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European Journal of Endocrinology -18-0549 in the therapeutic decision-making process towards an of patients’treatmentandwould enablearelevantshift markers wouldbetrulyhelpful fortheindividualization histological, immunological, geneticormolecular inhibition. Inthissetting,biochemical,radiological, in termsofPTbulkreductionand/orhormonalsecretion respond tothecurrentlyrecommendedmedicaltherapy attempted ( is notalwaysfeasibleorcurativeandadjuvanttherapy is the first-linetreatmentformanyPTs; however, surgery increased morbidityandmortality. Tumour resectionis and treatmentdifficulties,frequentlyassociatedwith entail achallengingsetofdiseaseswithintrinsicdiagnostic tumours(PTs)Functioning andnon-functioningpituitary Introduction the efficacy ofreceptorprofilingasareliableclinicalpredictivefactor. authors ofthisdebatearticleagreeontheneedprospectivestudiesusingstandardizedmethodsinorderto assess How canweovercomethedifficulties? Isthereatrueroleforpituitaryreceptorprofilinginthenearfuture?All with conflictingresults,keepingthedebateonutilityofpituitaryreceptorprofilingopen.Whydoesthis occur? interacting proteinamongstothers,havebeenlinkedtodifferential tumourphenotypeortreatmentresponsiveness transduction orinvolvementofotherproteins,suchascytoskeletonproteinsthearylhydrocarbonreceptor- resistance. Defectiveexpressionofpituitaryreceptors,geneticalterations,truncatedvariants,impairedsignal response iscomplexandsometimesjeopardizestheunderstandingofmolecularbasispharmacological However, itsutilityisnotalwaysstraightforward.Infact,agonist-receptorcouplingtotheconsequentbiological the responsetospecificpituitary-directedmedicaltherapy, mainlysomatostatinanaloguesanddopamineagonists. tailored patients’treatment.Pituitaryreceptorprofilinghasemergedasapotentiallyusefultoolforpredicting therapy. Inthissetting,theavailability ofspecificmarkersresponsiveness/resistancecouldbehelpfultoprovide Medical treatmentofpituitarytumoursmaypresentimportantchallengesinthepresenceresistancetofirst-line Abstract Sciences, UniversityofFerrara,Italy Autónoma deMadrid,Spainand 1 Maria Chiara Zatelli Monica Marazuela pituitary therapy? Is receptor profiling usefulforpredicting Department ofEndocrinology, HospitalUniversitarioLaPrincesa,InstitutodeInvestigaciónUniversidad https://doi.org/ https://eje.bioscientifica.com Debate 10.1530/EJE 1 ). Approximately10–30%ofpatientswillnot -18-0549 1 , Ana M Ramos-Leví 2 5 © 2018EuropeanSociety ofEndocrinology 2 M Marazuelaandothers Section ofEndocrinologyandInternalMedicine,DepartmentMedical 1 Printed inGreatBritain , Patricia Borges de Souza straightforward. Westraightforward. herereviewanddiscussthepros well asofsideeffects.However, itsutility isnotalways consequently, reduce theburdenofhealthcarecosts,as could allowtooptimize patients’ managementand, (SSAs) anddopamineagonists(DAs).Thisapproach directed treatments,mainlysomatostatinanalogues useful toolforpredictingtheresponsetospecificpituitary- receptorprofilinghasemerged asapotentially pituitary long term. efficient andcost-effectiveapproach,especiallyinthe and predictivevaluesofspecificbiomarkers,foramore this strategywouldallowtoestablishrealisticprognostic individualized andpersonalizedmedicine.Inaddition, treatment Pituitary receptorprofilingand Published byBioscientifica Ltd. In thissetting,intheeraofpersonalizedmedicine, 2 and

Downloaded fromBioscientifica.com at09/27/202108:02:01AM (2018) Endocrinology European Journal of madrid.org monica.marazuela@salud. Email Zatelli to MMarazuela or MC should beaddressed Correspondence 179 179 :5 , D15–D25 or [email protected]

D15 –D25 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com international multi-centre studies demonstratedthe GH ( of long-acting SSA in the treatment of PT, particularly Preclinical andclinicalstudies demonstratedtheefficacy endocytosis, reducingthe desensitization effect( rapid SSTR2recyclingtotheplasmamembraneafter SSTR2 andSSTR5( targeted SSTRligand,whichbindswithhighaffinityboth the new-generation drug, pasireotide, is a multi-receptor- and, toalesserextent,SSTR5andSSTR3( lanreotide (LAN),haveahighbindingaffinityforSSTR2 cell metabolism.Long-actingSSA,octreotide(OCT)and treatments maybedeveloped,allowingcontroloftumour 13 it isoverexpressedinPT, breastandthyroidcancer ( found toberarelyexpressedinnormaltissues,whilst cell type( elicits differenteffects,dependingonthespecificpituitary tissues ( subtypes ofDR,DR1andDR2,areexpressedinpituitary