The gastrointestinal
peptide cholecystokinin (CCK) causes the release of pancreatic digestive
enzymes and growth of the normal pancreas. Exogenous CCK administration has been used in animal models to study
pancreatitis and also as a promoter of
carcinogen-induced or Kras-driven
pancreatic cancer. Defining
CCK receptors in normal human pancreas has been problematic because of its retroperitoneal location, high concentrations of pancreatic
proteases, and endogenous
RNase. Most studies indicate that the predominant receptor in human pancreas is the CCK-B type, and CCK-A is the predominant form in rodent pancreas. In
pancreatic cancer cells and
tumors, the role of CCK is better established because receptors are often overexpressed by these
cancer cells and stimulation of such receptors promotes growth. Furthermore, in established
cancer, endogenous production of CCK and/or
gastrin occurs and their actions stimulate the synthesis of more receptors plus growth by an autocrine mechanism. Initially it was thought that the mechanism by which CCK served to potentiate
carcinogenesis was by interplay with
inflammation in the pancreatic microenvironment. But with the recent findings of
CCK receptors on early PanIN (pancreatic intraepithelial
neoplasia) lesions and on stellate cells, the question has been raised that perhaps CCK actions are not the result of
cancer but an early driving promoter of
cancer. This review will summarize what is known regarding CCK, its receptors, and
pancreatic cancer, and also what is unknown and requires further investigation to determine which comes first, the chicken or the egg, "CCK or the
cancer."