Rb and p53 Execute Distinct Roles in the Development of Pancreatic Neuroendocrine Tumors
Open Access
- 1 September 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 80 (17), 3620-3630
- https://doi.org/10.1158/0008-5472.CAN-19-2232
Abstract
Pancreatic neuroendocrine tumors (PanNET) were classified into grades (G) 1 to 3 by the World Health Organization in 2017, but the precise mechanisms of PanNET initiation and progression have remained unclear. In this study, we used a genetically engineered mouse model to investigate the mechanisms of PanNET formation. Although pancreas-specific deletion of the Rb gene (Pdx1-Cre;Rb-f/f) in mice did not affect pancreatic exocrine cells, the alpha-cell/beta-cell ratio of islet cells was decreased at 8 months of age. During long-term observation (18-20 months), mice formed well-differentiated PanNET with a Ki67-labeling index of 2.7%. In contrast, pan-creasspecific induction of a p53 mutation (Pdx1-Cre;Trp53(R172H)) had no effect on pancreatic exocrine and endocrine tissues, but simultaneous induction of a p53 mutation with Rb gene deletion (Pdx1-Cre; Trp53(R172H);Rb-f/f) resulted in the formation of aggressive PanNET with a Ki67-labeling index of 24.7% over the short-term (4 months). In Pdx1-Cre;Trp53(R172H);Rb-f/f mice, mRNA expression of Pten and Tsc2, negative regulators of the mTOR pathway, significantly decreased in the islet cells, and activation of the mTOR pathway was confirmed in subsequently formed PanNET. Thus, by manipulating Rb and p53 genes, we established a multistep progression model from dysplastic islet to indolent PanNET and aggressive metastatic PanNET in mice. These observations suggest that Rb and p53 have distinct roles in the development of PanNET. Significance: Pancreas-specific manipulation of Rb and p53 genes induced malignant transformation of islet cells, reproducing stepwise progression from microadenomas to indolent (grade 1) and subsequent aggressive PanNETs (grade 2-3).Other Versions
Funding Information
- MEXT (JP15J05143, JP17H06803, JP16K09395)
This publication has 41 references indexed in Scilit:
- Small Cell and Large Cell Neuroendocrine Carcinomas of the Pancreas are Genetically Similar and Distinct From Well-differentiated Pancreatic Neuroendocrine TumorsThe American Journal of Surgical Pathology, 2012
- DAXX / ATRX , MEN1 , and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine TumorsScience, 2011
- Survival Benefit With Proapoptotic Molecular and Pathologic Responses From Dual Targeting of Mammalian Target of Rapamycin and Epidermal Growth Factor Receptor in a Preclinical Model of Pancreatic Neuroendocrine CarcinogenesisJournal of Clinical Oncology, 2010
- Gene Amplifications in Well-Differentiated Pancreatic Neuroendocrine Tumors Inactivate the p53 PathwayGenes & Cancer, 2010
- Pancreatic Endocrine Tumors: Expression Profiling Evidences a Role for AKT-mTOR PathwayJournal of Clinical Oncology, 2010
- Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant MetastasisCancer Cell, 2009
- Loss of Nuclear p27 Expression and Its Prognostic Role in Relation to Cyclin E and p53 Mutation in Gastroenteropancreatic Neuroendocrine TumorsClinical Cancer Research, 2008
- One Hundred Years After “Carcinoid”: Epidemiology of and Prognostic Factors for Neuroendocrine Tumors in 35,825 Cases in the United StatesJournal of Clinical Oncology, 2008
- New roles for the RB tumor suppressor proteinCurrent Opinion in Genetics & Development, 2004
- Glucagon gene regulatory region directs oncoprotein expression to neurons and pancreatic a cellsNeuron, 1988