The gastrointestinal peptides cholecystokinin (CCK) and gastrin have been implicated in a variety of functions including secretion of gastric and pancreatic juices, satiety, and growth of the gastrointestinal tract. Apart from their role in the regulation of proliferation of normal tissues, CCK and gastrin have been shown to be important growth factors for several neoplasms. Studies from the investigator's laboratory indicate that both CCK and gastrin stimulate growth of human pancreatic cancer cells by interacting with cellular CCK-B/gastrin-like receptors. Preliminary results suggest that the receptor involved in CCK and gastrin- stimulated growth of human pancreatic cancer may be unique since it has several characteristics which differ from the CCK receptors of normal tissues. Unlike the previously described CCK receptors, the receptor identified in human pancreatic cancer has a 50 fold greater affinity for gastrin than CCK, and gastrin is a more potent stimulator of cellular proliferation. CCK does not increase cytosolic calcium after receptor binding in pancreatic cancer cells, like normal animal pancreatic cells, suggesting that either the growth effects of CCK and gastrin are mediated through a unique receptor, or that the signal transduction for growth in cancer cells differs from that described on normal cells. Recently, the investigator has discovered the presence of gastrin immunoreactivity and CCK and gastrin mRNA in human pancreatic cancer cells suggesting that human pancreatic cancer cells may be under growth regulation by gastrin and CCK. Based on these findings, it is hypothesized that growth of human pancreatic cancer is modulated by CCK and gastrin through a unique cellular receptor. In order to test this hypothesis, it is proposed to 1) examine the autocrine production of gastrin and CCK in human pancreatic cancer by performing immunocytochemistry, radioimmunoassay, measurement of peptide gene expression, and examining growth effects of antagonists, 2) define the uniqueness of the CCK-B/gastrin-like receptor in human pancreatic cancer by examining its cellular location, binding characteristics, intracellular signalling pathways, and evaluating its gene expression, 3) Examine the regulatory properties of the CCK/gastrin : receptor system, and 4) examine the similarities and differences of this system with fresh human tissues, benign and malignant. These studies are part of our long term goals to understand the role of peptide growth factors in pancreatic cancer. These results may have therapeutic potential in either the treatment or early detection of pancreatic cancer.
| Smith, J P; Verderame, M F; Zagon, I S (1999) Antisense oligonucleotides to gastrin inhibit growth of human pancreatic cancer. Cancer Lett 135:107-12 |
| Smith, J P; Hamory, M W; Verderame, M F et al. (1998) Quantitative analysis of gastrin mRNA and peptide in normal and cancerous human pancreas. Int J Mol Med 2:309-15 |
| Smith, J P; Stock, E A; Wotring, M G et al. (1996) Characterization of the CCK-B/gastrin-like receptor in human colon cancer. Am J Physiol 271:R797-805 |
| Smith, J P; Shih, A; Wu, Y et al. (1996) Gastrin regulates growth of human pancreatic cancer in a tonic and autocrine fashion. Am J Physiol 270:R1078-84 |
