CHOLECYSTOKININ AND THE PATHOGENESIS OF PANCR

年，胰腺癌是导致癌症死亡的第五大原因。 美国。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危险因素是男性，年龄较大 和吸烟，没有筛查或识别个人的方法 存在很高的风险。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 检验两个假设以解释CCK和人类之间的联系 胰腺癌：(1)慢性胰腺炎患者血清CCK水平升高 胰腺癌(2)CCK的定性和定量差异 与正常相比，新切除的恶性组织中存在受体的表达 胰腺组织。这项研究产生的发现可能有 应用于胰腺癌的筛查、诊断、 治疗和预后水平。 CCK是一种重要的调节因子，在正常的和正常的 恶性胰腺。使用外源性CCK的动物研究 或通过饮食添加剂、胆盐结合来操纵内源性CCK 药物或手术转移都证明了胰腺增生， 不典型增生与直肠癌的产生。类似的实验 诱导胰腺肿瘤后，报告生长加速， 对CCK的反应，相对于未受累的组织而言，是恶性的。在人类中 癌细胞系和移植的人类肿瘤，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受体最近被 进行了克隆和鉴定。在动物研究中，有一种新的表达 CCK-B受体与CCK-A受体在恶性肿瘤中的过度表达 与正常胰腺相比。更有限的人体研究一直无法 为了证明CCK-A受体在癌细胞系上的表达， 而CCK-B受体在一些癌细胞株上也有报道。 拟议的两部分项目将首次涉及 CCK在人胰腺癌发病机制中的作用第1部分是 2型糖尿病患者空腹和餐后血清CCK水平的病例对照研究 胰腺癌患者和适当的对照组。案件将会 通过全面运营的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。 100~150例胰腺癌发病病例的年累积率 是意料之中的。由于患者人口异常丰富，数据显示 许多其他胰腺癌风险因素也将被收集。第二部分 将研究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中的mRNA。 Northern印迹分析将使用CCK-A和CCK-B受体 衍生的cDNA.如果发现差异表达，受体定位 对胰腺腺泡细胞或导管细胞进行自体造影术。

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.