by doing so he cance cells p o ide hemsel es an oppo uni y o g ow in asi ely and mig a e wi hou inhibi o y ac i i y om DCN [30]. Ve y ecen ly, he educed DCN exp ession has been linked o os eosa coma de elopmen in Li-F aumeni syn- d ome (LFS) [33]. I was shown ha he LFS-cells exhibi impai ed exp ession o he imp in ed gene H19 [33]. Res o a- ion o H19 exp ession in LFS-cells acili a ed no mal cell di e en ia ion and ep essed umo igenic po en ial. I was ound ha H19 media es supp ession o LFS-associa ed os eosa coma o ma ion h ough DCN [33]. 4. DCN Seques e s T ans o ming G ow h Fac o -𝛽 T ans o ming g ow h ac o -𝛽(TGF-𝛽)was he i s g ow h ac o DCN was iden i ied o in e ac wi h [5] (Figu e 2), and i became e iden ha DCN e ec i ely inhibi s TGF-𝛽 induced cance cell sp eading and p oli e a ion in di e en cance cell lines [5]. La e i was shown in di e en animal models ha DCN is e y capable o educing issue ib osis and in lamma ion caused by TGF-𝛽[4, 34–38]. The DCN co e p o ein binds o all iso o ms o TGF-𝛽,namely,TGF-𝛽1, TGF-𝛽2, and TGF-𝛽3(Figu e2),al hough hechond oi in sul a e GAG side chain o DCN sligh ly in e e es wi h he co e p o ein’s binding o TGF-𝛽[39]. Thus, DCN aps TGF- 𝛽in he ECM be o e i can bind o i s ecep o s on he cell su ace [36]. In addi ion o neu alizing all iso o ms o TGF-𝛽, DCN also binds and neu alizes ano he membe o he TGF-𝛽supe amily capable o inducing ib osis and es ic ing issue egene a ion, myos a in [37, 40] (Figu e 2). In he case o myos a in inhibi ion, DCN seques a ion shu s down myos a in’s g ow h inhibi o y e ec s on myo ibe s and hus DCN s imula es skele al muscle egene a ion [37, 40, 41]. Due o i s po ency in educing in lamma ion and ib osis, DCN has been p oposed o be a physiological TGF- 𝛽inhibi o ha limi s he du a ion o TGF-𝛽 esponses in 4BioMed Resea ch In e na ional in lamma ion and issue epai [4, 36]. This claim is sup- po ed by he p o-in lamma o y pheno ype iden i ied in DCN KO in di e en ib o ic disease models as well as he in lamma ion supp essi e e ec s o exogenous DCN supplemen ed in expe imen al ea men ials [4, 34, 36, 42, 43]. 5. DCN: A Pan-Recep o Ty osine Kinase Inhibi o E bB ecep o y osine kinases (RTKs) a e hea ily in ol ed in he g ow h o se e al common human ca cinomas [44, 45]. These ecep o s a e ampli ied and o e exp essed in a la ge numbe o umo s, mos no ably in b eas cance , whe e he E bB2 gene a 17q12 is known o be ampli ied in 20% o he ca cinomas and known o d i e cance p og ession [44, 45]. DCN binds di ec ly o he epide mal g ow h ac o ecep o (EGFR/E bB1) and inhibi s i s ac i i y as well as he ac i i y o ano he membe o he E bB RTKs, namely, E bBs2–4 [46–50] (Figu e 2). A e binding DCN, he E bB ecep o s dime ize and subsequen ly unde go ca eolin-media ed in e - naliza ion and deg ada ion [50]. DCN is a pan-RTK inhibi o as i also inhibi s o he RTKs ou side o he E bB amily. I in e ac s wi h c-Me , hepa ocy e g ow h ac o (HGF) ecep o y osine kinase (Figu e 2). By binding o he c-Me ecep o DCN induces a sho ac i a ion, which is hen ollowed by a apid inac i a ion o he ecep o by in acellula deg ada ion [51, 52]. DCN also binds and inhibi s he biological unc ion o ascula endo helial g ow h ac o ecep o 2 (VEGFR2) (please see Sec ion 7 o mo e de ails) and insulin-like g ow h ac o -1 ecep o (IGF-IR) [53, 54]. 6. O he Signaling Molecules A ec ed by DCN In addi ion o TGF-𝛽and he RTKs, DCN also in e ac s wi h a wide se o di e en signaling molecules implica ed in cance p og ession. In an analogous an agonism o TGF- 𝛽, DCN seques e s pla ele -de i ed g ow h ac o (PDGF) be o e i can bind o i s ecep o s on he su ace o a ge cells[55](Figu e2).TheDCN-p o okedinhibi ionon he PDGF-dependen phospho yla ion o he PDGF ecep o esul s in he a enua ion o cance cell mig a ion [19, 55]. DCN also binds and neu alizes molecules such as connec i e issue g ow h ac o (CTGF/CCN2), low-densi y lipop o- ein ecep o - ela ed p o ein 1 (LRP-1), h ombospondin (THBS), and Wn -1-induced sec e ed p o ein 1 (WISP) [56– 59] (Figu e 2). All o hese molecules ha e been di ec ly shown o enhance cance g ow h and p og ession in di e en cance models and human cance s [56–59]. The ECM