neuroendocrine neoplasms( and degradation( showing differentdegreesofreceptorinternalization their responsiveness to continued agonist exposureby to otherG-protein-coupledreceptors,SSTRsregulate oligomers with unique pharmacological profiles. Similar or otherSSTRsubtypes( with dopamine,opioid,epidermalgrowthfactorreceptors profile onthecellsurface.SSTRcanformheterodimers but theelicitedeffectsaredifferentaccording to theSSTR The fivecanonicalSSTRsshare40–60%homology( four and five transmembrane domains, respectively ( sst5TMD4 andsst5TMD5,duetothefactthattheyexhibit SSTR5-splice variants have beenrevealed and termed splicing. Furthermore,twonon-canonicaltruncated isoforms, SSTR2AandSSTR2B,generatedviaalternative genes localizedondifferentchromosomes,withtwoSSTR2 have been described (SSTR1–5), which are encoded by and hormonalsecretion.Inthisregard,fiveSSTRsubtypes cellproliferation SSTR andDR,whichmodulatepituitary existence of several cell membrane receptors, including cellshaveprovedthe Pathological findingsinpituitary Somatostatin andDRsinPTs perspectives. (DR) profilinginPTandsuggestfutureinvestigational and consofsomatostatin(SSTR)dopaminereceptor Debate , PTs retainSSTRandDRexpression,whoseactivation 14 18 ). Thus,presumably, targetedpharmacological 10 ) andTSH-secretingtumours ( ). 11 ). sst5TMD4,ontheotherhand,hasbeen 16 8 ), asalsodemonstratedinother ). Inaddition,pasireotideinduces 4 , 5 , 6 , 9 7 ). Inaddition,twomain ), whichgeneratereceptor M Marazuelaandothers 19 3 ). Moreover, , 15 ), whilst 17 12 3 2 ). ), ). , these settings,SSTR2expression hasbeenthefocusof expressed SSTRreportedin acromegalystudies( Nonetheless, SSTR2 has proved to be themost frequently SSA, whichcouldexplain thelackofresponse( in certainacromegalycases resistanttofirst-generation characterized SSTR3asthepredominantSSTRexpressed and techniques, fromqPCR( focused onSSTRcharacterizationwiththeuseofdifferent in PT, breastandthyroidcancer( sst5TMD4 splice variant has been found to be overexpressed SSTRs are heterogeneously expressed in PT, whereas the followed bySSTR2,SSTR1,SSTR3andSSTR4.Canonical is thepredominantsubtypeinnormalhumanpituitary, SSTRs arenormallyexpressedintheadultpituitary. SSTR5 pituitary tumourtreatment The somatostatinreceptor familyintheaidof receptor profiling FOR: Thecaseforpituitary not express aparticular receptor mayadequately respond to specific therapy, whilstsomepatientswhosetumoursdo tumours mayexpressthereceptorbutdonotrespondto response.Forinstance,some receptor andtheobserved sometimes adissociationbetweenthepresenceof desire from a clinical point of view. In fact, there is aswewould is notalwaysassimpleandstraightforward non-functioning PT( useful alsoforselectedACTH-andGH-secretingPT tumour volumeshrinkage.Inaddition,thisdrugcouldbe clinical symptoms,prolactin(PRL)levelreductionand management ofprolactinomas,asitallowscontrol 24 adrenergic, and 5-HT1- and 5-HT2-serotonin receptors ( affinity forDR2and loweraffinityfor DR1, Cabergoline, onitsside,isanergot-derivedDAwithhigh performed or Western blottechniques,andsomestudieswere (IHC) amount of protein using immunohistochemistry reverse-transcription (RT)-qPCR,othersquantifiedthe with quantitativepolymerasechainreaction(qPCR)or SSTRs acrosstheliterature;somestudiesdetectedmRNA have been differences in the techniques used for analysing targeted treatment. To complicate things even more, there Cushing’s disease ( efficacy ofpasireotide in the medical management of treatment Pituitary receptorprofilingand ). Cabergolinehasprovedtobeeffectiveforthemedical However, thetandemmediator–receptorresponse in vivo in vivo scintigraphy( usingscintigraphy. 20 25 , , 11 Downloaded fromBioscientifica.com at09/27/202108:02:01AM 21 26 31 , ) and GH-secreting PTs ( , 28 , 27 34 , ). 29 12 , 35 , , 30 13 ). Somereportshave 179 ) toIHC( , 14 :5 ). Severalstudies α 1- and 31 , 29 32 D16 ). In , 36 22 33 α 23 via freeaccess 2- ). ). ) , European Journal of Endocrinology from SSAtreatment( identifying patientswithacromegaly whocouldbenefit has beenrecommendedsince theresultswereusefulin for SSTR2A detection in specimens obtained bysurgery has alsobeendescribedin IHC reports.Theuseof could helppredictPTresponsetofirst-generationSSA GH-secreting tumours ( positively correlatedwithSSTR2mRNAlevels,mainly in OCT efficacy in decreasing hormonal secretion has been SSTR expressionandmedicaloutcome.Specifically, of studiesattemptingtodefineacorrelationbetween become accessible and has been used by the majority therapy. With