title: EMT and dissemination precede pancreatic tumor formation.
abstract: 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.
authors.affiliation: Gastroenterology Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Rhim
authors.forename: Emily T
authors.initials: ET
authors.lastname: Mirek
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Aiello
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Bailey
authors.forename: Florencia
authors.initials: F
authors.lastname: McAllister
authors.forename: Maximilian
authors.initials: M
authors.lastname: Reichert
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Beatty
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vonderheide
authors.forename: Steven D
authors.initials: SD
authors.lastname: Leach
authors.forename: Ben Z
authors.initials: BZ
authors.lastname: Stanger
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology / Q000473:pathology*; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology*; D010195:Pancreatitis / Q000473:pathology