The investigator's long term objectives are to understand the molecular biology of pancreatic cancer and apply this knowledge to patient care. The central hypothesis of this proposal is that the gastrointestinal hormone, cholecystokinin (CCK), which is trophic for normal pancreatic tissue in animal models is also trophic for pancreatic cancer. The effects of CCK have been studied extensively in animal models and in isolated acinar cell preparations. In these experimental models, CCK promotes growth and production of pancreatic enzymes by a sequence of intracellular event that release cytosolic calcium after receptor binding. Receptors for CCK have been described not only in normal pancreatic acinar cells but also in some pancreatic cancers. Since human pancreatic cancer is of ductal origin (rather than acinar) and does not secrete enzymes, the presence and purpose of CCK receptors on pancreatic cancer cells is uncertain. Post-receptor binding vent which play an integral role in cell proliferation have not been examined in pancreatic cancer cells. Recent studies from the investigator's laboratory indicate that CCK promotes growth of human pancreatic cancer. It is proposed to determine the role of CCK on growth of human pancreatic cancer as follows: 1) characterize the effects of CCK and CCK-receptor antagonists on growth of several human pancreatic tumor lines in vivo by analyzing tumor volume, weight, protein and DNA content in nude mice bearing a pancreatic cancer xenograft) and in vitro (by measuring cell numbers, cell protein products, and DNA synthesis in cultured cells); 2) evaluate the presence, kinetics, and concentration of CCK receptors on pancreatic cancer cell lines and how these correlate with growth; 3) evaluate the intracellular messenger(s) by which CCK has its effect by defining receptor-mediated changes in calcium concentration, cellular pH, and cAMP production. These studies should define the cellular mechanisms by which CCK influences growth of pancreatic cancer. The results may have therapeutic potential in the treatment of pancreatic cancer in human subjects by hormonal manipulation.