theadventofqPCR,SSTRexpressionhas suppression and,hence,tumourresponsivenesstoSSA shown thatSSTR2stronglycorrelateswithhormonal to first-generationSSA. Indeed, severalstudieshave SSTR2 expression asabiomarkerto predict PT response ( Northern blot,and found betweenSSTR2expressionlevels,assessedby secretion byOCT( positively correlatedwiththeabilitytoreduceGH GH-secreting PTwith LAN ( SSTR positivityandhormonalresponsetoOCTand/or blot, PCR,researchers have foundacorrelationbetween such as SSA startedinthelate90s.Usingdifferenttechniques, possibility topredicttumourresponsefirst-generation levels forseveralmonths.StudiesconcerningPTandthe to thedeleteriouseffectsofexcessiveGHandIGF1 therapy, poorresponsivenessleadstopatientexposure treatment outcome.Apartfromaninefficienthigh-cost ( tumour massoranincreaseinsizeduringtreatment < patients aredefinedasthosewhoshowareduction present resistancetoOCTandLANtreatment.Resistant fails tocontrolthedisease.However, 20–25%ofpatients first-line medical treatment in acromegaly when surgery First-generation SSA,OCTandLAN,areconsideredthe SSTR2 andSSTR5:roleinresponsetoSSA predict theresponsetospecifictreatments. receptorprofilingcouldhelp SSA and,therefore,pituitary proportion ofpatientspartiallyorcompletelyresistantto SSTR levelsorreducedreceptordensitymayexplainthe SSA response.BesidesSSTRheterogeneousexpression,low many studiesattemptingtoidentifyapatternpredict 39 37 50% inGHandIGF1levels,adecreaseof Debate ). Inthefollowingyears,severalstudiesinvestigated toassess monthsarenecessary ). Ingeneral,9–12 35 , 111 38 In-pentetreotide scintigraphy, MRI,Northern , 39 , 40 38 ). Forinstance,theabilitytovisualize in vivo 32 ). Aclearcorrelationhasalsobeen , 11 111 33 and , In-pentetreotide scintigraphy , 29 42 , , in vitro 41 43 M Marazuelaandothers ). The fact that SSTR2 ). sensitivitytoOCT < 20% in predicting SSA responsiveness in GH-secreting tumours. the evidencethatmRNAlevelsmaystillbeusefulin not evaluated in this study, the reported results support Even though final SSTR presence on cell membrane was levels ascomparedtosparselygranulatedtumours( better responderstoSSA,havehigherSSTR2Aexpression Interestingly, densely granulated tumours, which are and IGF1normalizationafterSSAtreatment( a strongcorrelationbetweenSSTR2Aimmunostaining overlap thoseofRT-PCR. Inthisstudy, theauthorsfound performed withaSSTR2Arabbitmonoclonalantibody, by Gatto improve patientmanagement.Indeed,anotherstudy help predict responsiveness tofirst-generation SSAand is routinelyusedtoassessPT, IHCSSTR2analysiscould between SSTR2mRNAandproteinlevels( was assessedbyIHC,andthereapositivecorrelation to first-generationSSA.Inthisstudy, SSTRexpression strong negativepredictivefactorforbiochemicalresponse Wildemberg In another study considering 88 somatotropinomas, OCT LAR when compared with those uncontrolled ( in controlled patients with SSTR5 ratio was observed decrease inhormonelevels.Furthermore,ahigherSSTR2/ On theotherhand,SSTR5negativelycorrelatedwith monthsoftreatment. tumour volumereductionafter6 as wellas and decreasedhormonesecretionat3 months, correlation was foundbetween SSTR2 expression levels followed bySSTR2,SSTR3,SSTR1andSSTR4.Apositive this study, SSTR5wasthepredominantlyexpressedSSTR, hormone levels(GHandIGF1)tumourvolume.In long-acting repeatable(LAR)wasevaluatedbymeasuring numbers wereassessedbyRT-PCR andresponsetoOCT 22 somatotropinomas, SSTR1–5 mRNA absolute copy of SSTRprofilingislongandstillgrowing.Inaseries showed agreaterreduction inIGF1levels. In addition, treatment, whereascaseswith higherSSTR5expression None ofthepatientslacking SSTR5wasresponsivetothe not controlledbytreatment withfirst-generationSSA. of responsetopasireotidein patientswhosediseasewas an IHCstudy, whereSSTR5wasfoundto be apredictor SSTR ligand( at mRNAlevelwerebetterresponderstothisnovel that exhibitedlowSSTR2andlowerSSTR2/SSTR5ratio study betweenOCTandpasireotide,somatotropinomas displaying high SSTR2 expression ( the resistance to first-generation SSA in patients with PT negative effect on SSTR2 signalling and could explain addition, sst5TMD4hasbeenreportedtohaveadominant treatment Pituitary receptorprofilingand The listofevidencesregardingtheusefulness t al et et al 48 . demonstratedthattheresultsofIHC, ). Asimilarresulthasbeendescribedin . foundthatalowSSTR2Aexpressionis Downloaded fromBioscientifica.com at09/27/202108:02:01AM 47 179 ). In a comparison https://eje.bioscientifica.com :5 44 ). SinceIHC 46 D17 ). In 45 29 via freeaccess ). ).

