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.

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00302-15.

ACKNOWLEDGMENTS

We thank all the members of the animal facilities ALECS-Co, ALECS-SPF, and ANICAN. We are also grateful to the staff from the CECIL imaging facility and especially Christophe Vanbelle. We are especially grateful to Jan N. Jensen for providing the Ngn3^wt/tTA mouse line, Christopher V. E. Wright for providing Ptf1a-Cre mice, J. Chayvialle and Colette Roche for anti-CCK antibodies, Beatriz Sosa-Pineda for anti-Pax4 antibodies, and Julie Pannequin for antiprogastrin antibodies. We thank Chloe Tessereau, Philippe Ruszniewski, Gérard Gradwohl, and Xianxin Hua for stimulating discussions.

This study was supported by the Ligue contre le Cancer du Rhône (to C.X.Z.) and de la Loire (to P.B.), the Agence National de Recherche (grant SVSE2 ANR 10 BLAN 1240 04), and the CMIRA program of the Region Rhône-Alpes (12004959-01); R.B. was the recipient of a 4th year doctoral fellowship from the Fondation ARC (DOC20120605135).

R.B. conducted the experiments, analyzed and interpreted the data, and prepared the figures and manuscript; R.T., R.J., and D.R. provided technical and material support and participated in interpretation of the data; E.L., J.-Y.S., F.L., V.H., Y.-J.C., F.P., and M.-C.V. supervised the development of the tissue banks, performed pathological analyses, provided material support, and participated in interpretation of the data; J.F.R. participated in development of the study concept and provided critical revision of the manuscript; P.B. participated in development of the study concept, design, and supervision and provided critical revision of the manuscript; and C.X.Z. conceived of the study, supervised the study and manuscript preparation, and obtained funding.

We have nothing to disclose.