cholecystokinin and Biliary-Tract-Neoplasms

The gut hormone cholecystokinin exerts various actions on the gastrointestinal tract, including the regulation of growth. The hormone has been reported to induce hypertrophy and hyperplasia of the pancreas and to enhance chemically-induced pancreatic carcinogenesis in animals. Stimulation of endogenous cholecystokinin secretion through the induction of deficiency of intraintestinal proteases and bile salts by trypsin-inhibiting nutrients, bile salt-binding drugs or surgical intervention is also capable of stimulating growth and tumour development in the rat. In man, factors suggested to increase the risk of pancreatic cancer, such as a high-fat and high-protein diet or gastrectomy, are known to stimulate plasma cholecystokinin secretion. Receptors for cholecystokinin have been demonstrated on human pancreatic adenocarcinomas, and cholecystokinin has been demonstrated to enhance the growth of xenografted pancreatic cancer and to inhibit growth of gastric and bile duct cancer. The recently developed cholecystokinin-receptor antagonists inhibit not only pancreatic growth but also pancreatic carcinogenesis in animals. These new drugs may be valuable new tools for inhibiting pancreatic cancer growth in humans.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Biliary Tract Neoplasms; Cholecystokinin; Gastrointestinal Neoplasms; Humans; Pancreatic Neoplasms

Altered motility of the gallbladder is associated with an increased risk of gallstones and can result in biliary tract cancers. Cholecystokinin (CCK) is an important modulator of gallbladder motility which functions by activating CCK type-A receptor (CCKAR). The aim of this study was to determine whether genetic variants in CCK and CCKAR are associated with the risk of biliary tract cancers and stones.. We investigated the associations between nine single nucleotide polymorphisms in CCK and CCKAR in a population-based case-control study, including 439 biliary tract cancer cases (253 gallbladder, 133 extrahepatic bile duct, and 53 ampulla of Vater cancer cases), 429 biliary stone cases, and 447 population controls in Shanghai, China.. We found that women with the CCKAR rs1800855 AA genotype had an increased risk of gallbladder cancer (odds ratio = 2.37, 95% confidence interval (CI): 1.36-4.14) compared with subjects with the TT genotype, and remained significant after Bonferroni correction (P = 0.0056). Additionally, female carriers of the CCKAR haplotype C-T-C-T (rs2071011-rs915889-rs3822222-rs1800855) had a reduced risk of gallbladder cancer (odds ratio = 0.61, 95% confidence interval: 0.43-0.86) compared with those with the G-C-C-A haplotype; the association also remained significant after Bonferroni correction.. These findings suggest that variants in the CCKAR gene may influence the risk of gallbladder cancer in women. Additional studies are needed to confirm our findings.

Topics: Adult; Aged; Biliary Tract Neoplasms; Case-Control Studies; China; Cholecystokinin; Female; Gallstones; Genetic Predisposition to Disease; Genotyping Techniques; Haplotypes; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Receptor, Cholecystokinin A; Risk Assessment; Sex Factors

To investigate the effects of gastrin and cholecystokinin (CCK) and their specific antagonists on the growth of pancreatic and biliary tract cancer cell lines.. Five pancreatic and 6 biliary cancer cell lines with 2 conrtol cells were used in this study. Cell proliferation study was done using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) test and direct cell count method. Reverse transcription-polymerase chain reaction (RT-PCR) and slot blot hybridization were performed to examine and quantify the expression of hormonal receptors in these cell lines.. SNU-308 showed a growth stimulating effect by gastrin-17, as did SNU-478 by both gastrin-17 and CCK-8. The trophic effect of these two hormones was completely blocked by specific antagonists (L-365, 260 for gastrin and L-364, 718 for CCK). Other cell lines did not respond to gastrin or CCK. In RT-PCR, the presence of CCK-A receptor and CCK-B/gastrin receptor mRNA was detected in all biliary and pancreatic cancer cell lines. In slot blot hybridization, compared to the cell lines which did not respond to hormones, those that responded to hormones showed high expression of receptor mRNA.. Gastrin and CCK exert a trophic action on some of the biliary tract cancers.