European Journal of Endocrinology https://eje.bioscientifica.com ratio associate with responsiveness to first-generation SSA, in GH-secretingPThighSSTR2 levelsandSSTR2/SSTR5 medical treatmentofcorticotropinomas ( therapy and,infact,thisdrug hasbeenapprovedforthe ligands. Cushing’s diseaseusuallybenefitsfrompasireotide influencing theresponsivenessofGH-secretingPTs toSSTR GH circulating levelsmayaffectSSTRexpression,thereby disease ( levels, mayprofoundlyimpairSSAefficacyinCushing’s disease activity, mainlydependingoncirculating cortisol tumour responsivenesstoPasireotide,indicatingthat SSTR2/SSTR5 expressionmaydeeplyinfluencecorticotroph that arenotfoundinacromegaly. Indeed,the imbalancein levels are probably due to high circulating cortisol levels, reported in ACTH-secreting tumours ( ( is aprerequisitefortheresponsivenesstothesedrugs treatment, confirmingthatSSTRpresenceoncellmembrane membranous receptorexpressionwereresponsivetothe SSA responsewasconfirmed.Asexpected,onlycaseswith assessed withthesameIHCapproach,andfirst-generation a positivecorrelationbetweenSSTR2Aimmunostaining, of pituitarytumours.DR,dopaminereceptors;SSA,somatostatinanalogues;SSTR,receptors. Summary ofthemainconcernsregardingadvantagesanddisadvantagespituitaryreceptorprofilingformanagement Figure 1 49 Debate ). High SSTR5 and low SSTR2 expression has also been ). HighSSTR5andlowSSTR2expressionhasalsobeen The resultsofthestudiesreported hereindicatethat 51 ). Onthecontrary, thereis noevidencethat M Marazuelaandothers 50 ), where low SSTR2 ), where low SSTR2 20 , 21 , 52 , 53 , 54 ). NFPT ( in mediatingtumourshrinkage insomatotropinomas( is SSTR3,forwhichanimportant rolehasbeenproposed possible roleforthisSSTRinSSA response.Anotherexample viability innon-functioning PT (NFPT)( able toinhibitchromograninAsecretionandreducecell another inhibition inducedbytheSSTR1-selectiveagonist( mRNA levelscorrelatedwiththeextentofhormonesecretion cells derivedfromacromegalicpatients.Inthisstudy, SSTR1 and PRLsecretion,aswellreducedcellviability, intumour activation ofSSTR1byaSSTR1-selectiveliganddecreasedGH responsive toSSA.An SSTR5, whichcouldplayanimportantroleinpatientspoorly SSTR familycomprisesreceptorsdifferentfromSSTR2and Other SSTRinvolved? which mayalsoactbybindingSSTR5. of first-generationSSA,supportingtheusepasireotide, hand, lowSSTR2levelsmayaccountforthescantefficacy pasireotide efficacy. InACTH-secretingPT, ontheother whilst lowSSTR2levelsandhighSSTR/SSTR5ratiofavours treatment Pituitary receptorprofilingand 11 in vitro ) andgonadotropinomas( study, thesameSSTR1-selectiveagonistwas in vitro Downloaded fromBioscientifica.com at09/27/202108:02:01AM study has demonstrated that studyhasdemonstratedthat 57 ). 179 56 :5 ), confirming a ), confirming 55 D18 ). In ). In 36 via freeaccess ), ), European Journal of Endocrinology and, consequently, DAresistance.Fusco which couldexplainreduced receptorexpression( gene has been associated with faster DR2 mRNA decay, a cytosine-to-thyminetransition atposition957in prolactinomas ( in DR2expressionwhencomparedwithresponsive are bromocriptineresistanthaveafour-folddecrease prolactinomas ( for the lack of a gender prevalence in D-resistant 68 phenotype (i.e.duetodecreasedDR2expression)( later, possibly allowingthedevelopmentofaDA-resistant males isusuallyneglectedandmedicalattentionsought be inpartexplainedbythefactthathypogonadism in proposed thatthesedifferencesinpresentationcould symptoms ofhypogonadism.Someauthorshave presenting usually diagnosedinwomenaged20–50 years mass effectatpresentationwhilstmicroprolactinomasare harbour macroprolactinomaswithsymptomsofsellar gender andtumourdiameter in prolactinomas have been suggested, such as male to 12 achieved in96.2%ofpatientsafterincreasingthedoseup cabergoline doses,normalizationofPRLlevelswas accurately evaluated.Inaprospectivestudyusinghigh increase DAdose,althoughadverseeffectsshouldbe treatment intheseresistantpatientsistogradually DA ( (5–10%) isdefinedasnon-responderduetoresistance Practice Guidelines( adenomas accordingtotheEndocrineSocietyClinical the gold-standardtreatmentforbothmicro-andmacro- tumours, DAsuchascabergolineandbromocriptine,are ACTH-secreting PT and NFPT ( is presentinnearly90%ofallPTincludingPRL-,GH-, are scarce, thoughithasbeendemonstratedthatDR2 expression profileinthedifferenttumourcellpopulations Systematic andmeta-analysisstudiesregardingDR Is theDRpathwayuseful? the burdenofhealthcarecosts,aswellsideeffects. optimize patientmanagementand,consequently, reduce could leadtopersonalizedmedicineinPT, allowingto relatively low cost,could represent a valid option that evaluation ofSSTRexpression,whichisfeasibleand useful toolforPTpatientstratification.Astandardized profilingcouldbea the proposalthatreceptorpituitary Debate ). Onthecontrary, other authorsprovideevidence Previous reportshavefoundthatprolactinomas Overall, these findings regarding SSTR family support 63 mg perweek( ). Ithasbeenreportedthatonestrategytoimprove 66 69 ). ). Inaddition,apolymorphism causing 64 61 ). Possiblepredictorsofresistance , 62 ). Asmallnumberofpatients > 58 m ( 1 cm , M Marazuelaandothers 59 , 65 60 , ). In PRL-secreting 66 t al. et ). Menusually reported DR2 70 67 ) ,

