Role of Somatostatin Receptors in Pancreatic Cancer

生长抑素受体在胰腺癌中的作用

基本信息

批准号：
6327145
负责人：
WILLIAM E FISHER
金额：
$ 13.3万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-07-01 至 2004-06-30
项目状态：
已结题

项目摘要

D E S CRIPTION: (provided by Applicant) The incidence of pancreatic adenocarcinoma has increased in recent decades and the prognosis for patients with this disease remains poor. New information about the pathogenesis of pancreatic cancer that has translational potential would be of great medical and economic importance. Cell culture and animal studies suggest that somatostatin can inhibit pancreatic cancer growth if the tumor cells express somatostatin receptors. Despite these promising results, recent clinical trials of somatostatin analogs as adjuvant treatment of pancreatic cancer have failed because most pancreatic cancer cells do not express somatostatin receptors. This application is centered on the hypothesis that functional somatostatin receptors maintain normal homeostasis within pancreatic cells and loss of these receptors is a critical step in pancreatic carcinogenesis. Three specific aims will test this hypothesis by carefully defining both the mechanisms of somatostatin receptor loss and function in several experimental models. The first specific aim will, for the first time, carefully demonstrate the lack of expression of specific somatostatin receptor subtypes at both the mRNA and protein level in clinical samples of human pancreatic cancer and preneoplastic lesions. The molecular mechanisms responsible for somatostatin receptor gene silencing will be discovered. The second aim will correlate the loss of somatostatin receptor expression to tumorigenicity in experimental models of pancreatic carcinogenesis. These experiments will be performed on cultured pancreatic cells and in an animal model. In vitro studies will examine multiple time points during carcinogen exposure for transformation and tumorigenicity while serial sacrifices of exposed animals will capture the progressive development of pancreatic cancer. The third aim will determine which somatostatin receptor subtypes are important in the inhibition of pancreatic cancer growth. Each somatostatin receptor gene will be individually transfected into a human pancreatic cancer cell line that lacks somatostatin receptors. Effects on growth and responsiveness to somatostatin will be determined using tissue culture and xenografts in nude mice. The molecular mechanisms responsible for the growth inhibitory signal of each receptor subtype in human pancreatic cancer will be determined. The aims outlined in this application will discover a novel aspect of pancreatic carcinogenesis. Gene therapy to restore the responsiveness of pancreatic cancer to somatostatin analogs by somatostatin receptor gene transfer may become possible from the knowledge gained in these experiments. Since somatostatin expression has been demonstrated in other tumor types, the findings may also be relevant to other cancers.

d e s cription ：（由申请人提供）胰腺的发生率腺癌近几十年来增加了，患者的预后这种疾病仍然很差。有关发病机理的新信息具有转化潜力的胰腺癌将具有很大的医疗和经济重要性。细胞培养和动物研究表明如果肿瘤细胞表达，生长抑素可以抑制胰腺癌生长生长抑素受体。尽管这些有希望的结果，但最近的临床生长抑素类似物作为胰腺癌的辅助治疗的试验具有失败，因为大多数胰腺癌细胞都不表达生长抑素受体。该应用集中在功能性生长告诉的假设上受体在胰腺细胞中保持正常的稳态，并丧失这些受体是胰腺癌发生的关键步骤。三具体目的将通过仔细定义同时定义生长抑素受体丧失和功能的机制型号。第一个特定目标将首次仔细证明缺乏特定生长抑素受体亚型的表达在人胰腺的临床样品中的mRNA和蛋白质水平上癌症和肿瘤性病变。负责的分子机制生长抑素受体基因沉默将被发现。第二个目标将生长抑素受体表达的丧失与肿瘤性丧失有关胰腺癌发生的实验模型。这些实验将是在培养的胰腺细胞和动物模型上进行。体外研究将检查在致癌期间的多个时间点转化和肿瘤性，而暴露动物的串行牺牲将捕获胰腺癌的逐步发展。第三个目标将确定哪些生长抑素受体亚型在抑制胰腺癌生长。每个生长抑素受体基因将被单独转染到人类胰腺癌细胞系中缺乏生长抑素受体。对增长和响应能力的影响生长抑素将使用组织培养和异种移植在裸体中确定老鼠。负责生长抑制信号的分子机制将确定人类胰腺癌中每个受体亚型的亚型。此应用程序中概述的目的将发现胰腺癌发生。基因治疗以恢复生长抑素受体基因对生长抑素类似物的胰腺癌从这些实验中获得的知识可能可以转移。由于在其他肿瘤类型中已经证明了生长抑素的表达，因此发现也可能与其他癌症有关。