Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse.
To evaluate the role of oncogenic RAS mutations in pancreatic tumorigenesis, we directed endogenous expression of KRAS(G12D) to progenitor cells of the mouse pancreas. We find that physiological levels of Kras(G12D) induce ductal lesions that recapitulate the full spectrum of human pancreatic intraepithelial neoplasias (PanINs), putative precursors to invasive pancreatic cancer. The PanINs are highly proliferative, show evidence of histological progression, and activate signaling pathways normally quiescent in ductal epithelium, suggesting potential therapeutic and chemopreventive targets for the cognate human condition. At low frequency, these lesions also progress spontaneously to invasive and metastatic adenocarcinomas, establishing PanINs as definitive precursors to the invasive disease. Finally, mice with PanINs have an identifiable serum proteomic signature, suggesting a means of detecting the preinvasive state in patients.
Hingorani
Sunil R
SR
Department of Medicine, Abramson Family Cancer Research Institute, Abramson Center at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Petricoin
Emanuel F
EF
Maitra
Anirban
A
Rajapakse
Vinodh
V
King
Catrina
C
Jacobetz
Michael A
MA
Ross
Sally
S
Conrads
Thomas P
TP
Veenstra
Timothy D
TD
Hitt
Ben A
BA
Kawaguchi
Yoshiya
Y
Johann
Don
D
Liotta
Lance A
LA
Crawford
Howard C
HC
Putt
Mary E
ME
Jacks
Tyler
T
Wright
Christopher V E
CV
Hruban
Ralph H
RH
Lowy
Andrew M
AM
Tuveson
David A
DA
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism; D051546:Cyclooxygenase 2; D011905:Genes, ras / Q000502:physiology*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D000072056:Transcription Factor HES-1
D051792:Basic Helix-Loop-Helix Proteins; D051546:Cyclooxygenase 2; D018398:Homeodomain Proteins; D007527:Isoenzymes; D020783:Matrix Metalloproteinase 7; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C078493:HES1 protein, human; C496540:PTGS2 protein, human