and othermedicaltherapies,suchaschimericSSA-DA account for the limited DA efficacy inresistant patients responsiveness toDA.DRdecreasedexpressionlevelsmay that DR2statuscouldinfluencePRL-secretingtumour selection ofthebesttherapeuticapproach. could helppredictreceptortargetstatus,aidingthe receptorprofiling particularly resistantsubjects.Pituitary to transsphenoidal surgery, the second-line treatment, in response ( indicating a possible correlation between DR status and DA compared tothosefoundinDA-sensitiveprolactinomas, levels inDA-resistanttumoursweresignificantlyloweras the treatmentofprolactinomas.Moreover, DR2mRNA compounds targetingDR2remainthebestoptionin prolactinomas. Theresultsofthisstudyconfirmedthat 23A760) in suppressingPRLsecretion in DA-resistant cabergoline andachimericSSA-DAcompound(BIM- a comparison study between the efficacy of SSA, levels ofSSTR2,buthigh ofSSTR5( point of view. For instance, some tumours express low specific receptors,bothfrom aqualitativeandquantitative PTs maybeheterogeneousregardingtheexpression of Variability intheexpressionofSSTRs and comparableconclusions. volume. All these heterogeneities encumber trustworthy and/or iftheywerestudyingapossibledecreaseintumour if theywereevaluatingthedecreaseinGHandIGF1levels important toknowwhichoutcomewasmeasured,thatis, been pretreatedornotwithSSA.Inaddition,itisalso Another pointofheterogeneityiswhetherpatientshad SSA, whilstothersusedthenewlyavailablepasireotide. same; somestudieswereperformedusingfirst-generation treatment usedindifferent studies hasnotalwaysbeenthe SSTRs havebeenvariableacrossstudies.Inaddition,the Second, theexpressionandmethodsfordetectionof there isavariableexpressionofSSTRindifferenttumours. responses may be explained by several reasons. First, use ofSSAanditsassociatedpathologicalclinical between the The occasional lack of correlation observed cumbersome route The somatostatinreceptor pathway:a receptor profiling AGAINST: thecaseagainstpituitary compounds, shouldbeconsidered. treatment Pituitary receptorprofilingand The resultsofthestudiesreportedhereindicate 71 ). Failureofmedicaltreatmentusuallyleads Downloaded fromBioscientifica.com at09/27/202108:02:01AM 179 https://eje.bioscientifica.com :5 46 , 72 , 73 ); other D19 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com generation SSA(OCTandLAN), somepatientsreceived Whilst insomestudiespatients weretreatedwithfirst- Preoperative treatmentand specificSSAused different SSAactions. to overcome someoftheseheterogeneitieswhencomparing 79 amount ortheRemmeleIRSscore,etc.)( cell membrane fraction) and the scoring system (intensity, cell fraction (cell membrane fraction or both cytoplasm plus antibody (monoclonalvspolyclonalantibodies),thestudied range ofheterogeneity, mainlybecauseof theemployed differences reportedinstudiesthatusedIHCdenoteawide and SSTR expression pattern. Moreover, analysis of the viability, withoutevidentcorrelationbetweentheresponse significantly andsimilarlydecreasedGHsecretioncell in 32 somatotropinomas and described that OCT and LAN levels. Ibañez-Costa contrast, SSTR5 did notshowany correlation withGH levels correlatedpositivelywithGHsuppression,but,in somatotropinomas usingIHCandfoundthatSSTR2protein IHC in60somatotropinomas.Takei post OCTGHorIGF1levelstumourvolumebyqPCR SSTR2 norSSTR5expressioncorrelatedwithbaselineor somatotropinomas. Gonzalez SSTR2 andSSTR5mRNAexpressionGHvaluesin16 Park mRNA, and by find any significant correlation between SSTR,measured been alwaysthecase.Inthisregard, Corbetta between SSTRmeasurementandresponsetoSSA,thishasnot studies havefailedtoproveitsrelevance( this lattertechniquecouldpredictSSAresponse,butlarge in vivo Western blottechniquesandsomestudieswereperformed others quantifiedtheamountof proteinusingIHCor SSTRs; somestudiesdetectedmRNAwithqPCRorRT-qPCR, have beendifferencesinthetechniquesusedforanalysing Concerning studiesinthesettingofacromegaly, there Heterogeneity inthetechniquesusedforanalysingSSTRs functional interactionbetweenSSTR2andSSTR5. response toSSAbecauseofanadditiveeffectmediatedbya SSTR2, andthelattercouldstillbesufficientforanadequate first-generation SSA that mainly exert their action by binding former situationcouldleadtoanincompleteresistance tumours expresslowlevelsofbothSSTR2andSSTR5.The Debate ). A universal scoring system has been proposed ( Although many studies have reported a correlation Although manystudieshavereportedacorrelation t al et usingscintigraphy. Itwouldbetrulyinterestingif . ( in vivo 28 ) could not prove a correlation between ) couldnotproveacorrelationbetween responsiveness in 19 somatotropinomas. responsivenessin19somatotropinomas. et al . ( 76 ) evaluated IHC and function ) evaluatedIHCandfunction et al . ( M Marazuelaandothers 75 ) reported that neither ) reportedthatneither t al et 42 . ( 34 et al , 42 44 , 38 ) studied 22 ) studied22 . ( , 74 45 ). 