p o ein pe ios in, which is abundan ly exp essed by a la ge numbe o di e en human cance s, binds and neu alizes DCN [30]. The ac i e/binding si es o DCN o TGF-𝛽,CCN2,c- Me and EGFR neu aliza ion/binding all eside in di e - en pa s o he DCN molecule [57, 59] (Figu e 2). Thus, in heo y, a single DCN molecule could simul aneously seques e mul iple impo an media o s o umo g ow h and an agonize mul iple signaling pa hways c ucial o umo g ow h and p og ession [36] (Figu e 2). Thus, owing o his mul i unc ionali y, DCN may exe i s an icance e ec s h ough mul iple molecula app oaches ha all con ibu e o a ying deg ee o i s biological e ec s on cance cells and umo en i onmen [6] (Figu e 2). 7. DCN in Angiogenesis Tumo s induce heg ow h o new blood essels om p eex- is ing ones. This p ocess, angiogenesis, is a i al equi emen o umo g ow h because he o ma ion o new blood essels allows a a ie y o media o s, nu ien s, and oxygen o each he apidlyg owing umo cells[60,61].DCN hasbeenimplica ed obein ol edin he egula iono angiogenesis wi h con lic ing ou comes. In e ms o cance , DCNhasbeenshown oha eanan iangiogenice ec on umo angiogenesis [62]. Among he RTKs DCN inhibi s, VEGFR2 inhibi ion is he mos signi ican o DCN induced inhibi ion o umo angiogenesis [54]. DCN binds di ec ly o he ec odomain o VEGFR2 a a si e ha pa ially o e laps wi h he canonical binding si e o VEGF-A [54]. DCN has been shown o inhibi umo cell-media ed p oduc ion o he angiogenic molecules ascula endo helial g ow h ac o A (VEGF-A), hypoxia inducible ac o -1𝛼(HIF-1𝛼), and c-Me , whils simul aneously inducing he p oduc ion o he an iangiogenic, angios a ic molecules h ombospondin- 1 and issue inhibi o o me allop o einases 3 (TIMP3) [63, 64]. In addi ion o in luencing he balance o an i- and p oangiogenic ac o s, he an iangiogenic mechanisms o DCNin umo angiogenesisin ol eau ophagy[62].Namely, DCN induces he exp ession o pa e nally exp essed gene 3 (Peg3), an imp in ed umo supp esso gene, and Peg3 eloca esin oau ophagosomes[65].DCNe okesPeg3- dependen au ophagy in bo h mic o ascula and mac o as- cula endo helial cells leading o supp ession o angiogenesis [65]. On he o he hand, he e is also e idence o DCN suppo ing angiogenesis ou side o umo angiogenesis [66, 67]. DCN has been shown o play a p oangiogenic ole by suppo ing endo helial cell adhesion o ype I collagen (Figu e 2) and o 𝛼1𝛽2-in eg in and hus p omo ing he in eg in-collagen in e ac ion [68]. DCN de iciency, in u n, leads o impai ed angiogenesis in he inju ed co nea [66], while a deco in mimic suppo s endo helial cell p oli e a ion and mig a ion [69]. Fu he mo e, DCN was also iden i ied as an angioc ine (endo helial cell de i ed g ow h ac o o o gan-speci ic issue egene a ion) ac o o endo helial cell- d i en li e egene a ion [70]. Thus, depending on he cel- lula and molecula mic oen i onmen whe e angiogenesis occu s, DCN can exhibi ei he a p oangiogenic o an an ian- giogenic ac i i y [71]. Ne e heless, DCN exhibi s exclusi ely an iangiogenic ac i i y in umo igenesis-associa ed angio- genesis and in a ious in lamma o y p ocesses [70, 71]. 8. DCN as a The apeu ic An icance D ug In Vi o Vas amoun s o scien i ic da a ha e shown ha he adminis a ion o DCN can inhibi umo g ow h and BioMed Resea ch In e na ional 5 p og ession in i o. Ea ly s udies u ilizing i us-media ed gene he apy showed DCN ansduced in o umo cells inhib- i ed he g ow h o lung, colon, and squamous cell ca cinomas in i o [72]. DCN exp ession by os eosa coma cells, in u n, inhibi ed hei capabili y o send dis an me as ases o he lungs [73]. Simila ly, i us-deli e ed DCN slowed he g ow h o b eas cance and p e en ed i s dis an sp eading, ha is, me as asis o a ious o gans [74–76]. The exp ession o DCN by i us-media ed gene he apy in an expe imen al glioma model p olonged su i al and inhibi ed umo g ow h [77, 78]. The size o he umo s was di ec ly p opo ional o he iming o he DCN gene ans e as well as o he exp ession le els o DCN a ained by he gene ans e [77]. The umo g ow h inhibi o y ac i i y o DCN gene he apy has also been shown in p os a e and panc ea ic cance models [79, 80]. In addi ion o in i o gene he apy s udies, whe e DCN has been exp essed om wi hin i us-in ec ed cells, in i o umo ea men s udies wi h a ecombinan DCN co e p o ein ha e been ca ied ou wi h conside able success. T ea men o A431 squamous cell ca cinoma and b eas ca cinomas ans ec ed wi h DCN cDNA esul ed in umo cell apop osis, educed EGFR signaling, and e a ded umo g ow h [46, 49, 81]. Sys emic adminis a ion o DCN p o ein o ea b eas cance inhibi ed umo g ow h e ec i ely and educed me as a ic sp eading o he umo cells [52, 82]. 