ETIOLOGY OF ESTROGEN-INDUCED PROLACTIN TUMORS

雌二醇(E_2)诱导的催乳素瘤的发生发展涉及细胞 哺乳细胞分裂，毛囊形态变化- 星状细胞(FSC)与直接动脉血的发育 供给。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作用 雌激素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Fisher 344上测试这一假设 对雌二醇致癌作用极为敏感的大鼠 以及相对不敏感的SpragueDawley大鼠。雌二醇会 单独使用或与DA拮抗剂联合使用 三氟拉嗪或激动剂溴麦角隐亭(CB154)。FSC包含 大量碱性成纤维细胞生长因子(BFGF)并显示 Fisher 344治疗后的形态变化 雌二醇组大鼠。我们将确定在肿瘤形成过程中 通过测量碱性成纤维细胞生长因子的含量来增加碱性成纤维细胞生长因子的产量。 通过RIA和mRNA通过Northern印迹杂交或通过bFGF活性通过 测定成纤维细胞生长因子受体的数量和亲和力。地点： 碱性成纤维细胞生长因子的产生将通过免疫细胞化学来确定。我们会 确定FCS是否也会产生大量的蛋白水解物 肿瘤中的酶、纤溶酶原激活物和IV型胶原酶 队形。这些酶是组织的重要组成部分。 重塑是肿瘤生长所必需的，可能是一种 碱性成纤维细胞生长因子的释放滞留在基底膜。第三，我们 将决定原癌基因的表达是否与Key相关 AP中的调控过程在不同阶段增加 肿瘤的形成。将确定INT-2和INT-2的mRNA水平 HST与成纤维细胞生长因子以及erb-B有相当大的同源性， SIS、Ha-ras、N-ras、Ki-ras、fos和myc。蜂窝站点 癌基因的表达将通过免疫细胞化学来确定。 最后，我们最近发现催乳素的16K片段 (PRL)抑制内皮细胞的生长。我们将确定是否 16K 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16K催乳素是否能抑制产生的E2的生长 Fisher 344大鼠的催乳素瘤和Wistar Furth大鼠的GH3肿瘤 7315a在雌性水牛大鼠体内的肿瘤。这些研究将 增加我们对细胞病变的机制和部位的了解 雌激素在肿瘤形成中的作用。使用16K PRL的研究可能会导致 致力于开发一类新的治疗血管溶解药物 癌症的威胁。

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.