45 ) did not ) did not , 77 ) to try ) to try , 78 , who were pretreated with OCT. Moreover, SSTR2 protein contrast, theydidnotfindanycorrelationinpatient patients whodidnotreceiveSSApre-treatmentbut,in correlated withGHreductionafteranacuteOCTtestin also treatedwithOCTandfoundthatSSTR2waspositively et al between tumour volume reduction and SSTRs.Fougner IGF1 reduction.However, nocorrelationwasfound pretreated groupandpositivelycorrelatedwithGH with OCT, SSTR2expressionlevelswerereducedinthe Casar-Borota becomes evenmoredifficulttointerpret.Inthestudyby between SSTR expression and GH-IGF1 reduction, which encumbering a reliable interpretation on the relationship expression isprobablyconsequentlyreduced,thus different SSTRs,resultsarenotalwaysoverlapping. generation andthenewSSTRagonistinteractwith therapy withthenewlyavailablepasireotide.Asfirst variability intheefficacyof SSA( apoptosis functionsmaybe impaired, leadingtopotential migration, angiogenesis,secretion, proliferation and These pathwaysmaybedefective, sothecorresponding AIP-ZAC1, E-cadherin,B-arrestin andfilaminApathways. the SHP1-PI3k-Akt,SHP2-MAPK,PLC,PKAA,RKIP, gsp, signal transductionmediatedbySSTRs,whichconcern Several mechanismsareinvolvedintheimpairment of Impaired signaltransduction SSA. does not unequivocally ensure an adequate response to Thepresence ofSSTR outcomes isnotsostraightforward. it isdifficult,anditsutilityforthepredictionofclinical measurement ofSSTRexpressionmaybepromising,but studies andelaborationofdefinitiveconclusions.Infact, expression jeopardizetrustworthyinterpretation of expression ( relationship between tumour volume reduction and SSTR2 regard, althoughtherearesomestudiesthatfounda SSA efficacyregardingtumourvolumereduction.Inthis SSA. However, therearefewstudiesthathaveevaluated Many studieshaveevaluatedGHandIGF1responseto volume reduction Outcome evaluation:GH/IGF1reductionand/ortumour response toOCT. level assessedbyWestern blotdidnotcorrelatewiththe treatment Pituitary receptorprofilingand Regarding pre-surgical therapy with SSA, SSTR2 All theabove-mentionedfindingsregardingSSTR . ( 80 ), ontheirpart,evaluated71somatotropinomas 29 t al et ), norelationshipwasfoundinothers. . ( 77 ) of65somatotropinomastreated Downloaded fromBioscientifica.com at09/27/202108:02:01AM 45 , 81 179 , :5 82 ). D20 via freeaccess European Journal of Endocrinology ones thathaveprovidedmolecular information.Inthis aggressively andareresistant tomedicaltreatmentarethe fact thatonlythoseprolactinomas thatbehavemore A possiblebiasthatwemust considerispreciselythe some studies have not corroborated this correlation. association betweenDR2expressionandDAresponse, fact, althoughthemajorityofreportsshowanapparent prediction ofclinicaloutcomesinprolactinomas.In up todatedonotseemaidunequivocallyinthe secretion and reduce tumourvolume. However, findings in mostcasesduetoDAfailurenormalizehormone of patientswiththesetumoursfinallyundergosurgery, DR expressioninprolactinomas,sinceonlyaround10% through theirinteractionwithDR.We know lessabout setting, DAseemsarelevanttargetedtreatment,mediated PT, including GH,PRL,ACTHsecretingandNFPT. Inthis techniques, that DRsareexpressedinthelargemajority of It hasbeen extensively demonstrated, with various The DRpathway:anotherchallengetoovercome predictive factorsofPTtherapeuticresponse. toexplore should betakenintoaccountwhentrying expression levelsmayinfluenceSSAresponsivenessand and SSAresponse( somatotroph PTwasrelatedtotumoursize,invasiveness SSA ( signalling, havebeenassociatedtoaworseresponse A, whichisrequiredforbothDR2andSSTR2intracellular in vitro better responsetoSSAintermsofGHsuppression,both active receptorexposedonthecellmembrane,anda recycling rateofSSTR2,ahigheramountbiologically in comparisontoNFPT, hasbeenassociatedwithreduced expression ofB-arrestininGH-andPRL-secretingtumours, recycling ofSSTRsinGH-andPRL-secretingPT. Thus,low SSTR, andtheyhavebeeninvolved,forinstance,inthe process ofG-protein-coupled receptors, including part, seemtoaffectthedesensitization–internalization with a worse response to SSA ( howitslowexpressionmaybealsoassociated observed is anotherissueofinterest,sinceseveralstudieshave hydrocarbon receptor-interacting protein (AIP) The aryl in some PT ( attenuated response to SSA observed somatotropinomas, suggesting its potential role in the was reported as