title: Islet Cells Serve as Cells of Origin of Pancreatic Gastrin-Positive Endocrine Tumors.
abstract: The cells of origin of pancreatic gastrinomas remain an enigma, since no gastrin-expressing cells are found in the normal adult pancreas. It was proposed that the cellular origin of pancreatic gastrinomas may come from either the pancreatic cells themselves or gastrin-expressing cells which have migrated from the duodenum. In the current study, we further characterized previously described transient pancreatic gastrin-expressing cells using cell lineage tracing in a pan-pancreatic progenitor and a pancreatic endocrine progenitor model. We provide evidence showing that pancreatic gastrin-expressing cells, found from embryonic day 12.5 until postnatal day 7, are derived from pancreatic Ptf1a(+) and neurogenin 3-expressing (Ngn3(+)) progenitors. Importantly, the majority of them coexpress glucagon, with 4% coexpressing insulin, indicating that they are a temporary subpopulation of both alpha and beta cells. Interestingly, Men1 disruption in both Ngn3 progenitors and beta and alpha cells resulted in the development of pancreatic gastrin-expressing tumors, suggesting that the latter developed from islet cells. Finally, we detected gastrin expression using three human cohorts with pancreatic endocrine tumors (pNETs) that have not been diagnosed as gastrinomas (in 9/34 pNETs from 6/14 patients with multiple endocrine neoplasia type 1, in 5/35 sporadic nonfunctioning pNETs, and in 2/20 sporadic insulinomas), consistent with observations made in mouse models. Our work provides insight into the histogenesis of pancreatic gastrin-expressing tumors.
authors.affiliation: INSERM U1052, Lyon, France CNRS UMR5286, Lyon, France Université de Lyon, Lyon, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Bonnavion
authors.affiliation: INSERM U1052, Lyon, France CNRS UMR5286, Lyon, France Université de Lyon, Lyon, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Teinturier
authors.affiliation: INSERM U1052, Lyon, France CNRS UMR5286, Lyon, France Université de Lyon, Lyon, France.
authors.forename: Rami
authors.initials: R
authors.lastname: Jaafar
authors.affiliation: INSERM U1052, Lyon, France CNRS UMR5286, Lyon, France Université de Lyon, Lyon, France.
authors.forename: Doriane
authors.initials: D
authors.lastname: Ripoche
authors.affiliation: Institut de Pathologie, CHRU de Lille, Lille, France Université Lille 2, INSERM UMR 859, Lille, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Leteurtre
authors.affiliation: Department of Gastroenterology, Peking Union Medical College Hospital, Beijing, China.
authors.forename: Yuan-Jia
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens F
authors.initials: JF
authors.lastname: Rehfeld
authors.affiliation: Hospices Civils de Lyon, Hôpital Edouard Herriot, Service d'Anatomie Pathologique, Lyon, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Lepinasse
authors.affiliation: INSERM U1052, Lyon, France CNRS UMR5286, Lyon, France Université de Lyon, Lyon, France Hospices Civils de Lyon, Hôpital Edouard Herriot, Service d'Anatomie Pathologique, Lyon, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Hervieu
authors.affiliation: Université Lille 2, INSERM UMR 859, Lille, France CHRU Lille, Endocrine Surgery, Lille, France.
authors.forename: François
authors.initials: F
authors.lastname: Pattou
authors.affiliation: Université Lille 2, INSERM UMR 859, Lille, France CHRU Lille, Endocrinology, Lille, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Vantyghem
authors.affiliation: INSERM U1052, Lyon, France CNRS UMR5286, Lyon, France Université de Lyon, Lyon, France Hospices Civils de Lyon, Hôpital Edouard Herriot, Service d'Anatomie Pathologique, Lyon, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.affiliation: INSERM U1052, Lyon, France CNRS UMR5286, Lyon, France Université de Lyon, Lyon, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bertolino
authors.affiliation: INSERM U1052, Lyon, France CNRS UMR5286, Lyon, France Université de Lyon, Lyon, France Sino-French Life Science and Genomic Center, Ruijin Hospital, Shanghai, China chang.zhang@lyon.unicancer.fr.
authors.forename: Chang Xian
authors.initials: CX
authors.lastname: Zhang
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000473:pathology; D005755:Gastrins / Q000378:metabolism*; D006801:Humans; D007515:Islets of Langerhans / Q000473:pathology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009377:Multiple Endocrine Neoplasia / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D005755:Gastrins; C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins