p53 and p16 Ink4a/p19 Arf Loss Promotes Different Pancreatic Tumor Types from PyMT-Expressing Progenitor Cells

Neoplasia. 2016 Oct;18(10):610-617. doi: 10.1016/j.neo.2016.08.003. Epub 2016 Sep 21.

Abstract

In human studies and mouse models, the contributions of p53 and p16Ink4a/p19Arf 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.

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / deficiency*
  • Cyclin-Dependent Kinase Inhibitor p19 / deficiency*
  • Disease Models, Animal
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kaplan-Meier Estimate
  • Mice
  • Mice, Transgenic
  • Neoplasm Metastasis
  • Neoplastic Stem Cells / metabolism*
  • Neuroendocrine Tumors / genetics
  • Neuroendocrine Tumors / mortality
  • Neuroendocrine Tumors / pathology
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / mortality
  • Pancreatic Neoplasms / pathology*
  • Phenotype
  • Prognosis
  • Tumor Burden
  • Tumor Suppressor Protein p53 / deficiency*

Substances

  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p19
  • Tumor Suppressor Protein p53