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

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 a-cell/b-cell ratio of islet cells was decreased at 8 months of age. During long-term observation (18-20 months), mice formed well-differentiated Pan-NET with a Ki67-labeling index of 2.7%. In contrast, pancreasspecific 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).

Cross-talk among MEN1, p53 and Notch regulates the proliferation of pancreatic neuroendocrine tumor cells by modulating INSM1 expression and subcellular localization

“…It has been shown that Notch signaling regulates INSM1 expression and acts as an upstream regulator of INSM1 in SCLCs, influencing cell proliferation and differentiation [ 13 , 47 ]. Recent mice studies have shown that during the early stages of PanNET tumorigenesis, p53 is typically activated to higher levels compared to normal islets, revealing a potential role for p53 in PanNET tumorigenesis [48] . Additionally, the Notch and p53 pathways have been directly correlated in a variety of cancers, including late-stage cervical cancer and Ewing's sarcoma [49] .…”

“…In these cells, when Notch signalling is inhibited, INSM1 localizes in the cytoplasm, inducing cell cycle arrest and a progenitor non-proliferating cell phenotype. It has been shown that different mechanisms influence early tumor formation and malignant progression in PanNETs [ 48 , 50 ]. For instance, it has been suggested that mutation of p53 may be involved in the late stages of PanNETs tumorigenesis [48] .…”

“…It has been shown that different mechanisms influence early tumor formation and malignant progression in PanNETs [ 48 , 50 ]. For instance, it has been suggested that mutation of p53 may be involved in the late stages of PanNETs tumorigenesis [48] . Here, we hypothesize that wild-type p53 may play a role in early PanNET tumorigenesis influencing INSM1 transcription and subcellular localization depending on Notch activation.…”

An update on genetically engineered mouse models of pancreatic neuroendocrine neoplasms

“…In contrast, the column totals concern the selected gene promoters' total (Rip, Ins, Pdx1, Ren, or Glu) regardless of the targeted protein. (Yamauchi et al 2020). This different design led to WD IA formation by 18-20 months (graded as G1 and comparable to human pancreatic neuroendocrine microadenomas); by adding the additional Tp53 mutation to the previous model, they were able to generate IC (aggressive insulinomas) (graded as G2-G3) within a shorter period (4 months), associated with liver metastases (9 months).…”

Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets

“…Since PyMT stimulates multiple oncogenic pathways including mitogen-activated protein kinase (MAPK), PI3K signaling and the Hippo pathway [162,163], and SV40 large T antigen inhibits both p53 and Rb, none of the above studies addressed the individual role of p53 loss in driving pNET formation. That was examined in a recent study, in which mice with pancreas-specific mutant p53 expression (Pdx1-Cre; Trp53 R172H ) failed to develop pNETs, although Trp53 mutation greatly accelerated pNET progression to G3 pNETs when combined with Rb1 deletion [75]. Likewise, Xu et al, found Trp53 loss alone yielded no pNETs whereas its deletion with Rb1 in the pancreas resulted in aggressive pNETs [76].…”