9. Inac i a ion o DCN by P o ease Media ed Clea age in Human Pa hologies The mul i unc ional oles o DCN a e due o i s capaci y o modula e he ac i i y o a wide a ie y o p o eins, such as g ow h ac o s o hei cell su ace ecep o s, and s uc u al ma ix p o eins, ia di ec binding. Impai men o DCN binding o i s pa ne s due o abe an DCN deg ada ion is linked o ib o ic diseases and ib o ic wound healing. Se e al p o eases as well as g ow h ac o s a e known o be capable o clea ing DCN making i inac i e agains some o he g ow h ac o s o collagen i is capable o binding o. Amongs di e en p o eases, DCN has been shown o be clea ed by ma ix me allop o einases-2 (MMP-2), MMP-3, MMP- 7, memb ane ype 1-ma ix me allop o einase (MT1-MMP), ca hepsin D, ADAMST-4 (adamalysin wi h h ombospondin ype 1 mo i s), ADAMST-5, and in e leukin-1𝛽[83–86]. Fu he mo e, in lamma o y cells p oduce p o eases capable o clea ing DCN. Cy o oxic lymphocy es p oduce g anzyme B, a se ine p o ease, while neu ophils p oduce neu ophil elas ase, bo h o which a e capable o clea ing DCN [87–90]. The clea age o DCN by p o eases de i ed om in lamma o y cells is o special signi icance, because ecen e idence sug- ges s ha DCN agmen s can unc ion as p oin lamma o y signaling molecules, so-called damage-associa ed molecula pa e ns (DAMPs), capable o inducing s e ile in lamma ion [91]. DAMPs a e ecognized by pa e n ecogni ion ecep o s (PRRs), such as Toll-like ecep o s (TLR), and can igge an in lamma o y esponse [91]. Whe he he DCN-induced s e ile in lamma ion has any clinical signi icance is a ele an ques ion, as an o e whelming amoun o e idence poin s o DCN ha ing a subs an ial an i-in lamma o y e ec in in lamma o y, ib o ic diseases; pheno ype in he absence o DCN(KO)isalwaysbo hp oin lamma o yandp o ib o ic, whe eas he in i o ea men ials wi h exogenous DCN exclusi ely epo bo h an i-in lamma o y as well as an i i- b o ic e ec s [2, 4, 34, 36–38, 92]. Inac i e DCN agmen s gene a ed by p o ease clea age as well as he gene al educed exp ession o DCN ha e been linked o human pa hologies [93]. Namely, ca abolic agmen so humanDCNha ebeeniden i ied omsca s and ib o ic diseases, and he impai men o DCN binding o i s pa ne s due o abe an DCN deg ada ion has been di ec ly linked o ib o ic wound healing [94, 95]. Recen ly, i wasshown ha UVligh exposu eonskincaninduce he exp ession o g anzyme B, which clea es DCN and leads o he appea ance o w inkles and he loss o no mal collagen densi y in he skin [87]. In a simila ashion, i has been shown ha DCN clea age by g anzyme B leads o aneu ysm up u es and subsequen dea hs o he animals in an expe imen al ao al aneu ysm model [88]. Fu he mo e, g anzyme B can ac i a e TGF-𝛽[87]. In o he wo ds, he simul aneous clea age o an i ib o ic DCN and he ac i a ion o p o ib o ic TGF-𝛽by g anzyme B u n on a “p o ib o ic p og am” in in lamma o y si ua ions. Fu he mo e, i has been shown ha he majo i y o DCN exis s in a clea ed, inac i e o m called “deco un ” in aged humanskin,whe easmos o heDCNinyounghuman skin is in i s ull size [94, 95]. As DCN is in ol ed in he egula ion o collagen ib illogenesis, i has been pos ula ed ha he loss o skin ex ensibili y and agili y associa ed wi h aging is ela ed o DCN being clea ed in o inac i e “deco un ” agmen s [94, 95]. In e es ingly, none o he DCN clea age si es epo ed o di e en p o eases gene a e heDCN agmen siden i iedin“deco un ”[94,95].Thus, one can pos ula e on he exis ence o as ye uniden i ied p o ease(s) capable o clea ing and inac i a ing DCN [94, 95]. 