Topics: Biliary Tract Neoplasms; Cell Count; Cell Division; Cell Line, Tumor; Cholecystokinin; Gastrins; Hormone Antagonists; Humans; Pancreatic Neoplasms; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Reverse Transcriptase Polymerase Chain Reaction; Tetrazolium Salts; Thiazoles

The aim of this study was to examine whether the type of bilioenterostomy enhances biliary carcinogenesis in the hamster model. Syrian hamsters were divided into the following groups; simple laparotomy (control group), cholecystoduodenostomy with dissection of the extrahepatic bile duct on the distal end of the common duct (CDDB group) and cholecystoileostomy with dissection of the extrahepatic bile duct on the distal end of the common duct (CIDB group). Following these procedures, all hamsters received N-nitrosobis(2-oxopropyl)amine. The diameter of the extrahepatic bile duct and plasma levels of cholecystokinin (CCK) were measured and the number of neoplastic lesions was counted microscopically. Proliferative effect of the procedures on the biliary epithelium was examined by proliferative cell nuclear antigen. In the CDDB group the extrahepatic bile duct was significantly dilated and carcinogenesis of the gall-bladder and extrahepatic bile ducts was enhanced. In the CIDB group the CCK bioactivity was stimulated and intrahepatic biliary duct, but not gall bladder and extrahepatic bile duct, carcinogenesis was promoted more than that observed in the CDDB group. Proliferation of the biliary duct epithelium was enhanced in both the CDDB and CIDB groups. Cholecystoduodenostomy enhanced intra- and extrahepatic bile duct carcinoma, whereas cholecystoileostomy promoted only intrahepatic bile duct carcinoma. Some factors in the intestinal juice seem to play a role in the promotion of biliary tract carcinoma.

Topics: Animals; Bile Duct Neoplasms; Bile Ducts; Bile Ducts, Extrahepatic; Biliary Tract; Biliary Tract Neoplasms; Carcinogens; Carcinoma, Papillary; Cell Division; Cholecystokinin; Cricetinae; Epithelium; Female; Gallbladder; Gallbladder Neoplasms; Ileum; Mesocricetus; Nitrosamines; Proliferating Cell Nuclear Antigen

Gastrointestinal hormones regulate growth of cancers as well as normal tissues. We investigated whether long-term cholecystokinin (CCK) administration might affect growth or metabolism of human tumors xenografted in nude mice. In each experiment, approximately 20 nude mice bearing subcutaneous xenografts of the particular cancer line being studied were used. Half received CCK and half received saline solution intraperitoneally twice daily for 14 days. Tumor volume and body weight were measured every 3 days. If the tumors produced marker substances, these were measured in nude mouse serum and also in the xenografts. Tumor growth was significantly retarded by CCK in two of the six cancers studied. In each case, DNA, RNA, and protein reflected tumor volumes. In one of these tumors (SLU 077), serum carcinoembryonic antigen (CEA) levels paralleled the tumor volumes. In another tumor (SLU 132), serum CEA levels and tumor immunolabeling for CEA and pancreatic oncofetal antigen increased in response to CCK administration, whereas tumor volumes did not. These findings suggest that exogenous highdose CCK altered the growth and metabolism in two of six human cancers studied.

Topics: alpha-Fetoproteins; Animals; Antigens, Neoplasm; Biliary Tract Neoplasms; Biomarkers, Tumor; Carcinoembryonic Antigen; Cell Line; Cholecystokinin; Gastrointestinal Neoplasms; Humans; Liver Neoplasms; Male; Mice; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms; Stomach Neoplasms

The influence of intraduodenal bile deficiency due to chronic bile duct obstruction and acute exogenous administration of bile acids on plasma cholecystokinin (CCK) and pancreatic polypeptide (PP) was investigated. Fourteen patients with tumor-induced bile duct stenosis and five healthy volunteers were given a liquid test meal. Four of the patients had a simultaneous pancreatic duct stenosis. On another day 4 g chenodeoxycholic acid were administered concomitantly with the liquid test meal in six of the patients and all controls. Basal and meal-stimulated plasma CCK did not differ between patients and controls. A pancreatic duct stenosis, which was associated with diminished plasma PP concentrations, had no influence on plasma CCK release. Exogenous bile acids significantly reduced the postprandial CCK response in both groups. Bile-induced inhibition was significantly greater in patients than in controls (75 +/- 7% and 44 +/- 11%, respectively; p less than 0.05). It is concluded that intraduodenal bile is an important modulator of the postprandial secretory activity of the CCK cell. Although chronic intraduodenal bile acid reduction in tumor-induced biliary duct stenosis did not influence plasma CCK levels, a negative feedback control of plasma CCK by acute bile acid administration could be demonstrated.

Topics: Adult; Aged; Bile Acids and Salts; Biliary Tract Neoplasms; Cholecystokinin; Cholestasis; Feedback; Gallbladder Neoplasms; Humans; Middle Aged; Pancreatic Neoplasms; Pancreatic Polypeptide

Topics: Biliary Tract Neoplasms; Carcinoembryonic Antigen; Chemistry, Clinical; Cholecystokinin; Cost Control; Humans; Research Design