vasoactive-intestinal-peptide and Uterine-Neoplasms

Histopathological and experimental observations indicate that tumors composed wholly or in part of neuroendocrine elements may arise in tissues derived from ectoderm (including neuroectoderm), mesoderm, and endoderm. These tumors frequently exhibit multidirectional differentiation as manifested by multihormonality and by the presence of morphological features indicative of divergent differentiation both in vivo and in vitro. The existence of stem cells, plasticity of differentiated cells, microenvironmental influences, and random events are factors which might all interact to determine the characteristics of any particular tumor. The production of characteristic regulatory peptide products in association with tumors of specific histological subtypes and with other neuroendocrine markers suggests mechanisms for nonrandom activation of multiple genes common to neuroendocrine-programmed cells. Future studies applying new molecular biological techniques to intact tissues and to in vitro models may help to clarify the mechanisms that regulate the expression of the neuroendocrine phenotype in normal and neoplastic states.

Topics: Adrenal Gland Neoplasms; Animals; Apudoma; Calcitonin; Carcinoid Tumor; Cricetinae; Female; Gastrins; Hormones, Ectopic; Humans; Neurotensin; Ovarian Neoplasms; Pancreatic Neoplasms; Pheochromocytoma; Rats; Somatostatin; Thyroid Neoplasms; Uterine Neoplasms; Vasoactive Intestinal Peptide

Expression of the human chorionic gonadotropin (hCG)-alpha gene in placental trophoblasts is markedly stimulated by cAMP, a property preserved in a reporter plasmid containing its cAMP response elements (CREs) linked to the chloramphenicol acetyltransferase coding sequence (CRE alpha CAT). In search of a potential physiologic regulator of hCG gene expression via cAMP, we found that JEG-3 syncytial trophoblast cells have specific binding sites for vasoactive intestinal peptide (VIP) with dissociation constant of 1 nM. VIP maximally increased the transient expression of CRE alpha CAT and the expression of endogenous hCG-alpha mRNA in JEG-3 cells by 4- and 9-fold, respectively. Exposure of JEG-3 cells to 30 nM VIP increased cAMP levels 60-fold after 10-30 min, but cAMP rapidly declined thereafter. As a consequence of this desensitization, the effect of VIP on stimulation of both CRE alpha CAT and endogenous hCG-alpha and hCG-beta mRNA levels more closely resembled that of forskolin or 8-br-cAMP at time points much less than 24 h. Moreover, transient exposure to 8-br-cAMP was much less effective than 24 h of continuous incubation on CRE alpha CAT activity. We conclude that VIP rapidly increases cAMP content and activates hCG-alpha gene expression in JEG-3 cells, but sustained elevations in cAMP are necessary for maximal accumulation of this CRE-regulated gene product.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Binding, Competitive; Cell Line; Chloramphenicol O-Acetyltransferase; Choriocarcinoma; Colforsin; Cyclic AMP; Female; Gene Expression; Glycoprotein Hormones, alpha Subunit; Hormones; Humans; Kinetics; Pregnancy; Receptors, Gastrointestinal Hormone; Receptors, Vasoactive Intestinal Peptide; RNA, Messenger; Transfection; Uterine Neoplasms; Vasoactive Intestinal Peptide