Deletion of Rb accelerates pancreatic carcinogenesis by oncogenic kras and impairs senescence in premalignant lesions

Catherine Carrire, A. Jesse Gore, Alixanna M. Norris, Jason R. Gunn, Alison L. Young, Daniel S. Longnecker, Murray Korc

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46 Scopus citations

Abstract

Background & Aims: Rb1 encodes a cell-cycle regulator that is functionally disrupted in most human cancers. Pancreatic ductal adenocarcinomas (PDACs) have a high frequency of mutations in KRAS and INK4A/CDKN2A that might allow cells to bypass the regulatory actions of retinoblastoma (RB). To determine the role of loss of RB function in PDAC progression, we investigated the effects of Rb disruption during pancreatic malignant transformation initiated by oncogenic Kras. Methods: We generated mice with pancreas-specific disruption of Rb, in the absence or presence of oncogenic Kras, to examine the role of RB in pancreatic carcinogenesis. Results: In the presence of oncogenic Kras, loss of Rb from the pancreatic epithelium accelerated formation of pancreatic intraepithelial neoplasia (PanIN), increased the frequency of cystic neoplasms, and promoted rapid progression toward PDAC. Early stage cancers were characterized by acute pancreatic inflammation, associated with up-regulation of proinflammatory cytokines within the pancreas. Despite the presence of markers associated with oncogene-induced senescence, low-grade PanIN were highly proliferative and expressed high levels of p53. Pancreatic cancer cell lines derived from these mice expressed high levels of cytokines, and transcriptional activity of p53 was impaired. Conclusions: Rb encodes a tumor suppressor that attenuates progression of oncogenic Kras-induced carcinogenesis in the pancreas by mediating the senescence response and promoting activity of the tumor suppressor p53.

Original languageEnglish (US)
Pages (from-to)1091-1101
Number of pages11
JournalGastroenterology
Volume141
Issue number3
DOIs
StatePublished - Sep 2011

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Keywords

  • Chemokine
  • Proliferation
  • Signaling
  • Transformation

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Carrire, C., Gore, A. J., Norris, A. M., Gunn, J. R., Young, A. L., Longnecker, D. S., & Korc, M. (2011). Deletion of Rb accelerates pancreatic carcinogenesis by oncogenic kras and impairs senescence in premalignant lesions. Gastroenterology, 141(3), 1091-1101. https://doi.org/10.1053/j.gastro.2011.05.041