10. Limi a ions o DCN Despi e he as amoun o posi i e an icance and an i i- b o ic esul s ob ained wi h DCN ea men in a ious animal models, lack o any de ec able oxici y, and ex ensi e p eclinical wo k conduc ed on i , DCN has no eached he clinic as a d ug. The e migh be se e al easons o ha , such as an inadequa e hal -li e in he ci cula ion and he need o highdosing,bu ano he easonis he ac ha DCNisha d o mass-p oduce in a ashion ha mee s he egula o y c i e ia o human d ugs. Namely, DCN is a p o eoglycan, and he he e ogenei y o i s single GAG chain makes ecombinan DCN p oduced in mammalian cells he e ogeneous in size and composi ion [5]. The GAG chain is no needed o he an i ib o ic ac i i y o DCN [39], mos o he an icance e ec s o DCN ha e been gene a ed wi h ecombinan DCN wi h no GAG a ached o i , and mos o he in e ac ions DCN has wi h g ow h ac o s o hei ecep o s a e h ough di ec binding o heDCNco ep o ein.TheGAGisa ached o a se ine esidue a posi ion 4 o DCN [1], and i is possible o p oduce ecombinan DCN wi hou GAG a ached o i 6BioMed Resea ch In e na ional 1 23 4 Deco in CAR TGF-𝛽1 HSPG S-S TGF-𝛽RII TGF-𝛽RI Figu e 3: Schema ic ep esen a ion o he mechanism o ac ion o he mul i unc ional he apeu ic molecule CAR-deco in. CAR-deco in Ais a sys emically adminis e ed, a ge -seeking, mul i unc ional bio he apeu ic ha inhibi s nume ous g ow h ac o s in ol ed in umo g ow h and p og ession. The molecule can be a ge ed o he angiogenic ascula u e, whe he i is induced by inju y o by apid cance g ow h, aking place a any o gan o he body B(o mul iple o gans, i.e., me as ases, simul aneously). The CAR homing pep ide a ge s angiogenic ascula u e Band as i is a po en cell and issue pene a ing pep ide, i can pene a e deep in o a ge o gan C.Thus, hepep ide(and any payload a ached o i ) hen ex a asa es in o su ounding issue C, whe e i binds o i s ecep o (s) on he cell su ace o he a ge cells C. CAR binding o hepa an sul a e p o eoglycans p o ides docking si es in he p oximi y o such g ow h ac o s as TGF-𝛽1andTGF- 𝛽2D, acili a ing he neu aliza ion o hese g ow h ac o s by he he apeu ic pa o he molecule, deco in D. This mechanism esul s in a he apeu ic esponse. Pic u e by Helena Schmid ; ep oduced wi h pe mission om Finnish Medical Jou nal Duodecim (o iginally published in [96]). BioMed Resea ch In e na ional 7 by simply mu a ing he se ine esidue c i ical o he GAG a achmen [7, 97]. 11. Recombinan DCN Va ian wi h Enhanced Biological Ac i i y As hemanu ac u ingissueso DCNcanbesol ed ai ly easily by a simple si e-di ec ed mu agenesis [7], u he enhancemen o i s biological ac i i y could make i an e en mo e appealing d ug candida e o pu sue as a human he apeu ic d ug. We ha e ecen ly a ained ha goal by de eloping a sys emically adminis e ed, a ge ed, o exam- ple, in lamma ion- and angiogenesis-homing e sion o DCN co e p o ein [34, 36, 98] (Figu e 3). The angiogenesis- and in lamma ion-speci ici y o ou enhanced DCN co e p o ein is ob ained by usion o a small pep ide ha unc ions as an add ess ag and deli e s sys emically adminis e ed DCN o angiogenic and in lamma o y ascula u e [34, 36] (Figu e 3). This small pep ide, dubbed “CAR” (i s sequence being CARSKNKDC) homes speci ically o angiogenic blood essels o ming in umo s and egene a ing issues (such as wounds) [99, 100] and can deli e inc eased amoun s o DCN in a issue-speci ic manne wi h a signi ican he apeu ic ad an age o e o dina y DCN co e p o ein [34] (Figu e 3). Fu he mo e, he usion o CAR o ecombinan DCN u he enhances i s neu aliza ion o TGF-𝛽s imula ed cance cell p oli e a ion and sp eading signi ican ly [34] (Figu e 3). The molecula explana ion o he enhanced biological ac i i y o CAR-DCN is ha he CAR pep ide binds o hepa an sul a e p o eoglycans (HSPGs) on cells [34, 99]. TGF-𝛽1 and TGF-𝛽2, in u n, also bind hepa an sul a e and HSPG binding inc eases hei biological ac i i y (Figu e 3). Thus, CAR media ed binding o CAR-DCN o HSPGs may enhance he neu alizing e ec o he usion p o ein by b inging i in o he p oximi y o he HSPG-binding TGF-𝛽s[34,36,97] (Figu e 3). The CAR pep ide has also been ecen ly shown o a ge in lamma o y ascula u e, bu no no mal ascula u e, in diseases a ec ing lungs [100–105] and o deli e di e en pha maceu ical agen s (e en la ge nanopa icle conjuga es con aining d ugs) in a ge o gan-speci ic ashion o diseased lungs [101–105]. Fu he mo e, CAR pep ide has been used success ully o a ge mesenchymal s em cells o in a c ed myoca dium [106, 107]. Thus, CAR- a ge ed DCN could also be use ul in he ea men o o he condi ions ou side o cance and healing wounds in which non a ge ed DCN has shown ac i i y and whe e he e is angiogenesis o in lamma- ion a ec ing nea by ascula u e (Figu e 3). 