Arising in rim of pituitary tissue Exceedingly rare with extracranial metastases

Arising in rim of pituitary tissue Exceedingly rare with extracranial metastases Abdominal, pancreatic, or lymphoma; extremely uncommon GH administrationtranscriptionfactorcelllineagecharacterizesadistinctbalanceof GHsecretionversussomatotrophtrophicactivity.GH-secreting tumorformationensuesasaconsequenceofunrestrainedsomatotrophproliferationassociatedwithintrinsiccell-cycledysfunction aswellasalteredendocrineandorparacrinefactorsregulatingGH synthesis,GHsecretion,andsomatotrophcellgrowth. GH-secretingadenomasveryrarelyexhibitactivatingrasmutationsininvasiveormetastaticlesions(49,S14).Uniquely,pituitary mitoticactivityisrelativelylow,evenininvasiveadenomas.Severalgrowthfactors,includingdysregulatedreceptorsforfibroblast growthfactors,dopamine,estrogen,andnervegrowthfactor(50), havebeenimplicatedpredominantlyinprolactinomapathogenesis,butnotuniformlyinacromegaly(Table1). cAMP signaling SeverallinesofevidencesupporttheroleoftheGHRH-cAMP signalingpathwayinmediatingsomatotrophtumorigenesis (Figure4).EctopicGHRHproductionbyperipheralcarcinoid tumors(51)leadstosomatotrophhyperplasiaandGHhypersecretion,butrarelyadenomaformation.GHRHsignalsviathe GHRHreceptor(GHRH-R),aGprotein oupledreceptor,by inducingcAMP,whichinducesGHtranscriptionmediatedby cAMPresponseelement indingprotein(CREB).Aconstitutivelyactivatedmurinepituitary-directedGproteinsubunit(Gs) transgeneresultedinhighGHlevelsandgigantism(S15).Guaninenucleotide indingprotein,stimulating(GNAS)encodes thestimulatoryGs(Gs),andactivatingGNASmutationslead toconstitutivelyelevatedcAMPlevels,proteinkinaseAactivity, andGHsynthesisandsecretion(52).PostzygoticGNASmutationsresultinamosaicpatternoforganspecificitywithclinical featuresofMcCune-Albrightsyndrome(OMIM174800),includingpigmentedskinlesionsandpolyostoticfibrousdysplasia, andendocrinedysfunctionincludingprecociouspuberty,thyrotoxicosis,andGHandACTHhypersecretion(53).GHhypersecretionlikelyoccursasaconsequenceofpituitaryhyperplasia, andtruepituitaryadenomashaverarelybeenidentified(53). About40 ofpatientswithsporadicacromegalyharborGNAS mutationswithaasubstitutionsatArg201orGln227,major toconstitutivelyelevatedcAMP(52)withnodistinctiveclinical phenotype.Fludarabine phosphate Thegeneisimprintedinpituitarytissue,andmutationsoccurintheexpressedmaternalallele(S16).SS-208 CREBisconstitutivelyactivatedinGH-secretingadenomasindependentlyof theGNASmutation(54)andlikelyafinalcommonpathwayfor cAMPsignalingforasubsetofadenomas.PMID:25023702 InactivatingmutationsoftheproteinkinasecAMP-dependent, regulatorytype1,(PRKAR1A)(55)gene,whichencodesthetype 1AregulatorysubunitofPKA,leadtoararesyndromeofspottyskin pigmentation,mucosalandcardiacmyxomas(benignneoplasms), andacromegaly(OMIM160908).Althoughmostidentifiedpatients exhibitelevatedGH,IGF1,andoftenPRLlevels,clinicalmanifestationsofacromegalyareusuallysubtle.Mechanismsunderlying acromegalyinthesepatientslikelyinvolveenhancedPKAactivityin pituitarysomatotrophcells.Analogoustotheclinicalphenotype, pituitary-specifictransgenicdeletionofPrkarlaresultedinformationofmurinetumorsderivedfromthePOU1F1lineage(S17). Cell-cycle disruption CyclinD1 ependentkinase4(CDK4)isrequiredforpostnatal somatotrophandlactotrophproliferation,andCdk4-nullmiceare resistanttothetrophiceffectsofGHRH(56).Incontrast,retinoblastomagene(Rb)inactivationleadstoendocrinetumorigenesis, andRb+/ icedevelopspontaneouspituitarytumorswithalmost 100 penetrance(57).RbactsasaG1/Scell-cyclecheckpointcontrol:cyclin-dependentkinases(CDKs)phosphorylateRb,triggering thereleaseofmembersoftheE2Ffamilyoftranscr.