Islet Cells Serve as Cells of Origin of Pancreatic Gastrin-Positive Endocrine Tumors

TY - JOUR

T1 - Islet Cells Serve as Cells of Origin of Pancreatic Gastrin-Positive Endocrine Tumors

AU - Bonnavion, Rémy

AU - Teinturier, Romain

AU - Jaafar, Rami

AU - Ripoche, Doriane

AU - Leteurtre, Emmanuelle

AU - Chen, Yuan-Jia

AU - Rehfeld, Jens F

AU - Lepinasse, Florian

AU - Hervieu, Valérie

AU - Pattou, François

AU - Vantyghem, Marie-Christine

AU - Scoazec, Jean-Yves

AU - Bertolino, Philippe

AU - Zhang, Chang Xian

N1 - Copyright © 2015, American Society for Microbiology. All Rights Reserved.

PY - 2015/10

Y1 - 2015/10

N2 - 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.

AB - 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.

KW - Animals

KW - Carcinogenesis

KW - Gastrins

KW - Humans

KW - Islets of Langerhans

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Multiple Endocrine Neoplasia

KW - Pancreatic Neoplasms

KW - Proto-Oncogene Proteins

U2 - 10.1128/mcb.00302-15

DO - 10.1128/mcb.00302-15

M3 - Journal article

C2 - 26169832

SN - 0270-7306

VL - 35

SP - 3274

EP - 3283

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

IS - 19

ER -