Data from Rb and p53 Execute Distinct Roles in the Development of Pancreatic Neuroendocrine Tumors

Abstract

<div>Abstract<p>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 <i>Rb</i> gene (<i>Pdx1-Cre;Rb<sup>f/f</sup></i>) in mice did not affect pancreatic exocrine cells, the α-cell/β-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, pancreas-specific induction of a <i>p53</i> mutation (<i>Pdx1-Cre;Trp53<sup>R172H</sup></i>) had no effect on pancreatic exocrine and endocrine tissues, but simultaneous induction of a <i>p53</i> mutation with <i>Rb</i> gene deletion (<i>Pdx1-Cre;Trp53<sup>R172H</sup>;Rb <sup>f/f</sup></i>) resulted in the formation of aggressive PanNET with a Ki67-labeling index of 24.7% over the short-term (4 months). In <i>Pdx1-Cre;Trp53<sup>R172H</sup>;Rb<sup>f/f</sup></i> mice, mRNA expression of <i>Pten</i> and <i>Tsc2</i>, 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 <i>Rb</i> and <i>p53</i> 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.</p>Significance:<p>Pancreas-specific manipulation of <i>Rb</i> and <i>p53</i> genes induced malignant transformation of islet cells, reproducing stepwise progression from microadenomas to indolent (grade 1) and subsequent aggressive PanNETs (grade 2–3).</p></div>