Abstract
Insulinomas are pancreatic neuroendocrine tumors (pNET), usually benign. Akt/p27kip1 is an intracellular pathway overexpressed in many pNET. There are no data regarding its expression in human insulinomas. We aimed to investigate the expression of Akt and p27kip1 in 24 human insulinomas and to compare them to their expression in normal surrounding islets. Staining was performed on embedded paraffin tissue using polyclonal antibodies against total Akt, p-Akt, p27kip1, and pp27kip1. p-Akt was the predominant form in insulinomas; they presented lower Akt and p-Akt expression than normal islets in 83.3% and 87.5% of tumors, respectively. p27kip1 and pp27kip1 were mainly cytoplasmic in both insulinomas and normal tissue. Cytoplasmic pp27kip1 staining was higher in insulinomas and surprisingly nearly half of the insulinomas also presented nuclear p27kip1 (p = 0.029). No differences were observed in the subcellular localization of p27kip1 and activation of Akt between benign and malignant insulinomas. The low expression of Akt seen in insulinomas might explain the usual benign behavior of this type of pNET. Cytoplasmic p27kip1 in both insulinomas and normal islet cells could reflect the low rate of replication of beta cells, while nuclear p27kip1 would seem to indicate stabilization and nuclear anchoring of the cyclin D-Cdk4 complex. Our data seem to suggest that the Akt pathway is not involved in human insulinoma tumorigenesis.
Highlights
Insulinomas are rare pancreatic neuroendocrine tumors, which arise from islet beta cells
When we compared the expression patterns of total Akt and phosphoS473Akt 1/2/3 (p-Akt) proteins in human insulinomas with their respective normal surrounding tissues, we found that normal islet cells showed higher or similar expression of total Akt than insulinoma cells (20/24, 83.3%) (Wilcoxon signed-rank test, p = 0 073); surprisingly, insulinoma cells showed markedly lower p-Akt staining than their surrounding normal islet cells in 21/ 24 tumors (87.5%) (Wilcoxon signed-rank test, p = 0 002) (Figures 2(b)–2(d) and 3)
Insulinomas, unlike other pancreatic neuroendocrine tumors (pNET), are typically benign tumors, and it is possible to speculate that this might be due to particular molecular events
Summary
Insulinomas are rare pancreatic neuroendocrine tumors (pNET), which arise from islet beta cells. Their incidence is very low, estimated in 1–4 cases per million, and their main clinical characteristic is that they present with hypoglycemic episodes. Most insulinomas occur sporadically or, less frequently, as part of familial cancer syndromes, including multiple endocrine neoplasia type 1 (MEN1), von Hippel Lindau syndrome, neurofibromatosis, and tuberous sclerosis complex [1]. Unlike other pNET, such as gastrinoma or somatostatinoma, insulinomas are usually benign, so it is possible to speculate that this peculiar behavior could be attributed to particular oncogenic events. Different in vitro and in vivo animal model studies have brought evidence of the involvement of insulin-like growth factor 2 (IGF2) in insulinoma tumorigenesis [2,3,4]. Both pathways act on p27kip: MAPK induces p27kip loss, while Akt leads to its mislocalization through the cytoplasm [5, 6]
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