ETIOLOGY OF ESTROGEN-INDUCED PROLACTIN TUMORS

雌二醇（E2）诱导的催乳素瘤的发生涉及细胞 催乳细胞的分裂，卵泡的形态变化， 星状细胞（FSC）和直接动脉血的发育 供应 我们假设这些变化是由直接的 E2在不同靶点的作用以及间接的 E2抑制下丘脑多巴胺能（DA）调节的作用。 我们将在两个品系的大鼠中检验这一假设， 对E2的致瘤作用极其敏感的大鼠 和相对不敏感的Sprague-Dawley大鼠 E2将 单独或与DA拮抗剂联合给药 三氟拉嗪或激动剂溴麦角隐亭（CB 154）。 FSC包含 大量碱性成纤维细胞生长因子（bFGF）并显示 Fisher 344处理后的显著形态学变化 大鼠E2 我们将确定在肿瘤形成过程中 通过测量bFGF含量， 通过RIA和mRNA通过北方印迹杂交或bFGF活性通过 测量FGF受体的数量和亲和力。 部位 将通过免疫细胞化学测定bFGF的产生。 我们将 确定FCS是否也产生大量的蛋白水解， 酶、纤溶酶原激活剂和IV型胶原酶 阵 这些酶是组织的重要组成部分 重塑是肿瘤生长所必需的，也可能是 基底膜上bFGF的释放。 三是 将决定是否表达原癌基因相关的关键 AP中的调节过程在各个阶段增加 肿瘤的形成。 将测定int-2和int-3的mRNA水平。 hst与FGF以及erb-B具有相当大的同源性， sis、Ha-ras、N-ras、Ki-ras、fos和myc。 细胞部位 通过免疫细胞化学测定癌基因表达。 最后，我们最近发现催乳素的16 K片段 (PRL)抑制内皮细胞的生长。 我们将确定是否 16 K PRL的产生和受体在肿瘤形成过程中发生变化。 我们还将测试16 K PRL是否能抑制产生的E2的生长， Fisher 344大鼠中的泌乳素瘤，Wistar Furth大鼠中的GH 3肿瘤 和雌性布法罗大鼠的7315 a肿瘤。 这些研究将 增加我们对机制和细胞位点的理解， E2在肿瘤形成中的作用 16 K PRL的研究可能导致 开发出一种新的血管溶解药物 癌症。

Development of estradiol: (E2) induced prolactinomas involves cell division of lactotrophs, morphological changes in folliculi- stellate cells (FSC) and development of a direct arterial blood supply. We hypothesize that these changes are caused by direct actions of E2 at various target sites as well as the indirect actions of E2 to inhibit hypothalamic dopaminergic (DA) regulation. We will test this hypothesis in two strains of rats, Fisher 344 rats that are extremely sensitive to the tumorogenic action of E2 and Sprague-Dawley rats that are relatively insensitive. E2 will be administered alone or in combination with the DA antagonist trifluoperazine or agonist bromoergocryptine (CB154). FSC contain large amounts of basic fibroblast growth factor (bFGF) and show dramatic morphological changes following treatment of Fisher 344 rats with E2. We will determine whether during tumor formation there is an increase in bFGF production by measuring bFGF content by RIA and mRNA by northern blot hybridization or bFGF activity by measuring the number and affinity of FGF receptors. The site of bFGF production will be determined by immunocytochemistry. We will determine if FCS also produces large amounts of the proteolytic enzymes, plasminogen activator and type IV collagenase during tumor formation. These enzymes are an important component of tissue remodeling necessary for tumor growth and possibly a mechanism for the release of bFGF sequestered in basement membrane. Thirdly, we will determine if the expression of proto-oncogenes related to key regulatory processes in the AP is increased during various stages of tumor formation. mRNA levels will be determined for int-2 and hst which have considerable homology with FGF as well as erb-B, sis, Ha-ras, N-ras, Ki-ras, fos and myc. Cellular sites of oncogene expression will be determined by immunocytochemistry. Lastly, we have recently shown that the 16K fragment of prolactin (PRL) inhibits growth of endothelial cells. We will determine if 16K PRL production and receptors change during tumor formation. We will also test whether 16K PRL can inhibit growth of E2 produced prolactinomas in Fisher 344 rats, GH3 tumors in Wistar Furth rats and 7315a tumors in female Buffalo rats. These studies will increase our understanding of the mechanisms and cellular sites of action of E2 in tumor formation. Studies with 16K PRL could lead to the development of a new class of angiolytic drugs for treatment of cancer.