particularlyabundant in OCT-resistant to SSA in GH-secreting tumours; for instance, sst5TMD4 isoforms hasbeencorrelatedwithareducedresponse Debate Therefore, othervariablesdifferentfromSSTR Specifically, thepresenceofSSTR5-truncated 85 and ). In addition, the expressionofE-cadherin in in vivo ( 86 85 ). ). Inaddition, low levelsoffilamin 81 , M Marazuelaandothers 84 ). B-arrestins, on their 83 ). levels. was correlatedwithareductioninDR2longisoform IHC level.Theydescribedthatresistancetocabergoline resistant prolactinomasthatwerestudiedatmRNAand and resistancetocabergolinein12surgicallytreated et al with norelationshipSSTRstatus.However, Shimazu between lowerDR2levelsandreducedresponsetoDA, line, Fusco tumours showed a reduced binding to DR2. In the same thatresistant expression inprolactinomasandobserved association between response to bromocriptine and DR2 mechanisms. Caccavelli effects followingligandactivationortopost-receptor distinct intracellularpathwaysandmediatedifferential short andlongisoforms,whicharethoughttoactivate or lossofDR2,tovariationsintheratiobetween regard, resistancetoDAhasbeenlinkedareduction as AIP, ZAC,B-arrestin,filaminor E-cadherin,whichmay into account,includingvariations inotherproteins,such but notbyothers.Manyother variablesshouldbetaken treatment inGH-secretingPT issupportedbysomestudies the evidencethatSSTRprofiling predictsresponsetoSSA as ausefultooltopredictPTtreatmentresponse.Indeed, receptors conclude infavouroragainstprofilingpituitary Based ontheavailableinformationuptodate,wecannot Conclusions sufficient toestablishfullyaccurateconclusions. help topredictresponseDA,butevidenceisstillnot response( the observed filamin AandG interaction, includingtheonesrelatedtoNGFreceptors, subsequent molecularpathwaysinvolvedintheDA–DR predictions on medicaloutcome. Moreover, aberration of DRstatuswillallowstraightforward knowledge ofpituitary expression andDAresponse,wecannotassurethat agreement regardingtherelationshipbetweenreceptor patients. between controlledanduncontrolledacromegalic significant difference intheexpressionofthisreceptor a predominantexpressionofDR2,couldnotprove ( by OCTin24somatotropinomas.Incontrast,Neto correlated with al et treatment Pituitary receptorprofilingand 58 ) who evaluated 39 somatotropinomas and observed ) whoevaluated39somatotropinomasandobserved If weconsiderthesettingofacromegaly, Ferone In lightofthesereports,wherethereisnotacomplete . ( . ( 87 43 ) didnotfindanassociationbetweenDR2status ) foundthatSSTR2andDR2werepositively t al et in vitro α . ( i2, may contribute to heterogeneities in 71 ) describedanapparentassociation and 63 Downloaded fromBioscientifica.com at09/27/202108:02:01AM t al et , in vivo 88 ). DRstatusmayprobably . ( percent GHsuppression 69 ) indeedfoundan 179 https://eje.bioscientifica.com :5 D21 et al via freeaccess . European Journal of Endocrinology https://eje.bioscientifica.com References the public,commercialornot-for-profit sector. This researchdidnotreceiveanyspecificgrantfromfundingagencyin Funding perceived asprejudicingtheimpartialityofthisarticle. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest allow reliableclinicalpredictions. routine evaluationofSSTRandDRexpressioninPT of auniformandstandardizedscoringsystem,tofacilitate of antibodiesinIHCstudies,aswellthedevelopment importanttoassessthequality methods. Itwouldbevery usingstandardized studies ofpatientsaftersurgery analysis of sensitivity and specificity. We need prospective of medicaloutcome.Inaddition,moststudieslackan analyses regardingreceptorsubtypinganddefinition the resultingconclusions( in thetreatmentsusedorcriteriaconsideredmaybias SSA/DA receptorprofilinganddifferencesacrossstudies measuring techniques may disguise the true relevance of lead todissociatedresponses.Moreover, heterogeneityin 7 6 5 4 3 2 1 Debate Watt HL, Kharmate GD &Kumar U.Somatostatinreceptors1and Pfeiffer M, Koch T, Schröder H,Laugsch M,Höllt V &Schulz S. Pfeiffer M, Koch T, Schröder H,Klutzny M,Kirscht S, Kreienkamp HJ, Rocheville M, Lange DC,Kumar U,Sasi R,Patel RC&Patel YC. Patel YC. Somatostatinanditsreceptorfamily. 