Pancreatic Neuroendocrine Tumors in Glucagon Receptor-Deficient Mice 英文参考文献.docVIP

PancreaticNeuroendocrineTumorsinGlucagon Receptor-DeficientMice RunYu1*,DeeptiDhall2,NicholasN.Nissen3,CuiqiZhou4,Song-GuangRen4 1Division of Endocrinology and Carcinoid and Neuroendocrine Tumor Center, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, California,UnitedStatesofAmerica,2DepartmentofPathology,Cedars-SinaiMedicalCenter,LosAngeles,California,UnitedStatesofAmerica,3DepartmentofSurgery, Cedars-Sinai Medical Center, and Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America, 4Division of Endocrinology,Diabetes,andMetabolism,Cedars-SinaiMedicalCenter,LosAngeles,California,UnitedStatesofAmerica Abstract Inhibition of glucagon signaling causes hyperglucagonemia and pancreatic a cell hyperplasia in mice. We have recently demonstratedthatapatientwithaninactivatingglucagonreceptormutation(P86S)alsoexhibitshyperglucagonemiaand pancreaticacellhyperplasiabutfurtherdevelopspancreaticneuroendocrinetumors(PNETs).Totestthehypothesisthat defectiveglucagonsignalingcausesPNETs,westudiedthepancreataofmicedeficientinglucagonreceptor(Gcgr2/2 )from 2 to 12 months, using WT and heterozygous mice as controls. At 2–3 months, Gcgr2/2 mice exhibited normal islet morphologybuttheisletsweremostlycomposedofacells.At5–7months,dysplasticisletswereevidentinGcgr2/2mice but absent in WT or heterozygous controls. At 10–12 months, gross PNETs ($1 mm) were detected in most Gcgr2/2 pancreata and micro-PNETs (,1mm) were found in all (n=14), whereas the islet morphology remained normal and no PNETswerefoundinanyWT(n=10)orheterozygous(n=25)pancreata.MostPNETsinGcgr2/2micewereglucagonomas, but some were non-functioning. No tumors predominantly expressed insulin, pancreatic polypeptide, or somatostatin, althoughsomeharboredfocalaggregatesoftumorcellsexpressingoneofthosehormones.ThePNETsinGcgr2/2 mice werewelldifferentiatedandoccasionallymetastasizedtotheliver.Meninexpressionwasaberrantinmostdysplaticislet