12. Conclusion DCN is a well-s udied membe o he ex acellula small leucine- ich p o eoglycan amily p esen in a a ie y o issues and has subs an ial in e es o clinical medicine owing o i s an i ib o ic and an icance e ec s. S udies on DCN knockou miceha ees ablished ha alacko DCNispe missi e o umo de elopmen and i is ega ded as a umo supp esso gene. A educed exp ession o a o al disappea ance o DCN has been epo ed o ake place in a ious o ms o human cance s du ing umo p og ession. Fu he mo e, when used as a he apeu ic molecule, DCN has been shown o inhibi umo p og ession and me as asis in expe imen al cance models. DCN a ec s he biology o a ious ypes o cance by di ec ly o indi ec ly a ge ing la ge numbe s o c ucial signaling molecules in ol ed in cell g ow h, su i al, me as- asis, au ophagy, and angiogenesis. The ac i e si es o he neu aliza ion/binding o di e en g ow h ac o s all eside in di e en pa s o he DCN molecule. Mul iple p o eases, especially hose p oduced by in lamma o y cells, a e capable o clea ing and inac i a ing DCN, indica ing ha DCN could be inac i e in a numbe o pa hological diseases in ol ing an in lamma o y componen . Thus, he e ec i e applica ion o DCN co e p o ein in human medicine will equi e s a egies o deli e la ge amoun s o he in ac and unc ional p o ein speci ically o whe e i is mos needed, as well as o he possible enhancemen s a egies. The usion o DCN co e p o ein oge he wi h he angiogenesis- and in lamma ion- homing pep ide “CAR” is a signi ican s ep in his di ec ion. Con lic o In e es s The au ho s decla e ha he e is no con lic o in e es s ega ding he publica ion o his pape . Acknowledgmen s The au ho s hank P o esso E kki Ruoslah i (San o d- Bu nham-P ebys Medical Disco e y Ins i u e, La Jolla, CA, USA) o his hough ul commen s on hei pape . The wo k was suppo ed by he Sig id Juselius Founda ion, he Academy o Finland, P¨ ai ikki and Saka i Sohlbe g Foun- da ion, Ins umen a ium Resea ch Founda ion, Pi kanmaa Hospi al Dis ic Resea ch Founda ion, and Tampe e Tube - culosis Founda ion. Re e ences [1] T. K usius and E. Ruoslah i, “P ima y s uc u e o an ex a- cellula ma ix p o eoglycan co e p o ein deduced om cloned cDNA,” P oceedings o he Na ional Academy o Sciences o he Uni ed S a es o Ame ica, ol. 83, no. 20, pp. 7683–7687, 1986. [2] E. Ruoslah i and Y. Yamaguchi, “P o eoglycans as modula o s o g ow h ac o ac i i ies,” Cell, ol.64,no.5,pp.867–869,1991. [3] Y. Yamaguchi and E. Ruoslah i, “Exp ession o human p o eo- glycan in Chinese hams e o a y cells inhibi s cell p oli e a ion,” Na u e, ol. 336, no. 6196, pp. 244–246, 1988. [4] W. A. Bo de , N. A. Noble, T. Yamamo o e al., “Na u al inhibi o o ans o ming g ow h ac o -𝛽p o ec s agains sca ing in expe imen al kidney disease,” Na u e, ol.360,no.6402,pp. 361–364, 1992. [5] Y. Yamaguchi, D. M. Mann, and E. Ruoslah i, “Nega i e eg- ula ion o ans o ming g ow h ac o -𝛽by he p o eoglycan deco in,” Na u e, ol.346,no.6281,pp.281–284,1990. [6] D. D. So eu Feugaing, M. G¨ o e, and M. Viola, “Mo e han ma ix: he mul i ace ed ole o deco in in cance ,” Eu opean Jou nal o Cell Biology, ol. 92, no. 1, pp. 1–11, 2013. 8BioMed Resea ch In e na ional [7] D. M. Mann, Y. Yamaguchi, M. A. Bou don, and E. Ruoslahi i, “Analysis o glycosaminoglycan subs i u ion in deco in by si e- di ec ed mu agenesis,” Jou nalo BiologicalChemis y, ol.265, no. 9, pp. 5317–5323, 1990. [8] P. A. McEwan, P. G. Sco , P. N. Bishop, and J. Bella, “S uc u al co ela ions in he amily o small leucine- ich epea p o eins and p o eoglycans,” Jou nal o S uc u al Biology, ol.155,no.2, pp.294–305,2006. [9] P. G. Sco , P. A. McEwan, C. M. Dodd, E. M. Be gmann, P. N. Bishop, and J. Bella, “C ys al s uc u e o he dime ic p o ein co e o deco in, he a che ypal small leucine- ich