cholecystokinin and Ovarian-Neoplasms

Cholecystokinin (CCK)-A and CCK-B/gastrin receptors were evaluated with in vitro receptor autoradiography in 406 human tumors of various origins using a sulfated 125I-labeled CCK decapeptide analogue 125I-(D-Tyr-Gly, Nle28,3l)-CCK 26-33 and 125I-labeled Leu15-gastrin as radioligands. CCK-B/gastrin receptors were found frequently in medullary thyroid carcinomas (92%), in small cell lung cancers (57%), in astrocytomas (65%), and in stromal ovarian cancers (100%). They were found occasionally in gastroenteropancreatic tumors, breast, endometrial, and ovarian adenocarcinomas. They were either not expressed or rarely expressed in colorectal cancers, differentiated thyroid cancers, non-small cell lung cancers, meningiomas, neuroblastomas, schwannomas, glioblastomas, lymphomas, renal cell cancers, prostate carcinomas, and the remaining neuroendocrine tumors (i.e., pituitary adenomas, pheochromocytomas, paragangliomas, and parathyroid adenomas). CCK-A receptors were expressed rarely in tumors except in gastroenteropancreatic tumors (38%), meningiomas (30%), and some neuroblastomas (19%). The identified CCK-A and CCK-B receptors were specific and of high affinity in the subnanomolar range. The rank order of potency of various CCK analogues was: sulfated CCK-8 = L-364,718 >> nonsulfated CCK-8 = L-365,260 > or = gastrin for CCK-A receptors and sulfated CCK-8 > gastrin = nonsulfated CCK-8 > L-365,260 > L-364,718 for CCK-B receptors. CCK-B receptors could also be selectively and specifically labeled with a newly designed nonsulfated 125I-(D-Tyr-Gly, Nle28,31)-CCK 26-33. Gastrin mRNA measured by in situ hybridization was present in most CCK-B receptor-positive small cell lung cancers, breast tumors, and ovarian tumors, representing the molecular basis of a possible autocrine growth regulation of these tumors. Gastrin and CCK mRNAs were lacking in medullary thyroid cancers. Thus, these results may have pathogenic, diagnostic, differential diagnostic, and therapeutic implications.

Topics: Autoradiography; Breast Neoplasms; Carcinoma, Small Cell; Cholecystokinin; Female; Gastrins; Humans; Lung Neoplasms; Neoplasms; Neuroendocrine Tumors; Ovarian Neoplasms; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Sincalide; Thyroid Neoplasms

Gastrin synthesis in ovarian tumors has been described in a few isolated cases associated with the Zollinger-Ellison syndrome. Consequently, ovarian gastrin synthesis has been considered exceptional. In order to evaluate whether expression of gastrin in ovarian tumors indeed is rare, we examined the expression and processing of progastrin in 16 malignant and 5 benign ovarian tumors and 4 normal postmenopausal ovaria. Using a library of sequence specific radioimmunoassays, cleavage by processing-like enzymes, and gel chromatography, we found that one-half of the malignant tumors expressed significant concentrations of amidated gastrins [6.7 +/- 2.7 (SEM) pmol/g; range, 1.4-20.0 pmol/g, n = 7]. The concentrations of glycine-extended gastrins and progastrins were low (0.25 +/- 0.03 and 1.4 +/- 0.4 pmol/g, respectively) but higher than in controls and benign tumors. Chromatography showed that the majority of the bioactive gastrins was unsulfated gastrin-17. The other half of the malignant tumors expressed glycine-extended gastrins and progastrins (0.2 +/- 0.03 and 0.6 +/- 0.1 pmol/g; n = 9), but the amidation of the peptides was impaired (0.1 +/- 0.03 pmol/g). Low concentrations of glycine-extended gastrins and progastrins were detected in the normal ovarian tissues (0.2 +/- 0.05 pmol/g tissue and 0.2 +/- 0.06 pmol/g, respectively, n = 4) and in the benign tumors (0.1 +/- 0.02 pmol/g and 0.5 +/- 0.03 pmol/g; n = 5). Amidated gastrins were undetectable, except in low amounts in a single benign tumor (0.2 pmol/g tissue). The results show that postmenopausal ovaria and neoplastic ovarian tissues express the gastrin gene at peptide level. The synthesis and processing of progastrin increase considerably in malignant tumors.

Topics: Cholecystokinin; Female; Gastrins; Humans; Ovarian Neoplasms; Protein Precursors

Topics: Adult; Aged; Cholecystokinin; Cystadenocarcinoma; Cystadenoma; Enkephalins; Female; Gastrins; Gastrointestinal Hormones; Glucagon; Humans; Middle Aged; Neurotensin; Ovarian Neoplasms; Somatostatin