Mechanisms of Pituitary Tumorigenesis

描述(申请人提供)：垂体瘤占颅内肿瘤的15%，是一种临床上无症状或分泌包括催乳素、生长激素、促肾上腺皮质激素等激素的良性单克隆性肿瘤，也可极少分泌促甲状腺激素或促性腺激素。这些腺瘤是临床不孕症、生长障碍和皮质醇增多症或与低垂体症相关的代谢功能障碍的原因。本研究旨在探讨垂体细胞增殖调控紊乱在这些良性腺瘤发病机制中的作用。在第一个目标中，我们将在转基因小鼠垂体肿瘤模型(1GSU.PTTG和Rb杂合子)中研究垂体非整倍体、过早增殖停滞(衰老)、细胞增殖标志和肿瘤发生的机制。遗传和激素诱导的脑下垂体肿瘤发生机制将在这些基因类型和脑垂体细胞培养中进行研究。在第二个目标中，我们将研究人类垂体肿瘤中的DNA损伤、非整倍体的细胞标记和衰老介质。在第三个目标中，我们将通过评估E2F1对Rb小鼠、缺失p53或p21的突变人癌细胞以及人垂体腺瘤中Pttg转录和蛋白表达的诱导，来研究Rb/E2F诱导垂体肿瘤的机制。这些实验的结果将使人们能够进一步深入了解细胞周期控制和生长限制在实验性和人类垂体瘤中的作用，这是它们未能进展为恶性肿瘤的根本原因。这些结果将提高我们对临床内分泌综合征的理解，这些综合征与不孕不育、生长障碍、皮质醇增多或由于垂体功能丧失而导致的肾上腺、甲状腺和性腺功能衰竭有关。

DESCRIPTION (provided by applicant): Pituitary tumors account for 15% of intracranial neoplasms and are benign monoclonal neoplasms which may be clinically silent or secrete hormones including prolactin, growth hormone, ACTH, or rarely TSH or gonadotropins. These adenomas account for clinical infertility, growth disorders and hypercortisolism or metabolic dysfunctions associated with hypo-pituitarism. This proposal is aimed at exploring the role of disordered pituitary cell proliferation control in the pathogenesis of these invariably benign adenomas. In the first Aim, we will study mechanisms underlying pituitary aneuploidy, premature proliferative arrest (senescence), markers of cell proliferation and tumorigenesis in transgenic models of murine pituitary tumors (1GSU.PTTG and Rb heterozygotes). Mechanisms for both genetic and hormonally induced pituitary tumorigenesis will be studied in these genotypes and in pituitary cell cultures. In the second Aim we will study DNA damage, cellular markers of aneuploidy and senescent mediators in human pituitary tumors. In the third Aim we will study mechanisms for Rb/E2F induction of pituitary tumors by assessing E2F1 induction of Pttg transcription and protein expression in Rb mice, in mutant human cancer cells devoid of p53 or p21, as well as in human pituitary adenomas. Results of these experiments will enable further insights into the role of cell cycle control and growth constraint of experimental and human pituitary tumors, underlying their failure to progress to malignancy. The results will improve our understanding of clinical endocrine syndromes associated with infertility, growth disorders, hypercortisolism or adrenal, thyroid and gonadal failure due to abrogated pituitary function.