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Pancreatic Neuroendocrine Tumors in Mice Deficient in Proglucagon-Derived Peptides.

Takano Y, Kasai K, Takagishi Y, Kikumori T, Imai T, Murata Y, Hayashi Y - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

Dissemination of GFP-positive cells and metastatic neuroendocrine tumors in the liver of GCGKO mice.A and B: Fluorescence with phase contrast imaging of the liver section. Livers from a 12-month-old GCGKO mouse (A) and an 18-month-old Gcggfp/+ mouse (B) are shown. C and D: H&E-staining of the metastatic neuroendocrine tumor. E–P: Fluorescent immunohistochemical analyses showing the GFP fluorescent signal (F, H, J, L, N, and P) or not (E, G, I, K, M, and O). Immunoreactivity for insulin (E and F), somatostatin (G and H), pancreatic polypeptide (I and J), chromogranin A (K and L), VEGF (M and N), and Ki-67 (O and P) is shown in red. Scale bars: 200 μm.
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pone.0133812.g004: Dissemination of GFP-positive cells and metastatic neuroendocrine tumors in the liver of GCGKO mice.A and B: Fluorescence with phase contrast imaging of the liver section. Livers from a 12-month-old GCGKO mouse (A) and an 18-month-old Gcggfp/+ mouse (B) are shown. C and D: H&E-staining of the metastatic neuroendocrine tumor. E–P: Fluorescent immunohistochemical analyses showing the GFP fluorescent signal (F, H, J, L, N, and P) or not (E, G, I, K, M, and O). Immunoreactivity for insulin (E and F), somatostatin (G and H), pancreatic polypeptide (I and J), chromogranin A (K and L), VEGF (M and N), and Ki-67 (O and P) is shown in red. Scale bars: 200 μm.

Mentions: Dissemination of GFP-positive cells in the liver was identified in some of the 12-month-old GCGKO mice and in all the 15-month-old GCGKO mice (Fig 4A and Table 1). GFP-positive cells were absent from the livers of the Gcggfp/+ mice (Fig 4B and Table 1). The macroscopic GFP-positive tumors in the liver were well-circumscribed. Microscopically, these metastatic tumor cells showed an organoid structure, as seen in the pancreata, and were separated from the hepatic parenchyma by fibrous capsules (Fig 4C and 4D). No cells in the metastatic tumors stained positive for insulin (Fig 4E and 4F), somatostatin (Fig 4G and 4H), or pancreatic polypeptide Y (Fig 4I and 4J). Expression patterns of chromogranin A (Fig 4K and 4L) and vascular endothelial growth factor (Fig 4M and 4N) in the metastatic tumors were similar to those observed in pancreatic tumors. Ki67-positive cells were also identified in the liver (Fig 4O and 4P), although the labeling index appeared to be lower than that of the pancreatic tumor (Fig 3O and 3P).


Pancreatic Neuroendocrine Tumors in Mice Deficient in Proglucagon-Derived Peptides.

Takano Y, Kasai K, Takagishi Y, Kikumori T, Imai T, Murata Y, Hayashi Y - PLoS ONE (2015)

Dissemination of GFP-positive cells and metastatic neuroendocrine tumors in the liver of GCGKO mice.A and B: Fluorescence with phase contrast imaging of the liver section. Livers from a 12-month-old GCGKO mouse (A) and an 18-month-old Gcggfp/+ mouse (B) are shown. C and D: H&E-staining of the metastatic neuroendocrine tumor. E–P: Fluorescent immunohistochemical analyses showing the GFP fluorescent signal (F, H, J, L, N, and P) or not (E, G, I, K, M, and O). Immunoreactivity for insulin (E and F), somatostatin (G and H), pancreatic polypeptide (I and J), chromogranin A (K and L), VEGF (M and N), and Ki-67 (O and P) is shown in red. Scale bars: 200 μm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4508046&req=5

pone.0133812.g004: Dissemination of GFP-positive cells and metastatic neuroendocrine tumors in the liver of GCGKO mice.A and B: Fluorescence with phase contrast imaging of the liver section. Livers from a 12-month-old GCGKO mouse (A) and an 18-month-old Gcggfp/+ mouse (B) are shown. C and D: H&E-staining of the metastatic neuroendocrine tumor. E–P: Fluorescent immunohistochemical analyses showing the GFP fluorescent signal (F, H, J, L, N, and P) or not (E, G, I, K, M, and O). Immunoreactivity for insulin (E and F), somatostatin (G and H), pancreatic polypeptide (I and J), chromogranin A (K and L), VEGF (M and N), and Ki-67 (O and P) is shown in red. Scale bars: 200 μm.
Mentions: Dissemination of GFP-positive cells in the liver was identified in some of the 12-month-old GCGKO mice and in all the 15-month-old GCGKO mice (Fig 4A and Table 1). GFP-positive cells were absent from the livers of the Gcggfp/+ mice (Fig 4B and Table 1). The macroscopic GFP-positive tumors in the liver were well-circumscribed. Microscopically, these metastatic tumor cells showed an organoid structure, as seen in the pancreata, and were separated from the hepatic parenchyma by fibrous capsules (Fig 4C and 4D). No cells in the metastatic tumors stained positive for insulin (Fig 4E and 4F), somatostatin (Fig 4G and 4H), or pancreatic polypeptide Y (Fig 4I and 4J). Expression patterns of chromogranin A (Fig 4K and 4L) and vascular endothelial growth factor (Fig 4M and 4N) in the metastatic tumors were similar to those observed in pancreatic tumors. Ki67-positive cells were also identified in the liver (Fig 4O and 4P), although the labeling index appeared to be lower than that of the pancreatic tumor (Fig 3O and 3P).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus