Studies of Normal and Neoplastic Human Pituitaries

垂体瘤与大量激素分泌过多和/或中枢神经系统占位性病变有关。调节人类垂体瘤生长的机制知之甚少。最近的研究表明，垂体腺瘤是单克隆的，并且在这些肿瘤中存在一些特定的遗传改变。然而，很少有人知道垂体瘤生长的调节，为什么只有少数这些肿瘤成为恶性，这通常导致病人的死亡，尽管积极的治疗。我们的实验室最近开发了人垂体细胞系永生化与复制缺陷型重组人腺病毒，应提供稳定的细胞系的许多拟议的研究。我们计划使用细胞和分子生物学方法来研究调节垂体生长和肿瘤进展的机制。初步研究表明，垂体细胞内PC 1/3和PC 2加工的嗜铬粒蛋白的蛋白水解产物胰蛋白酶抑制剂对垂体瘤细胞具有自分泌和旁分泌调节作用。我们的初步研究还表明胰蛋白酶抑制剂在体外抑制细胞增殖。将探讨可能解释p27对垂体瘤发生和进展的一些影响的单倍体不足范例。本实验室首次发现垂体前叶细胞产生和分泌瘦素。我们还注意到，瘦素栖息计划研究瘦素在垂体中的作用机制。具体目标包括：一、确定嗜铬粒蛋白/分泌粒蛋白蛋白水解产物和神经内分泌特异性前转化酶在垂体瘤生长和分化中的作用。二.确定特定细胞周期抑制剂在垂体瘤发生中的作用。a.探讨p27基因表达在垂体瘤发生发展中的调控机制。B.确定p16甲基化在垂体瘤发生中的作用。三.研究瘦素、瘦素受体、STAT和SOCS蛋白在垂体瘤发生和发展中的作用。从这些研究中获得的信息应该提供深入了解垂体瘤的病理生物学，并导致更有效的治疗方式。

Pituitary neoplasms are associated with a great deal off morbidity of excessive hormone production and/or as space occupying lesions in the central nervous system. The mechanisms regulating pituitary tumor growth in humans are poorly understood. Recent studies have shown that pituitary adenomas are monoclonal and that some specific genetic alterations are present in these tumors. However, very little is known about the regulation of the pituitary tumor growth and why only few of these neoplasms become malignant, which usually leads to the patient's demise in spite of aggressive treatment. Our laboratory has recently developed human pituitary cell lines immortalized with a replication-defective recombinant human adenovirus which should provide stable cell lined for many of the proposed studies. We plan to examine the mechanisms regulating pituitary growth and tumor progression using cell and molecular biological approaches. Preliminary studies indicate that pancreastain, a proteolytic product of chromogranin, which is processed by PC 1/3 and PC 2 in pituitary cells, has autocrine and paracrine regulatory functions on pituitary tumor cells. Our preliminary studies also showed that pancreastain inhabits cell proliferation in vitro. The haploid insufficiency paradigm will be explored to possibly explain some of the effects of p27 on pituitary tumor development and progression. Our laboratory was the first to discover leptin production and secretion by anterior pituitary cells. We also noted that leptin inhabit plan to examine the mechanism of leptin action in the pituitary. The specific aims include: I. Determine the role of chromogranin/secretogranin proteolytic products and neuroendocrine-specific proconvertases in pituitary tumor growth and differentiation. II. Determine the role of specific cell cycle inhibitors in the development of pituitary tumors. a. Examine the mechanism regulating p27 expression in pituitary tumor development and progression. b. Determine the role of p16 methylation in pituitary tumor development. III. Examine the role of leptin, leptin receptors, STAT and SOCS proteins in pituitary tumor development and progression. The information derived from these studies should provide insight into the pathobiology of pituitary tumors and lead to more effective treatment modalities.