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: Rémy Bonnavion, Romain Teinturier, Rami Jaafar, Doriane Ripoche, Emmanuelle Leteurtre, Yuan-Jia Chen, Jens F Rehfeld, Florian Lepinasse, Valérie Hervieu, François Pattou, Marie-Christine Vantyghem, Jean-Yves Scoazec, Philippe Bertolino, Chang Xian Zhang
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 35 Issue 19 Pg. 3274-83 (Oct 2015) ISSN: 1098-5549 [Electronic] United States
• PMID: 26169832 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• Gastrins
• Men1 protein, mouse
• Proto-Oncogene Proteins

Topics

• Animals
• Carcinogenesis (pathology)
• Gastrins (metabolism)
• Humans
• Islets of Langerhans (pathology)
• Mice, Inbred C57BL
• Mice, Knockout
• Multiple Endocrine Neoplasia (metabolism, pathology)
• Pancreatic Neoplasms (metabolism, pathology)
• Proto-Oncogene Proteins (genetics, metabolism)