epea p o eoglycan,” P oceedings o he Na ional Academy o Sciences o he Uni ed S a es o Ame ica, ol.101,no.44,pp.15633–15638, 2004. [10] M. Islam, J. Go , S. J. Pe kins, Y. Ishikawa, H. P. B¨ achinge , and E. Hohenes e , “The conca e ace o deco in media es e e sible dime iza ion and collagen binding,” Jou nal o Biological Chem- is y, ol.288,no.49,pp.35526–35533,2013. [11] P. Lo enzo, A. Aspbe g, P. ¨ Onne jo d, M. T. Bayliss, P. J. Neame, and D. Heineg˚ a d, “Iden i ica ion and cha ac e iza ion o aspo in. A no el membe o he leucine- ich epea p o ein amily closely ela ed o deco in and biglycan,” The Jou nal o Biological Chemis y, ol. 276, no. 15, pp. 12201–12211, 2001. [12] A. Co si, T. Xu, X.-D. Chen e al., “Pheno ypic e ec s o biglycan de iciency a e linked o collagen ib il abno mali ies, a e syne gized by deco in de iciency, and mimic Ehle s-Danlos- like changes in bone and o he connec i e issues,” Jou nal o Bone and Mine al Resea ch, ol.17,no.7,pp.1180–1189,2002. [13] S.Kalamajski,A.Aspbe g,K.Lindblom,D.Heineg ˚ a d, and ˚ A. Oldbe g, “Aspo in compe es wi h deco in o collagen binding, binds calcium and p omo es os eoblas collagen mine aliza- ion,” Biochemical Jou nal, ol.423,no.1,pp.53–59,2009. [14] K.G.Danielson,H.Ba ibaul ,D.F.Holmes,H.G aham,K.E. Kadle , and R. V. Iozzo, “Ta ge ed dis up ion o deco in leads o abno mal collagen ib il mo phology and skin agili y,” Jou nal o Cell Biology, ol.136,no.3,pp.729–743,1997. [15] L. Ameye and M. F. Young, “Mice de icien in small leucine- ich p o eoglycans: no el in i o models o os eopo osis, os eoa h i is, Ehle s-Danlos synd ome, muscula dys ophy, and co neal diseases,” Glycobiology, ol.12,no.9,pp.107R–116R, 2002. [16] X. Bi, C. Tong, A. Dockendo e al., “Gene ic de iciency o deco in causes in es inal umo o ma ion h ough dis up ion o in es inal cell ma u a ion,” Ca cinogenesis, ol.29,no.7,pp. 1435–1440, 2008. [17] R. V. Iozzo, F. Chak ani, D. Pe o i e al., “Coope a i e ac ion o ge m-line mu a ions in deco in and p53 accele a es lymphoma umo igenesis,” P oceedings o he Na ional Academy o Sciences o he Uni ed S a es o Ame ica, ol.96,no.6,pp.3092–3097, 1999. [18] Z. Ho ´ a h, I. Ko alszky, A. Full´ a e al., “Deco in de iciency p omo es hepa ic ca cinogenesis,” Ma ix Biology, ol.35,pp. 194–205, 2014. [19] K. Baghy, Z. Ho ´ a h, E. Regos e al., “Deco in in e e es wi h pla ele -de i ed g ow h ac o ecep o signaling in expe imen- al hepa oca cinogenesis,” FEBS Jou nal, ol.280,no.10,pp. 2150–2164, 2013. [20]S.Chen,M.Sun,R.V.Iozzo,W.W.-Y.Kao,andD.E.Bi k, “In acellula ly- e ained deco in lacking he C- e minal ea epea causes ER s ess: a cell-based e iological mechanism o congeni al s omal co neal dys ophy,” The Ame ican Jou nal o Pa hology, ol.183,no.1,pp.247–256,2013. [21] B. Bozoky, A. Sa chenko, H. Gu en, F. Pon en, G. Klein, and L. Szekely, “Dec eased deco in exp ession in he umo mic oen i onmen ,” Cance Medicine, ol.3,no.3,pp.485–491, 2014. [22] S. Liang, J.-F. Xu, W.-J. Cao, H.-P. Li, and C.-P. Hu, “Human deco in egula es p oli e a ion and mig a ion o human lung cance A549 cells,” Chinese Medical Jou nal, ol.126,no.24,pp. 4736–4741, 2013. [23] P. Bos ¨ om, A. Sainio, T. Kakko, M. Sa on aus, M. S¨ ode s ¨ om, and H. J¨ a el¨ ainen, “Localiza ion o deco in gene exp ession in no mal human b eas issue and in benign and malignan umo s o he human b eas ,” His ochemis y and Cell Biology, ol. 139, no. 1, pp. 161–171, 2013. [24] A. Sainio, M. Nyman, R. Lund e al., “Lack o deco in exp ession by human bladde cance cells o e s new ools in he he apy o u o helial malignancies,” PLoS ONE, ol.8,no.10,A icleID e76190, 2013. [25] H. H. Salom¨ aki, A. O. Sainio, M. S¨ ode s ¨ om, S. Pakkanen, J. Laine, and H. T. J¨ a el¨ ainen, “Di e en ial exp ession o deco in by human malignan and benign ascula umo s,” Jou nal o His ochemis y and Cy ochemis y, ol. 56, no. 7, pp. 639–646, 2008. [26] M. C. Nyman, A. O. Sainio, M. M. Pennanen e al., “Deco in in human colon cance -localiza ion in i o and e ec on cance cell beha io in i o,” Jou nal o His ochemis y & Cy ochemis y, ol.63,no.9,pp.710–720,2015. [27] A. D. Theocha is, S. S. Skandalis, T. Neill e al., “Insigh s in o he key oles o p o eoglycans in b eas cance biology and ansla ional medicine,” Biochimica e Biophysica Ac a—Re iews on Cance , ol.1855,no.2,pp.276–300,2015. [28] S.