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.
Highlights
Glucagon is produced in islet α-cells through cleavage of proglucagon by prohormone convertase 2 (Pcsk2) and increases glucose production in liver, the major target organ of glucagon [1,2,3]
At 12 months of age, the size of the islets increased further (2–5 mm in diameter; Fig 1D, 1I, 1N and 1S), and GFP-positive cells were detected in the liver by fluorescent microscopy, suggesting micro-metastasis
The Ki-67 labeling index of the tumors that were transplanted into the glucagon/green fluorescent protein knock-in allele (GCGKO) mice was significantly higher (12±5.8%, n = 6, p = 0.013), compared with 0±0% (n = 4) for the control mice (Fig 6I). These results indicate that growth of the tumor graft in the subrenal capsule was dependent on the humoral conditions specific to the GCGKO, such as the presence of growth-promoting factors, and the absence of growth inhibitory factors, or both
Summary
Glucagon is produced in islet α-cells through cleavage of proglucagon by prohormone convertase 2 (Pcsk2) and increases glucose production in liver, the major target organ of glucagon [1,2,3].
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