PMID- 25042889
OWN - NLM
STAT- MEDLINE
DCOM- 20141117
LR  - 20140910
IS  - 1096-9896 (Electronic)
IS  - 0022-3417 (Linking)
VI  - 234
IP  - 2
DP  - 2014 Oct
TI  - A genetically engineered mouse model developing rapid progressive pancreatic 
      ductal adenocarcinoma.
PG  - 228-38
LID - 10.1002/path.4402 [doi]
AB  - The premalignant lesions of pancreatic cancer, pancreatic intraepithelial 
      neoplasia (PanIN), have a high frequency of mutations in Kirsten rat sarcoma 
      viral oncogene homologue (KRAS), and genetic alterations in the retinoblastoma 
      (Rb)-E2 factor (E2F) and transformed 3T3 cell double minute 2 (MDM2)-p53 pathways 
      accelerate development of pancreatic ductal adenocarcinoma. The viral oncoprotein 
      SV40 large T antigen (TAg) can inhibit the effects of the Rb family of molecules 
      and of p53 on these pathways, and targeted expression of TAg in mouse pancreas is 
      associated with the development of endocrine or acinar cell tumours. In this 
      study, to determine whether the viral oncoprotein promotes pancreatic duct 
      carcinogenesis initiated by oncogenic KRAS, we generated mice expressing 
      temperature-sensitive SV40 large T antigen (tsTAg) on pancreatic epithelial cells 
      in the presence or absence of Kras(G12D) . Mice with pancreas-specific tsTAg 
      expression developed acinar cell dysplasia by 22 weeks without PanIN formation, 
      while mice expressing both tsTAg and Kras(G12D) developed highly aggressive 
      adenocarcinoma with a ductal cell phenotype within a short period, and died 
      within 3 weeks. The tumours resembled human pancreatic ductal adenocarcinoma 
      (PDAC) at the histological level, and oncogenic Kras and tsTAg synergistically 
      activated E2f and Sre transcription in established PDAC cell lines. These results 
      suggest that tsTAg synergistically promotes Kras(G12D) -associated PDAC 
      formation, and our study identifies a new mouse model of PDAC that may allow a 
      better understanding of the mechanism of carcinogenesis in pancreatic carcinoma, 
      which shows a catastrophic clinical course.
CI  - Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by 
      John Wiley & Sons, Ltd.
FAU - Yamaguchi, Takashi
AU  - Yamaguchi T
AD  - Molecular Medicine Team, Research Centre for Medical Glycoscience, National 
      Institute of Advanced Industrial Science and Technology, Ibaraki, Japan.
FAU - Ikehara, Sanae
AU  - Ikehara S
FAU - Nakanishi, Hayao
AU  - Nakanishi H
FAU - Ikehara, Yuzuru
AU  - Ikehara Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140804
PL  - England
TA  - J Pathol
JT  - The Journal of pathology
JID - 0204634
RN  - 0 (Antigens, Viral, Tumor)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
SB  - IM
MH  - Animals
MH  - Antigens, Viral, Tumor/*metabolism
MH  - Carcinoma, Pancreatic Ductal/*genetics/pathology
MH  - Cell Line, Tumor
MH  - Cell Transformation, Neoplastic
MH  - *Disease Models, Animal
MH  - Disease Progression
MH  - Humans
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Pancreatic Neoplasms/*genetics/pathology
MH  - Proto-Oncogene Proteins p21(ras)/*genetics
MH  - Tumor Suppressor Protein p53/*genetics
OTO - NOTNLM
OT  - KrasG12D
OT  - genetically engineered mouse model
OT  - temperature-sensitive T antigen
EDAT- 2014/07/22 06:00
MHDA- 2014/11/18 06:00
CRDT- 2014/07/22 06:00
PHST- 2014/01/20 00:00 [received]
PHST- 2014/06/14 00:00 [revised]
PHST- 2014/07/02 00:00 [accepted]
PHST- 2014/07/22 06:00 [entrez]
PHST- 2014/07/22 06:00 [pubmed]
PHST- 2014/11/18 06:00 [medline]
AID - 10.1002/path.4402 [doi]
PST - ppublish
SO  - J Pathol. 2014 Oct;234(2):228-38. doi: 10.1002/path.4402. Epub 2014 Aug 4.