Abstract
Gonadotroph adenomas comprise 15–40 % of all pituitary tumors, are usually non-functioning and are often large and invasive at presentation. Surgery is the first-choice treatment, but complete resection is not always achieved, leading to high recurrence rates. As gonadotroph adenomas poorly respond to conventional pharmacological therapies, novel treatment strategies are needed. Their identification has been hampered by our incomplete understanding of the molecular pathogenesis of these tumors. Recently, we demonstrated that MENX-affected rats develop gonadotroph adenomas closely resembling their human counterparts. To discover new genes/pathways involved in gonadotroph cells tumorigenesis, we performed transcriptome profiling of rat tumors versus normal pituitary. Adenomas showed overrepresentation of genes involved in cell cycle, development, cell differentiation/proliferation, and lipid metabolism. Bioinformatic analysis identified downstream targets of the transcription factor SF-1 as being up-regulated in rat (and human) adenomas. Meta-analyses demonstrated remarkable similarities between gonadotroph adenomas in rats and humans, and highlighted common dysregulated genes, several of which were not previously implicated in pituitary tumorigenesis. Two such genes, CYP11A1 and NUSAP1, were analyzed in 39 human gonadotroph adenomas by qRT-PCR and found to be up-regulated in 77 and 95 % of cases, respectively. Immunohistochemistry detected high P450scc (encoded by CYP11A1) and NuSAP expression in 18 human gonadotroph tumors. In vitro studies demonstrated for the first time that Cyp11a1 is a target of SF-1 in gonadotroph cells and promotes proliferation/survival of rat pituitary adenoma primary cells and cell lines. Our studies reveal clues about the molecular mechanisms driving rat and human gonadotroph adenomas development, and may help identify previously unexplored biomarkers for clinical use.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1132-7) contains supplementary material, which is available to authorized users.
Highlights
Non-functioning adenomas of the pituitary gland account for about 30 % of all adenomas
Genes encoding proteins involved in cell cycle regulation and especially in mitosis such as Aurka, Bub1, Bub1b, Ccna1, Ccnb1, Ccnb2, Ccne1, Cdc2, Cdc20, Cdkn3, Kif4, Kif11, Nusap1, Prc1, as well as genes involved in pituitary development or adenohypophyseal cell differentiation, such as Dax-1/Nr0b1, Egr1, Fgfr2, Neurod1, Notch2, Nr5a1, Pou1f1, Tbx19 [6, 10, 23] were differentially expressed in rat pituitary adenoma (PA) (Table 1)
Array data mining found that genes such as Ccnb1, Igfbp3, Nusap1, Pttg1, Racgap1, Top2a, Tpx2, which are associated with the aggressive behaviour of various human tumors, including PAs, and proto-oncogenes such as Ect2, Kit, Kras, Lyn, Ret are up-regulated in rat adenomas [12, 15, 42, 43]
Summary
Non-functioning adenomas of the pituitary gland account for about 30 % of all adenomas. About 80 % of them belong to the gonadotroph lineage. They are usually diagnosed when signs and symptoms of mass effects occur, and about 40 % of them extend to the cavernous sinus and, less commonly, invade the sellar floor, making their resection and post-operative radiotherapy challenging [14, 34]. They are usually resistant to pharmacological treatment with somatostatin analogs and dopamine agonists.
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