title: Pancreatic Neuroendocrine Tumors in Mice Deficient in Proglucagon-Derived Peptides.
abstract: Animal models with defective glucagon action show hyperplasia of islet α-cells, however, the regulatory mechanisms underlying the proliferation of islet endocrine cells remain largely to be elucidated. The Gcggfp/gfp mice, which are homozygous for glucagon/green fluorescent protein knock-in allele (GCGKO), lack all proglucagon-derived peptides including glucagon and GLP-1. The present study was aimed to characterize pancreatic neuroendocrine tumors (panNETs), which develop in the GCGKO mice. At 15 months of age, macroscopic GFP-positive tumors were identified in the pancreas of all the GCGKO mice, but not in that of the control heterozygous mice. The tumor manifested several features that were consistent with pancreatic neuroendocrine tumors (panNETs), such as organoid structures with trabecular and cribriform patterns, and the expression of chromogranin A and synaptophysin. Dissemination of GFP-positive cells was observed in the liver and lungs in 100% and 95%, respectively, of 15-month-old GCGKO mice. To elucidate the regulatory mechanism for tumor growth, PanNET grafts were transplanted into subrenal capsules in GCGKO and control mice. Ki-67 positive cells were identified in panNET grafts transplanted to GCGKO mice 1 month after transplantation, but not in those to control mice. These results suggest that humoral factors or conditions specific to GCGKO mice, are involved in the proliferation of panNETs. Taken together, GCGKO mice are novel animal model for studying the development, pathogenesis, and metastasis panNETs.
authors.affiliation: Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, 464-8601, Nagoya, Aichi, Japan; Department of Transplantation and Endocrine Surgery, Nagoya University Graduate School of Medicine, 466-8550, Nagoya, Aichi, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Takano
authors.affiliation: Department of Pathology, Aichi Medical University, 480-1195, Nagakute, Aichi, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kasai
authors.affiliation: Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, 464-8601, Nagoya, Aichi, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Takagishi
authors.affiliation: Department of Transplantation and Endocrine Surgery, Nagoya University Graduate School of Medicine, 466-8550, Nagoya, Aichi, Japan.
authors.forename: Toyone
authors.initials: T
authors.lastname: Kikumori
authors.affiliation: Department of Transplantation and Endocrine Surgery, Nagoya University Graduate School of Medicine, 466-8550, Nagoya, Aichi, Japan; Department of Breast and Endocrine Surgery, Aichi Medical University, 480-1195, Nagakute, Aichi, Japan.
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Imai
authors.affiliation: Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, 464-8601, Nagoya, Aichi, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Murata
authors.affiliation: Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, 464-8601, Nagoya, Aichi, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D005934:Glucagon / Q000235:genetics / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D052336:Proglucagon / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D049452:Green Fluorescent Proteins; D052336:Proglucagon; D052216:Glucagon-Like Peptide 1; D005934:Glucagon