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

• Published in: Cancer research (Chicago, Ill.) Vol. 80; no. 17; pp. 3620 - 3630
• Main Authors: Yamauchi, Yuki, Kodama, Yuzo, Shiokawa, Masahiro, Kakiuchi, Nobuyuki, Marui, Saiko, Kuwada, Takeshi, Sogabe, Yuko, Tomono, Teruko, Mima, Atsushi, Morita, Toshihiro, Matsumori, Tomoaki, Ueda, Tatsuki, Tsuda, Motoyuki, Nishikawa, Yoshihiro, Kuriyama, Katsutoshi, Sakuma, Yojiro, Ota, Yuji, Maruno, Takahisa, Uza, Norimitsu, Masuda, Atsuhiro, Tatsuoka, Hisato, Yabe, Daisuke, Minamiguchi, Sachiko, Masui, Toshihiko, Inagaki, Nobuya, Uemoto, Shinji, Chiba, Tsutomu, Seno, Hiroshi
• Format: Journal Article
• Language: English
• Published: United States 01.09.2020
• Subjects: Animals; Cell Transformation, Neoplastic - genetics; Mice; Mice, Transgenic; Neuroendocrine Tumors - genetics; Pancreatic Neoplasms - genetics; Retinoblastoma Protein - genetics; Tumor Suppressor Protein p53 - genetics
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-19-2232

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 gene ( ) 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 mutation ( ) had no effect on pancreatic exocrine and endocrine tissues, but simultaneous induction of a mutation with gene deletion ( ) resulted in the formation of aggressive PanNET with a Ki67-labeling index of 24.7% over the short-term (4 months). In mice, mRNA expression of and , 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 and 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 and genes induced malignant transformation of islet cells, reproducing stepwise progression from microadenomas to indolent (grade 1) and subsequent aggressive PanNETs (grade 2-3).