-Y. Huang, H.-H. Lin, M. Yao e al., “Highe deco in le els in bone ma ow plasma a e associa ed wi h supe io ea men esponse o no el agen -based induc ion in pa ien s wi h newly diagnosed myeloma—a e ospec i e s udy,” PLoS ONE, ol.10, no.9,A icleIDe0137552,2015. [29] X. Li, A. Pennisi, and S. Yaccoby, “Role o deco in in he an imyeloma e ec s o os eoblas s,” Blood, ol.112,no.1,pp.159– 168, 2008. [30] T. Ishiba, M. Nagaha a, T. Nakagawa e al., “Pe ios in supp es- sion induces deco in sec e ion leading o educed b eas cance cell mo ili y and in asion,” Scien i ic Repo s, ol.4,a icle7069, 2014. [31] N.Nemani,L.San o,H.Edae al.,“Roleo deco ininmul iple myeloma (MM) bone ma ow mic oen i onmen ,” Jou nal o Bone and Mine al Resea ch, ol.30,no.3,pp.533–538,2015. [32] I. B. K is ensen, L. Pede sen, T. B. Rø e al., “Deco in is down- egula ed in mul iple myeloma and MGUS bone ma ow plasma and inhibi s HGF-induced myeloma plasma cell iabil- i y and mig a ion,” Eu opean Jou nal o Haema ology, ol.91,no. 3,pp.196–200,2013. [33] D.F.Lee,J.Su,H.S.Kime al.,“Modeling amilialcance wi h induced plu ipo en s em cells,” Cell, ol.161,no.2,pp.240–254, 2015. [34] T. A. H. J¨ a inen and E. Ruoslah i, “Ta ge -seeking an i ib o ic compound enhances wound healing and supp esses sca o ma- ion in mice,” P oceedings o he Na ional Academy o Sciences o he Uni ed S a es o Ame ica, ol. 107, no. 50, pp. 21671–21676, 2010. [35] W. A. Bo de and E. Ruoslah i, “T ans o ming g ow h ac o -𝛽 in disease: he da k side o issue epai ,” The Jou nal o Clinical In es iga ion, ol.90,no.1,pp.1–7,1992. BioMed Resea ch In e na ional 9 [36] T. A. H. J¨ a inen and E. Ruoslah i, “Ta ge ed an isca ing he apy o issue inju ies,” Ad ances in Wound Ca e, ol.2,no. 2, pp. 50–54, 2013. [37] J.Zhu,Y.Li,W.Shene al.,“Rela ionshipsbe ween ans o ming g ow h ac o -be a1, myos a in, and deco in: implica ions o skele al muscle ib osis,” The Jou nal o Biological Chemis y, ol. 282, no. 35, pp. 25852–25863, 2007. [38] R. R. Mohan, J. C. K. To ey, R. Gup a, A. Sha ma, and A. Tandon, “Deco in biology, exp ession, unc ion and he apy in he co nea,” Cu en Molecula Medicine, ol.11,no.2,pp.110– 128, 2011. [39] A. Hildeb and, M. Roma is, M. Rasmussen e al., “In e ac ion o he small in e s i ial p o eoglycans biglycan, deco in and ib omodulin wi h ans o ming g ow h ac o 𝛽,” Biochemical Jou nal, ol.302,no.2,pp.527–534,1994. [40] T. Miu a, Y. Kishioka, J.-I. Wakama su e al., “Deco in binds myos a in and modula es i s ac i i y o muscle cells,” Biochem- ical and Biophysical Resea ch Communica ions, ol.340,no.2, pp.675–680,2006. [41] T. Kanzlei e , M. Ra h, S. W. G¨ o gens e al., “The myokine deco in is egula ed by con ac ion and in ol ed in muscle hype ophy,” Biochemical and Biophysical Resea ch Communi- ca ions, ol.450,no.2,pp.1089–1094,2014. [42] H. J¨ a el¨ ainen, P. Puolakkainen, S. Pakkanen e al., “A ole o deco in in cu aneous wound healing and angiogenesis,” Wound Repai and Regene a ion, ol.14,no.4,pp.443–452,2006. [43] H. J¨ a el¨ ainen, A. Sainio, M. Koulu, T. N. Wigh , and R. Pen inen, “Ex acellula ma ix molecules: po en ial a ge s in pha maco he apy,” Pha macological Re iews, ol.61,no.2,pp. 198–223, 2009. [44] T. A. H. J¨ a inen and E. T. Liu, “HER-2/neu and opoisome ase II𝛼–simul aneous d ug a ge s in cance ,” Combina o ial Chem- is y and High Th oughpu Sc eening, ol.6,no.5,pp.455–470, 2003. [45] T. A. H. J¨ a inen and E. T. Liu, “Simul aneous ampli ica ion o HER-2 (ERBB2) and opoisome ase II𝛼(TOP2A) genes— molecula basis o combina ion chemo he apy in cance ,” Cu en Cance D ug Ta ge s, ol.6,no.7,pp.579–602,2006. [46] G. Cso das, M. San a, C. C. Reed e al., “Sus ained down- egula ion o he epide mal g ow h ac o ecep o by deco in. Amechanism o con olling umo g ow hin i o,”The Jou nal o Biological Chemis y, ol.275,no.42,pp.32879–32887,2000. [47] R.V.Iozzo,D.K.Mosca ello,D.J.McQuillan,andI.Eichs e e , “Deco in is a biological ligand o he epide mal g ow h ac o ecep o ,” The Jou nal o Biological Chemis