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.
|Weinberg, D S; So, C; Ruggeri, B et al. (2000) Human cholecystokinin-A receptor is not an oncofetal protein. Dig Dis Sci 45:538-43|
|Weinberg, D S; Ruggeri, B; Barber, M T et al. (1997) Cholecystokinin A and B receptors are differentially expressed in normal pancreas and pancreatic adenocarcinoma. J Clin Invest 100:597-603|