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79 78 77 76 75 74 73 72 70 71 Debate Casarini APM, Jallad RS,Pinto EM,Soares IC,Nonogaki S,Giannella- Liu W, Xie L,He M,Shen M,Zhu J,Yang Y, Wang M, Hu J,Ye H, Li Y Casar-Borota O, Heck A,Schulz S,Nesland JM,Ramm-Pettersen J, Ibáñez-Costa A, Rivero-Cortés E,Vázquez-Borrego MC, Gahete MD, Gonzalez B, Vargas G, Ramirez C,Asa S,Cheng S,Sandoval C Corbetta S, Ballaré E,Mantovani G,Lania A,Losa M,DiBlasio AM Nielsen S, Mellemkjaer S,Rasmussen LM,Ledet T, Olsen N, Reubi JC, Schaer JC,Waser B &Mengod G.Expressionand Fusco A, Gunz G,Jaquet P, Dufour H,Germanetti AL,Guller MD, Filopanti M, Barbieri AM,Angioni AR,Colao A,Gasco V, Grottoli S, correlation betweenexpressionofsomatostatinreceptorsubtypes Neto D, Musolino NR,Alves VAF &Bronstein MD.Acromegaly: doi.org/10.1155/2017/9606985) ofEndocrinology Journal International correlated withtheshort-termefficacyofsomatostatinanalogues. et al. jc.2013-2145) and Metabolism and long-termeffectsofoctreotide. antibodies wasreducedbyoctreotideandcorrelatedwiththeacute SSTRs 1,3,or5insomatotrophadenomasassessedbymonoclonal Lekva T, Alafuzoff I&Bollerslev J.ExpressionofSSTR2a,butnot 2016 tumorcellsinvitro. similarly inhibitpituitary González-Molero I, Schmid HA Jiménez-Reina L, Venegas-Moreno E, delaRiva A,Arráez MÁ, 2014 pharmacological responsetooctreotide. andbyRT/PCRisnotassociatedwiththe immunohistochemistry & Mercado M. Cytoplasmic expressionofSSTR2and5by 208–214. mRNA expression. adenomas:analysisofgenesequenceand GH-secreting pituitary & Spada A.Somatostatinreceptorsubtype2and5inhuman (https://doi.org/10.1007/BF03351043) ex vivo. adenomasinvivoand somatostatin receptorsonhumanpituitary Bojsen-Moller M, Astrup J,Weeke J &Jorgensen JO.Expressionof hybridization. humantumorsusinginsitu messenger RNAsinprimary localization ofsomatostatinreceptorSSTR1,SSTR2,andSSTR3 2008 sensitive and-resistantprolactinomas. Barlier A &Saveanu A.Somatostatinergicligandsindopamine- Journal adenomas. with prolactin-secretingpituitary gene polymorphismsandresponsetocabergolinetherapyinpatients Peri A, Baglioni S,Fustini MF, Pigliaru F org/10.1159/000126764) prolactinomas. Expressionofsomatostatinreceptor2inSomatotropinoma 158 231 61 2008 523–530. Journal ofEndocrinologicalInvestigation Journal 595–603. 135–145. (https://doi.org/10.1046/j.1365-2362.2001.00786.x) 8 357–363. Cancer Research 2013 Neuroendocrinology (https://doi.org/10.1016/j.endonu.2014.05.006) European Journal ofClinicalInvestigation European Journal (https://doi.org/10.1530/EJE-07-0806) (https://doi.org/10.1530/JOE-16-0332) 98 E1730–E1739. (https://doi.org/10.1038/tpj.2008.1) 1994 et al. 1994 2017 Journal ofClinicalEndocrinology Journal 54 Octreotideandpasireotide(dis) M Marazuelaandothers European Journal ofEndocrinology European Journal 3455–3459. (https://doi.org/10.1210/ et al. 60 Endocrinologia yNutricion 2017 314–322. DopamineD2receptor Pharmacogenomics Pharmacogenomics 2001 Journal ofEndocrinology Journal 9606985. 24 (https://doi. 430–437. (https:// 2001 31

Accepted 22August2018 Revised versionreceived13August2018 Received 29June2018

treatment Pituitary receptorprofilingand 84 83 82 81 88 87 86 85 80 Ibáñez-Costa A, López-Sánchez LM,Gahete MD,Rivero-Cortés E, Córdoba-Chacón J, Gahete MD,Durán-Prado M,Luque RM& Peverelli E, Giardino E,Vitali E, Treppiedi D, Lania AG& Gadelha MR, Kasuki L&Korbonits M.Novelpathwayfor Peverelli E, Mantovani G,Vitali E, Elli FM,Olgiati L,Ferrero S, Shimazu S, Shimatsu A,Yamada S, Inoshita N,Nagamura Y, Usui T Fougner SL, Lekva T, Borota OC,Hald JK,Bollerslev J&Berg JP. Gatto F, Feelders R,Van DerPas R,Kros JM,Dogan F, Van Fougner SL, Borota OC,Berg JP, Hald JK,Ramm-Pettersen J& molecular mechanismsunderlyingthedifferentialresponsein adenomasand normal pituitaries: functional endpointsinpituitary Jiménez-Reina L, Moreno-Carazo A Vázquez-Borrego MC, Gálvez MA,LaDeRiva A,Venegas-Moreno E, 1749-6632.2011.05985.x) Academy ofSciences somatostatin-cortistatin pathophysiology. Castaño JP. Truncated somatostatinreceptorsasnewplayersin (https://doi.org/10.1055/s-0034-1384520) phosphorylation. andtheroleofcAMP/PKAdependent regulation inpituitary Mantovani G. FilaminAinsomatostatinanddopaminereceptor org/10.1016/j.tem.2012.11.007) Endocrinology andMetabolism somatostatin analogsinpatientswithacromegaly. 458–465. 2012 tumorous lactotrophs. essential fordopamined2receptorexpressionandsignalingin Laws ER, DellaMina P, Villa A, Beck-Peccoz P (https://doi.org/10.1530/EJE-11-0656) mRNA levels. correlated withreductionofdopamineD2receptorlongisoform & Tsukada T. Resistancetodopamineagonistsinprolactinomais 2334–2342. response. is relatedtotumorsize,invasiveness,andsomatostatinanalog adenomas The expressionofE-cadherininsomatotrophpituitary org/10.1210/en.2013-1672) acromegaly. of responsetosomatostatinanaloguetreatmentinpatientswith adenomas:roleintheregulation kinase 2expressioninpituitary Herder W Koetsveld PM, Van DerLelij AJ,Neggers SJCMM,Minuto F, De srep42002) adenomas. protein expressionoftheadenoma. acromegaly correlatestothesomatostatinreceptorsubtype2a Bollerslev J. Theclinicalresponsetosomatostatinanaloguesin (https://doi.org/10.1007/s11102-009-0175-1) and responsetooctreotide-lartreatment. 97 967–977. (https://doi.org/10.1111/j.1365-2265.2007.03065.x) Journal ofClinicalEndocrinologyandMetabolism Journal et al. Scientific Reports (https://doi.org/10.1210/jc.2009-2197) Endocrinology European Journal ofEndocrinology European Journal

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