CHOLECYSTOKININ AND THE PATHOGENESIS OF PANCR

胰腺癌是癌症死亡的第五大原因， 美国的 这种恶性肿瘤的病因在很大程度上是未知的。 因为唯一被普遍接受的风险因素是男性，年龄较大 和吸烟，没有办法筛选或识别个人， 存在高风险。 越来越多的动物和人类证据表明， 胃肠激素胆囊收缩素（CCK）在 这种疾病的发病机制。 所描述的研究项目将 测试两个假设来解释CCK与人类之间的关联 胰腺癌：（1）血清CCK水平升高， 胰腺癌（2）CCK的定性和定量差异 受体表达存在于新鲜切除的，恶性的与正常的相比， 胰腺组织 这项研究产生的结果可能有 在胰腺癌筛查、诊断 治疗和预后水平。 已知CCK是正常和非正常细胞生长中的重要介质， 胰腺恶性肿瘤 给予外源性CCK的动物研究 或通过膳食添加剂、胆盐结合 药物或手术转移都有胰腺增生的记录， 发育异常和产生明显的恶性肿瘤。 类似的实验 胰腺肿瘤诱导后，报告生长加速， 对CCK有反应，相对于未受累组织为恶性。 人 癌细胞系和异种移植的人类肿瘤，CCK已被证明， 促进恶性肿瘤的生长。 在受体水平上，CCK-A和CCK-B受体最近已被发现。 克隆并鉴定。 在动物研究中， CCK-B受体和CCK-A受体过度表达在恶性肿瘤中的作用 与正常胰腺相比。 更有限的人类研究已经无法 为了证明CCK-A受体在癌细胞系上的表达， 而CCK-B受体已在一些癌细胞系上被报道。 拟议的两部分项目将首次解决以下问题： 胆囊收缩素在胰腺癌发病中的作用 第1部分是 冠心病患者空腹及餐后血清胆囊收缩素水平的病例对照研究 胰腺癌患者和适当的对照组。 案件将 通过全面运作的4家医院网络进行识别， 包括2个NCI指定的癌症中心和2个大型社区医院。 胰腺癌年发病100-150例 有望 由于患者人群异常丰富， 还将收集许多其他胰腺癌风险因素。 第2部分 CCK受体的定性和定量表达 新鲜切除的正常和恶性人胰腺组织上的mRNA。 将使用CCK-A和CCK-B受体进行北方印迹分析 衍生的cDNA。 如果发现差异表达， 胰腺腺泡或导管细胞将通过自显影进行研究。

Pancreatic adenocarcinoma is the fifth leading cause of cancer death in the United States. The etiology of this malignancy is largely unknown. Because the only commonly accepted risk factors are male sex, older age and smoking, no methods for screening or identification of individuals at high risk exist. There is growing animal and human evidence to suggest an important role for the gastrointestinal hormone, cholecystokinin (CCK), in the pathogenesis of this disease. The research project described will test two hypotheses to explain the association between CCK and human pancreatic carcinoma: (1) serum levels of CCK are elevated in persons with pancreatic cancer (2) qualitative and quantitative differences in CCK receptor expression exist on freshly excised, malignant compared to normal pancreatic tissue. The findings generated by this study may have applications to pancreatic cancer at the screening, diagnostic, therapeutic and prognostic levels. CCK is known to be an important mediator in the growth of both normal and malignant pancreas. Animal studies which either administer exogenous CCK or manipulate endogenous CCK through dietary additives, bile salt binding drugs or surgical diversion have all documented pancreatic hyperplasia, dysplasia and the production of frank malignancy. Similar experiments after the induction of pancreatic tumors, report the accelerated growth, in response to CCK, of malignant relative to uninvolved tissue. In human cancer cell lines and xenografted human tumors, CCK has been shown to promote the growth of malignancy. At the receptor level, the CCK-A and CCK-B receptors have recently been cloned and characterized. In animal studies, there is novel expression of the CCK-B receptor and overexpression of the CCK-A receptor on malignant compared to normal pancreas. More limited human studies have been unable to demonstrate expression of the CCK-A receptor on cancer cell lines, while the CCK-B receptor has been reported on some cancer cell lines. The proposed two part project will address for the first time the role of CCK in the pathogenesis of human pancreatic adenocarcinoma. Part 1 is a case-control study of fasting and post-prandial serum CCK levels in patients with pancreatic cancer and in appropriate controls. Cases will be identified through a fully operational 4 hospital network which includes 2 NCI designated Cancer Centers and 2 large community hospitals. The annual accrual of 100-150 incident cases of pancreatic adenocarcinoma is expected. Because of the unusually rich patient population, data on many other pancreatic cancer risk factors will also be collected. Part 2 will study the qualitative and quantitative expression of CCK receptor mRNA on freshly excised normal and malignant human pancreatic tissue. Northern blot analyses will be performed using CCK-A and CCK-B receptor derived cDNA. If differential expression is found, receptor localization to pancreatic acinar or ductal cells will be investigated by autography.