TY - JOUR
T1 - EMT and dissemination precede pancreatic tumor formation
AU - Rhim, Andrew D.
AU - Mirek, Emily T.
AU - Aiello, Nicole M.
AU - Maitra, Anirban
AU - Bailey, Jennifer M.
AU - McAllister, Florencia
AU - Reichert, Maximilian
AU - Beatty, Gregory L.
AU - Rustgi, Anil K.
AU - Vonderheide, Robert H.
AU - Leach, Steven D.
AU - Stanger, Ben Z.
N1 - Funding Information:
We thank I. Ben-Porath, L. Chodosh, A. Minn, A. Rustgi, M.C. Simon, and H. Zong for helpful discussions; M. Emmett, A. Pannikar, and M. Rovira for technical assistance; N. Bardeesy, R. DePinho, S. Konieczny, and D. Melton for mouse strains; and J. Habener and D. Melton for gifts of antibodies. We are grateful to R. Hruban for providing confirmation of histological impressions. This work was supported by the NIH (DK088945 and DK007066 to A.D.R., CA134292 to A.M. and S.D.L., T32GM066691 to F.M., CA138907 to G.L.B., CA117969, DK083355, and DK083111 to B.Z.S.), AGA/FDHN (A.D.R.), National Pancreas Foundation (A.D.R. and M.R.), AACR and Pancreatic Cancer Action Network (Pathway to Leadership Award to J.M.B. and Career Development Award to B.Z.S.), Pennsylvania Department of Health (R.H.V. and B.Z.S.), and the Pew Charitable Trusts (B.Z.S.). Experiments utilized the Molecular Pathology and Imaging, Molecular Biology, and Cell Culture core facilities within the NIH/Penn Center for Molecular Studies in Digestive and Liver Diseases (P30-DK050306), the Abramson Family Cancer Research Institute, and the Diabetes and Endocrine Research Center (P30-DK19525).
PY - 2012/1/20
Y1 - 2012/1/20
N2 - Metastasis is the leading cause of cancer-associated death but has been difficult to study because it involves a series of rare, stochastic events. To capture these events, we developed a sensitive method to tag and track pancreatic epithelial cells in a mouse model of pancreatic cancer. Tagged cells invaded and entered the bloodstream unexpectedly early, before frank malignancy could be detected by rigorous histologic analysis; this behavior was widely associated with epithelial-to-mesenchymal transition (EMT). Circulating pancreatic cells maintained a mesenchymal phenotype, exhibited stem cell properties, and seeded the liver. EMT and invasiveness were most abundant at inflammatory foci, and induction of pancreatitis increased the number of circulating pancreatic cells. Conversely, treatment with the immunosuppressive agent dexamethasone abolished dissemination. These results provide insight into the earliest events of cellular invasion in situ and suggest that inflammation enhances cancer progression in part by facilitating EMT and entry into the circulation.
AB - Metastasis is the leading cause of cancer-associated death but has been difficult to study because it involves a series of rare, stochastic events. To capture these events, we developed a sensitive method to tag and track pancreatic epithelial cells in a mouse model of pancreatic cancer. Tagged cells invaded and entered the bloodstream unexpectedly early, before frank malignancy could be detected by rigorous histologic analysis; this behavior was widely associated with epithelial-to-mesenchymal transition (EMT). Circulating pancreatic cells maintained a mesenchymal phenotype, exhibited stem cell properties, and seeded the liver. EMT and invasiveness were most abundant at inflammatory foci, and induction of pancreatitis increased the number of circulating pancreatic cells. Conversely, treatment with the immunosuppressive agent dexamethasone abolished dissemination. These results provide insight into the earliest events of cellular invasion in situ and suggest that inflammation enhances cancer progression in part by facilitating EMT and entry into the circulation.
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U2 - 10.1016/j.cell.2011.11.025
DO - 10.1016/j.cell.2011.11.025
M3 - Article
C2 - 22265420
AN - SCOPUS:84856088337
SN - 0092-8674
VL - 148
SP - 349
EP - 361
JO - Cell
JF - Cell
IS - 1-2
ER -