FP35-5 Akt/p27 pathway activation might counteract human insulinoma tumorigenesis

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP35-Neoplasia of Endocrine Tissues
Bench to Bedside
Monday, June 17, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 11:05 AM
Room 122 (Moscone Center)

Poster Board MON-297
Adriana Graciela Diaz*1, Martha Krall1, Florencia Garcia1, Andrea Paes de Lima1 and Oscar Domingo Bruno2
1Hospital de Clinicas, Buenos Aires, Argentina, 2Estudios Metabólicos y Endocrino, Buenos Aires, Argentina
Insulinomas are rare endocrine pancreatic tumors. Little is known about their tumorigenesis. IGF2 has been implicated in it. IGF2 actives the IGF1-R, a tyrosine kinase receptor.Ras/MEK/MAPK and PI3K/Akt pathwaysare major intracellular down-stream effectorsof this type of receptors. Ras/MEK/MAPK contributes to oncogenesis by inducing p27 loss, while PI3K/Akt pathway induces p27 mislocalization through cytoplasm.  In a variety of cancer, cytoplasmic p27 localization has been correlated with pro-oncogenic effect of p27 to promote cancer invasion and metastasis. There are no data about Akt and p27 expression in human insulinomas. In this study a total of 24 human insulinomas (22 sporadic and 2 associated to MEN1) were analyzed. Twenty tumors were benign and 4 malignant. Immunohistochemical (IHC) staining was performed on embedded paraffin tissue using polyclonal antibodies raised against Akt 1/2/3(H-136) (total Akt), phosphoS475Akt 1/2/3 (p-Akt), p27(C-19) (p27: nuclear) and phosphoThr187-p27 (p-p27: cytoplasmic), from Santa Cruz Biotechnology.  Staining was assessed on an arbitrary scale as absent (-), sparse (+), moderate (++) or strong (+++). Each tumor was compared with their peripheral normal tissue. IHC analysis of total Akt as well as p-Akt revealed than 77% and 91% of the tumors, respectively, showed lower staining than their normal surrounding islets. Despite total Akt and p-Aktunderexpression, there was no statistical difference between both of them.  However, 19/24 (79%) insulinomas showed predominantly p-Akt staining (sparse 68.4% and moderate 31.6%). Seventeen of them showed similar or higher staining than normal islets. IHC analysis of p27 expression revealed that most insulinomas had p-p27 staining positive (absent in 2, sparse in 12, moderate in 9 and strong in 3insulinomas). However, ten insulinomas presented also nuclear staining (sparse in 6 of them, moderate in 4). In contrast, normal surrounding tissue had nuclear p27 staining only in 3 cases (sparse). No difference between benign and malignant behavior was found. Tumoral nuclear p27 levels correlated with total Akt staining (p= 0.035), while p-Akt correlated with cytoplasmic p-p27 staining (p=0.036). In conclusion, this is the first study showing the expression of Akt and p27 in a large series of insulinomas. Akt pathway seems to be underexpressed in insulinoma, although some expression was found. Unlike with others tumors, cytoplasmic p-p27, found in mostinsulinomas, had no correlation with clinical behavior. The persistence of nuclear p27 in nearly half of insulinomas, might explain the usual benign behavior of this type of neuroendocrine tumor, suggesting that Akt/p27 pathway could act as a negative factor to counter insulinomatumorigenesis.

Nothing to Disclose: AGD, MK, FG, AP, ODB

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