Title | p53 and p16/p19 Loss Promotes Different Pancreatic Tumor Types from PyMT-Expressing Progenitor Cells. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Azzopardi S, Pang S, Klimstra DS, Du Y-CNancy |
Journal | Neoplasia |
Volume | 18 |
Issue | 10 |
Pagination | 610-617 |
Date Published | 2016 Oct |
ISSN | 1476-5586 |
Keywords | Animals, Cell Transformation, Neoplastic, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p19, Disease Models, Animal, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Kaplan-Meier Estimate, Mice, Mice, Transgenic, Neoplasm Metastasis, Neoplastic Stem Cells, Neuroendocrine Tumors, Pancreatic Neoplasms, Phenotype, Prognosis, Tumor Burden, Tumor Suppressor Protein p53 |
Abstract | In human studies and mouse models, the contributions of p53 and p16/p19 loss are well established in pancreatic ductal adenocarcinoma (PDAC). Although loss of functional p53 pathway and loss of Ink4a/Arf in human pancreatic acinar cell carcinoma (PACC) and pancreatic neuroendocrine tumor (PanNET) are identified, their direct roles in tumorigenesis of PACC and PanNET remain to be determined. Using transgenic mouse models expressing the viral oncogene polyoma middle T antigen (PyMT), we demonstrate that p53 loss in pancreatic Pdx1+ progenitor cells results in aggressive PACC, whereas Ink4a/Arf loss results in PanNETs. Concurrent loss of p53 and Ink4a/Arf resembles loss of p53 alone, suggesting that Ink4a/Arf loss has no additive effect to PACC progression. Our results show that specific tumor suppressor genotypes provocatively influence the tumor biological phenotypes in pancreatic progenitor cells. Additionally, in a mouse model of β-cell hyperplasia, we demonstrate that p53 and Ink4a/Arf play cooperative roles in constraining the progression of PanNETs. |
DOI | 10.1016/j.neo.2016.08.003 |
Alternate Journal | Neoplasia |
PubMed ID | 27664376 |
PubMed Central ID | PMC5035259 |
Grant List | P30 CA008748 / CA / NCI NIH HHS / United States R21 CA173348 / CA / NCI NIH HHS / United States U01 DK072473 / DK / NIDDK NIH HHS / United States |
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