title: Unique mechanisms of growth regulation and tumor suppression upon Apc inactivation in the pancreas.
abstract: beta-catenin signaling is heavily involved in organogenesis. Here, we investigated how pancreas differentiation, growth and homeostasis are affected following inactivation of an endogenous inhibitor of beta-catenin, adenomatous polyposis coli (Apc). In adult mice, Apc-deficient pancreata were enlarged, solely as a result of hyperplasia of acinar cells, which accumulated beta-catenin, with the sparing of islets. Expression of a target of beta-catenin, the proto-oncogene c-myc (Myc), was increased in acinar cells lacking Apc, suggesting that c-myc expression is essential for hyperplasia. In support of this hypothesis, we found that conditional inactivation of c-myc in pancreata lacking Apc completely reversed the acinar hyperplasia. Apc loss in organs such as the liver, colon and kidney, as well as experimental misexpression of c-myc in pancreatic acinar cells, led to tumor formation with high penetrance. Surprisingly, pancreas tumors failed to develop following conditional pancreas Apc inactivation. In Apc-deficient acini of aged mice, our studies revealed a cessation of their exaggerated proliferation and a reduced expression of c-myc, in spite of the persistent accumulation of beta-catenin. In conclusion, our work shows that beta-catenin modulation of c-myc is an essential regulator of acinar growth control, and unveils an unprecedented example of Apc requirement in the pancreas that is both temporally restricted and cell-specific. This provides new insights into the mechanisms of tumor pathogenesis and tumor suppression in the pancreas.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Faculty of Medicine, 1 Rue Michel-Servet, CH-1211 Geneva 4, Switzerland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Strom
authors.forename: Claire
authors.initials: C
authors.lastname: Bonal
authors.forename: Ruth
authors.initials: R
authors.lastname: Ashery-Padan
authors.forename: Naoko
authors.initials: N
authors.lastname: Hashimoto
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Campos
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kido
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Thorel
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Herrera
mesh_terms: D000818:Animals; D017491:Genes, APC / Q000502:physiology*; D016147:Genes, Tumor Suppressor / Q000502:physiology; D016259:Genes, myc / Q000502:physiology; D006128:Growth / Q000235:genetics*; D006965:Hyperplasia / Q000235:genetics; D006984:Hypertrophy / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism / Q000502:physiology
chemical_list: D051176:beta Catenin