y, ol.274,no.8,pp. 4489–4492, 1999. [48] D. K. Mosca ello, M. San a, D. M. Mann, D. J. McQuillan, A. J. Wong, and R. V. Iozzo, “Deco in supp esses umo cell g ow h by ac i a ing he epide mal g ow h ac o ecep o ,” Jou nal o Clinical In es iga ion, ol.101,no.2,pp.406–412,1998. [49]M.San a,I.Eichs e e ,andR.V.Iozzo,“Anan i-oncogenic ole o deco in. Down- egula ion o E bB2 leads o g ow h supp ession and cy odi e en ia ion o mamma y ca cinoma cells,” Jou nalo BiologicalChemis y, ol.275,no.45,pp.35153– 35161, 2000. [50] M. San a, C. C. Reed, and R. V. Iozzo, “Deco in binds o a na ow egion o he epide mal g ow h ac o (EGF) ecep o , pa ially o e lapping bu dis inc om he EGF-binding epi- ope,” TheJou nalo BiologicalChemis y , ol.277,no.38,pp. 35671–35681, 2002. [51] S. Bu aschi, N. Pal, N. Tyle -Rubins ein, R. T. Owens, T. Neill, and R. V. Iozzo, “Deco in an agonizes Me ecep o ac i i y and down- egula es 𝛽-ca enin and Myc le els,” The Jou nal o Biological Chemis y, ol.285,no.53,pp.42075–42085,2010. [52] S. Goldoni, A. Humph ies, A. Nys ¨ om e al., “Deco in is a no el an agonis ic ligand o he Me ecep o ,” The Jou nal o Cell Biology, ol.185,no.4,pp.743–754,2009. [53] E. Sch¨ onhe , C. Sunde k¨ o e , R. V. Iozzo, and L. Schae e , “Deco in, a no el playe in he insulin-like g ow h ac o sys em,” TheJou nalo BiologicalChemis y, ol.280,no.16,pp. 15767–15772, 2005. [54] G.A.Khan,G.V.Gi ish,N.Lala,G.M.DiGuglielmo,andP.K. Lala, “Deco in is a no el VEGFR-2-binding an agonis o he human ex a illous ophoblas ,” Molecula Endoc inology, ol. 25,no.8,pp.1431–1443,2011. [55] N. Nili, A. N. Cheema, F. J. Gio dano e al., “Deco in inhibi ion o PDGF-s imula ed ascula smoo h muscle cell unc ion: po en ial mechanism o inhibi ion o in imal hype plasia a e balloon angioplas y,” The Ame ican Jou nal o Pa hology, ol. 163, no. 3, pp. 869–878, 2003. [56] C. Cabello-Ve ugio and E. B andan, “A no el modula o y mechanism o ans o ming g ow h ac o -𝛽signaling h ough deco in and LRP-1,” TheJou nalo BiologicalChemis y, ol.282, no. 26, pp. 18842–18850, 2007. [57] C. Cabello-Ve ugio, C. San ande , C. Co ´ e, M. J. Acu˜ na, F. Melo, and E. B andan, “The in e nal egion leucine- ich epea 6 o deco in in e ac s wi h low densi y lipop o ein ecep o - ela ed p o ein-1, modula es T ans o ming G ow h Fac o (TGF)-𝛽-dependen signaling, and inhibi s TGF-𝛽- dependen ib o ic esponse in skele al muscles,” The Jou nal o Biological Chemis y, ol.287,no.9,pp.6773–6787,2012. [58] L. Desnoye s, D. A no , and D. Pennica, “WISP-1 binds o deco in and biglycan,” The Jou nal o Biological Chemis y, ol. 276, no. 50, pp. 47599–47607, 2001. [59] C. Vial, J. Gu i´ e ez, C. San ande , D. Cab e a, and E. B an- dan, “Deco in in e ac s wi h connec i e issue g ow h ac o (CTGF)/CCN2 by LRR12 inhibi ing i s biological ac i i y,” Jou nalo BiologicalChemis y, ol.286,no.27,pp.24242– 24252, 2011. [60]P.S apo ,X.Wang,J.Go eia,S.Moens,andP.Ca melie , “Angiogenesis e isi ed— ole and he apeu ic po en ial o a - ge ing endo helial me abolism,” Jou nal o Cell Science, ol.127, pa 20, pp. 4331–4341, 2014. [61] J. Go eia, P. S apo , and P. Ca melie , “P inciples o a ge ing endo helial cell me abolism o ea angiogenesis and endo he- lial cell dys unc ion in disease,” EMBO Molecula Medicine, ol. 6, no. 9, pp. 1105–1120, 2014. [62] T. Neill, L. Schae e , and R. V. Iozzo, “Ins uc i e oles o ex acellula ma ix on au ophagy,” The Ame ican Jou nal o Pa hology, ol.184,no.8,pp.2146–2153,2014. [63]T.Neill,H.R.Jones,Z.C ane-Smi h,R.T.Owens,L.Schae- e , and R. V. Iozzo, “Deco in induces apid sec e ion o h ombospondin-1 in basal b eas ca cinoma cells ia inhibi ion o Ras homolog gene amily, membe A/Rho-associa ed coiled- coil con aining p o ein kinase 1,” The FEBS Jou nal, ol.280,no. 10, pp. 2353–2368, 2013. [64] T. Neill, H. Pain e , S. Bu aschi e al., “Deco in an agonizes he angiogenic ne wo k: concu en inhibi ion o me , hypoxia inducible ac o 1𝛼, ascula endo helial g ow h ac o A, and induc ion o h ombospondin-1 and iMP3,” The Jou nal o Biological Chemis y, ol.287,no.8,pp.5492–5506,2012. [65] S.Bu aschi,T.Neill,A.Goyale al.,“Deco incausesau ophagy in endo helial cells ia Peg3,” P oceedings o he Na ional