TY - JOUR
T1 - Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse
AU - Hingorani, Sunil R.
AU - Petricoin, Emanuel F.
AU - Maitra, Anirban
AU - Rajapakse, Vinodh
AU - King, Catrina
AU - Jacobetz, Michael A.
AU - Ross, Sally
AU - Conrads, Thomas P.
AU - Veenstra, Timothy D.
AU - Hitt, Ben A.
AU - Kawaguchi, Yoshiya
AU - Johann, Don
AU - Liotta, Lance A.
AU - Crawford, Howard C.
AU - Putt, Mary E.
AU - Jacks, Tyler
AU - Wright, Christopher V.E.
AU - Hruban, Ralph H.
AU - Lowy, Andrew M.
AU - Tuveson, David A.
N1 - Funding Information:
We acknowledge the assistance of Michael Ray in producing the Pdx-1 antibody; Dr. Q.C. Yu and the AFCRI histology core; and Dr. Deborah Silberg, Dr. Gary Swain, and the NIH/NIDDK Center for Molecular studies in Digestive and Liver Diseases (P30 DK050306) and its Morphology Core and Cell Culture facilities. We thank Dr. N. Volkan Adsy (Wayne State University) for performing Muc5 immunohistochemistry and Dr. Tetsuo Sudo for providing the anti-Hes1 antibody. Supported in part by NCI R25-CA87812 (S.R.H.); Johns Hopkins University Clinical Scientist Award (A.M.); NIDDK (C.V.E.W.); NCI-P50-CA-62924 (R.H.H.); and McCabe Foundation, Abramson Cancer Center of the University of Pennsylvania Pilot Projects Program, American Cancer Society IRG-78-002-26 and AACR-PanCAN Career Development Award (D.A.T.).
PY - 2003/12
Y1 - 2003/12
N2 - To evaluate the role of oncogenic RAS mutations in pancreatic tumorigenesis, we directed endogenous expression of KRASG12D to progenitor cells of the mouse pancreas. We find that physiological levels of KrasG12D 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.
AB - To evaluate the role of oncogenic RAS mutations in pancreatic tumorigenesis, we directed endogenous expression of KRASG12D to progenitor cells of the mouse pancreas. We find that physiological levels of KrasG12D 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.
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U2 - 10.1016/S1535-6108(03)00309-X
DO - 10.1016/S1535-6108(03)00309-X
M3 - Article
C2 - 14706336
AN - SCOPUS:9144266295
SN - 1535-6108
VL - 4
SP - 437
EP - 450
JO - Cancer cell
JF - Cancer cell
IS - 6
ER -