title: Characterization of pancreatic glucagon-producing tumors and pituitary gland tumors in transgenic mice overexpressing MYCN in hGFAP-positive cells.
abstract: Amplification or overexpression of MYCN is involved in development and maintenance of multiple malignancies. A subset of these tumors originates from neural precursors, including the most aggressive forms of the childhood tumors, neuroblastoma and medulloblastoma. In order to model the spectrum of MYCN-driven neoplasms in mice, we transgenically overexpressed MYCN under the control of the human GFAP-promoter that, among other targets, drives expression in neural progenitor cells. However, LSL-MYCN;hGFAP-Cre double transgenic mice did neither develop neural crest tumors nor tumors of the central nervous system, but presented with neuroendocrine tumors of the pancreas and, less frequently, the pituitary gland. Pituitary tumors expressed chromogranin A and closely resembled human pituitary adenomas. Pancreatic tumors strongly produced and secreted glucagon, suggesting that they derived from glucagon- and GFAP-positive islet cells. Interestingly, 3 out of 9 human pancreatic neuroendocrine tumors expressed MYCN, supporting the similarity of the mouse tumors to the human system. Serial transplantations of mouse tumor cells into immunocompromised mice confirmed their fully transformed phenotype. MYCN-directed treatment by AuroraA- or Brd4-inhibitors resulted in significantly decreased cell proliferation in vitro and reduced tumor growth in vivo. In summary, we provide a novel mouse model for neuroendocrine tumors of the pancreas and pituitary gland that is dependent on MYCN expression and that may help to evaluate MYCN-directed therapies.
authors: Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors: Kathrin
authors: K
authors: Fielitz
authors: Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors: Kristina
authors: K
authors: Althoff
authors: Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors: Katleen
authors: K
authors: De Preter
authors: Genetics and Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Julie
authors: J
authors: Nonnekens
authors: Center for Neuropathology, Ludwig-Maximilians University, Munich, Germany.
authors: Jasmin
authors: J
authors: Ohli
authors: Department of Pathology, University Hospital, Münster, Germany.
authors: Sandra
authors: S
authors: Elges
authors: Department of Pathology, University Hospital, Münster, Germany.
authors: Wolfgang
authors: W
authors: Hartmann
authors: Department of Pathology, Technical University, Munich, Germany.
authors: Günter
authors: G
authors: Klöppel
authors: Department of Pathology, Ludwig-Maximilians University, Munich, Germany.
authors: Thomas
authors: T
authors: Knösel
authors: Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors: Marc
authors: M
authors: Schulte
authors: Cell Biology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors: Ludger
authors: L
authors: Klein-Hitpass
authors: Genome Informatics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors: Daniela
authors: D
authors: Beisser
authors: Department of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors: Henning
authors: H
authors: Reis
authors: Division of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors: Annette
authors: A
authors: Eyking
authors: Division of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors: Elke
authors: E
authors: Cario
authors: Department of Pediatric Oncology and Hematology, Charité University Medicine, Berlin, Germany.
authors: Johannes H
authors: JH
authors: Schulte
authors: Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors: Alexander
authors: A
authors: Schramm
authors: Center for Neuropathology, Ludwig-Maximilians University, Munich, Germany.|Institute of Neuropathology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany.|Research Institute Childrens Cancer Center, Hamburg, Germany.|Department of Pediatric Oncology and Hematology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany.
authors: Ulrich
authors: U
authors: Schüller
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics* / Q000378:metabolism; D005934:Glucagon / Q000096:biosynthesis*; D005935:Glucagonoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D000071447:N-Myc Proto-Oncogene Protein / Q000235:genetics* / Q000378:metabolism; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D059467:Transcriptome
chemical_list: D005904:Glial Fibrillary Acidic Protein; D000071447:N-Myc Proto-Oncogene Protein; D005934:Glucagon
keywords: MYCN; glucagonoma; pancreatic neuroendocrine tumors