PMID- 14681207
OWN - NLM
STAT- MEDLINE
DCOM- 20040129
LR  - 20240109
IS  - 0890-9369 (Print)
IS  - 0890-9369 (Linking)
VI  - 17
IP  - 24
DP  - 2003 Dec 15
TI  - Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic 
      pancreatic ductal adenocarcinoma.
PG  - 3112-26
AB  - Pancreatic ductal adenocarcinoma ranks among the most lethal of human 
      malignancies. Here, we assess the cooperative interactions of two signature 
      mutations in mice engineered to sustain pancreas-specific Cre-mediated activation 
      of a mutant Kras allele (KrasG12D) and deletion of a conditional Ink4a/Arf tumor 
      suppressor allele. The phenotypic impact of KrasG12D alone was limited primarily 
      to the development of focal premalignant ductal lesions, termed pancreatic 
      intraepithelial neoplasias (PanINs), whereas the sole inactivation of Ink4a/Arf 
      failed to produce any neoplastic lesions in the pancreas. In combination, 
      KrasG12D expression and Ink4a/Arf deficiency resulted in an earlier appearance of 
      PanIN lesions and these neoplasms progressed rapidly to highly invasive and 
      metastatic cancers, resulting in death in all cases by 11 weeks. The evolution of 
      these tumors bears striking resemblance to the human disease, possessing a 
      proliferative stromal component and ductal lesions with a propensity to advance 
      to a poorly differentiated state. These findings in the mouse provide 
      experimental support for the widely accepted model of human pancreatic 
      adenocarcinoma in which activated KRAS serves to initiate PanIN lesions, and the 
      INK4A/ARF tumor suppressors function to constrain the malignant conversion of 
      these PanIN lesions into lethal ductal adenocarcinoma. This faithful mouse model 
      may permit the systematic analysis of genetic lesions implicated in the human 
      disease and serve as a platform for the identification of early disease markers 
      and for the efficient testing of novel therapies.
FAU - Aguirre, Andrew J
AU  - Aguirre AJ
AD  - Department of Medical Oncology, Dana Farber Cancer Institute and Department of 
      Genetics, Harvard Medical School, Boston, MA 02115, USA.
FAU - Bardeesy, Nabeel
AU  - Bardeesy N
FAU - Sinha, Manisha
AU  - Sinha M
FAU - Lopez, Lyle
AU  - Lopez L
FAU - Tuveson, David A
AU  - Tuveson DA
FAU - Horner, James
AU  - Horner J
FAU - Redston, Mark S
AU  - Redston MS
FAU - DePinho, Ronald A
AU  - DePinho RA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20031217
PL  - United States
TA  - Genes Dev
JT  - Genes & development
JID - 8711660
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Tumor Suppressor Protein p14ARF)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Viral Proteins)
RN  - EC 2.7.7.- (Cre recombinase)
RN  - EC 2.7.7.- (Integrases)
SB  - IM
MH  - Animals
MH  - Carcinoma, Pancreatic Ductal/*etiology/metabolism/pathology
MH  - Cyclin-Dependent Kinase Inhibitor p16/*physiology
MH  - Fibroblasts/metabolism
MH  - Genes, ras/*physiology
MH  - Humans
MH  - Integrases/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Pancreatic Neoplasms/*etiology/metabolism/pathology
MH  - Proto-Oncogene Proteins/*metabolism
MH  - Tumor Cells, Cultured
MH  - Tumor Suppressor Protein p14ARF/*physiology
MH  - Tumor Suppressor Protein p53/metabolism
MH  - Vascular Endothelial Growth Factor A/metabolism
MH  - Viral Proteins/metabolism
PMC - PMC305262
EDAT- 2003/12/19 05:00
MHDA- 2004/01/30 05:00
PMCR- 2004/06/15
CRDT- 2003/12/19 05:00
PHST- 2003/12/19 05:00 [pubmed]
PHST- 2004/01/30 05:00 [medline]
PHST- 2003/12/19 05:00 [entrez]
PHST- 2004/06/15 00:00 [pmc-release]
AID - 1158703 [pii]
AID - 0173112 [pii]
AID - 10.1101/gad.1158703 [doi]
PST - ppublish
SO  - Genes Dev. 2003 Dec 15;17(24):3112-26. doi: 10.1101/gad.1158703. Epub 2003 Dec 
      17.