Lineage-Specific Restraint of Pituitary Gonadotroph Cell Adenoma Growth

Yunguang Tong,Yoel Toledano,Cuiqi Zhou,Svetlana Zonis,Alfredo Fusco,Vera Chesnokova,Bernd Scheithauer,Kolja Wawrowsky,Anat Ben-Shlomo,Kalman Kovacs,Shlomo Melmed

doi:10.1371/journal.pone.0017924

Abstract

Although pituitary adenomas are usually benign, unique trophic mechanisms restraining cell proliferation are unclear. As GH-secreting adenomas are associated with p53/p21-dependent senescence, we tested mechanisms constraining non-functioning pituitary adenoma growth. Thirty six gonadotroph-derived non-functioning pituitary adenomas all exhibited DNA damage, but undetectable p21 expression. However, these adenomas all expressed p16, and >90% abundantly expressed cytoplasmic clusterin associated with induction of the Cdk inhibitor p15 in 70% of gonadotroph and in 26% of somatotroph lineage adenomas (p = 0.006). Murine LβT2 and αT3 gonadotroph pituitary cells, and αGSU.PTTG transgenic mice with targeted gonadotroph cell adenomas also abundantly expressed clusterin and exhibited features of oncogene-induced senescence as evidenced by C/EBPβ and C/EBPδ induction. In turn, C/EBPs activated the clusterin promoter ∼5 fold, and elevated clusterin subsequently elicited p15 and p16 expression, acting to arrest murine gonadotroph cell proliferation. In contrast, specific clusterin suppression by RNAis enhanced gonadotroph proliferation. FOXL2, a tissue-specific gonadotroph lineage factor, also induced the clusterin promoter ∼3 fold in αT3 pituitary cells. As nine of 12 pituitary carcinomas were devoid of clusterin expression, this protein may limit proliferation of benign adenomatous pituitary cells. These results point to lineage-specific pathways restricting uncontrolled murine and human pituitary gonadotroph adenoma cell growth.

Highlights

Pituitary tumors arise from highly specialized cell types expressing the respective pituitary polypeptide hormones
DNA damage and senescence markers are induced in human pituitary adenomas Immunoreactive Pituitary tumor transforming gene (PTTG) was induced in all 36 gonadotroph cell adenomas analyzed, but not in normal pituitary tissue (Figure 1A), confirming previous reports [22,23,24]
Markers of DNA damage and aneuploidy including cH2A.X foci and phopsphorylated kinase mutated in ataxia telangiectasia [36,37] were not detected by fluorescent immunohistochemistry in two nontumorous human pituitary specimens

Summary

Introduction

Pituitary tumors arise from highly specialized cell types expressing the respective pituitary polypeptide hormones. Tumors derived from somatotrophs secrete growth hormone (GH), lactotrophs, prolactin (PRL), thyrotrophs, thyrotropin (TSH), and corticotrophs, adrenocorticotropin (ACTH). Nonfunctioning pituitary tumors usually arise from non-secreting cells of gonadotroph origin [1]. Pituitary tumors are usually benign neoplasms (adenomas), they may exhibit invasive or recurrent growth. Encountered malignant pituitary carcinomas comprise 0.02% of all pituitary tumors, proliferate rapidly and show extracranial metastases [2,3,4]. Most aggressive pituitary adenomas persistently exhibit low mitotic activity [3], mechanisms underlying these unique growth properties are largely elusive. We postulate that intrinsic cell-specific trophic properties as well as the lineage-origin of highly differentiated and specialized pituitary cells underlies constrained adenoma proliferation

Methods

Results

Conclusion