Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007095 (carcinoid)
 6,990 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To define the molecular changes occurring in endocrine tumours, we have analysed three human endocrine tumours established in our laboratory: BON, a functioning carcinoid tumour from the pancreas; SIM, a nonfunctioning carcinoid of the ileum; and STAN, a pheochromocytoma. A homozygous point mutation of the N-ras gene was identified at codon 61 in BON cells in conjunction with overexpression of N-ras mRNA and protein. BON cells also exhibited increased expression of c-myc and cdc2 kinase mRNA and protein; TGF-beta 1, p53 and retinoblastoma (RB) mRNA and protein levels were decreased. In addition, increased expression of the mdm2 oncogene and both the truncated and the wild-type RB protein were noted in BON. SIM cells exhibited moderately increased N-ras and c-myc mRNA levels along with decreased levels of RB mRNA and protein. Similar to BON and SIM, analysis of STAN showed increased N-ras and c-myc levels. Our data show multiple molecular changes in the three human endocrine tumours with the BON cell line exhibiting the most dramatic changes. Furthermore, our data suggest the existence of different molecular pathways in the pathogenesis of endocrine tumours. These cell lines will provide unique in vitro models to further analyse the significance of these molecular alterations.
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PMID:Analysis of multiple molecular changes in human endocrine tumours. 795 99

Studies of growth-regulation of neuroendocrine cells have been hampered by a lack of suitable in vitro models. We established and have maintained a functioning human pancreatic carcinoid cell (BON) line. BON cells synthesize and secrete several growth factors. Among those, we have found that serotonin stimulates growth of BON cells through specific receptors linked to cyclic AMP pathway. In this study, effects of other growth factors on growth and serotonin release, and the effects of serotonin and TGF-beta 1 on the polyamine biosynthetic pathway, were examined. TGF-beta 1 inhibited both growth and serotonin release in a dose-dependent fashion. Basic FGF stimulated growth, but failed to affect serotonin release. Other peptide growth factors had no effect on either growth or serotonin release. Serotonin stimulated ODC enzyme activity, but TGF-beta 1 failed to affect ODC enzyme activity. These findings suggest that growth of neuroendocrine cells can be delicately regulated by their own products in an autocrine fashion.
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PMID:Studies of growth regulation in a neuroendocrine cell line. 832 53

We have shown recently that 5-HT is an autocrine growth stimulatory factor for a cell line (BON) that is derived from a human pancreatic carcinoid tumor. This action is mediated by a 5-HT receptor-linked decrease of cyclic adenosine monophosphate (AMP) production, but not mediated by a 5-HT receptor-linked stimulation of phosphatidylinositol hydrolysis. The BON cells also express transforming growth factor betas (TGF beta s) (1, 2, and 3) and release TGF beta into their medium. In this study, we examined the effects of TGF beta on the secretion of 5-HT, on signal transduction pathways involved in 5-HT secretion, and on growth of BON cells. TGF beta 1 inhibited basal and acetylcholine-stimulated release of 5-HT, but did not inhibit isobutylmethylxanthine-stimulated release of 5-HT. TGF beta 1 inhibited both basal and acetylcholine-stimulated hydrolysis of phosphatidylinositol in a dose dependent manner, but did not affect cyclic AMP production. TGF-beta 1 inhibited growth of BON cells in culture; this effect was reversed by exogenously administered 5-HT. Three different specific and saturable TGF beta 1 binding sites were identified; binding assays performed after mild acid wash (0.1% acetic acid, pH 2.5) conditions uncovered TGF beta receptors that were apparently occupied by endogenously produced TGF beta species. Affinity cross-linking assay showed that BON cells had three different TGF beta binding proteins. These results suggest that TGF beta 1 can inhibit growth of BON cells by altering secretory responses of 5-HT by means of receptor-mediated inhibition of phosphatidylinositol hydrolysis. We conclude that growth of BON cells is regulated, at least in part, by the opposing receptor-mediated autocrine actions of 5-HT and TGF beta.
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PMID:Novel action of transforming growth factor beta 1 in functioning human pancreatic carcinoid cells. 839 Oct 3

Clinical disorders associated with increased serotonin [5-hydroxytryptamine (5-HT)] levels, such as carcinoid syndrome, and the use of serotonin agonists, such as fenfluoramine have been associated with a valvulopathy characterized by hyperplastic valvular and endocardial lesions with increased extracellular matrix. Furthermore, 5-HT has been demonstrated to up-regulate transforming growth factor (TGF)-beta in mesangial cells via G-protein signal transduction. We investigated the hypothesis that increased exposure of heart valve interstitial cells to 5-HT may result in increased TGF-beta1 expression and activity because of serotonin receptor-mediated signal transduction with activation of Galphaq, and subsequently up-regulation of phospholipase C. Thus, in the present study we performed a clinical-pathological investigation of retrieved carcinoid and normal valve cusps using immunohistochemical techniques to detect the presence of TGF-beta1 and other proteins associated with TGF-beta expression, including TGF-beta receptors I and II, latent TGF-beta-associated peptide (LAP), and alpha-smooth muscle actin. Carcinoid valve cusps demonstrated the unusual finding of widespread smooth muscle actin involving the interstitial cells in the periphery of carcinoid nodules; these same cells were also positive for LAP. Normal valve cusps were only focally positive for smooth muscle actin and LAP. In sheep aortic valve interstitial cell cultures 5-HT induced TGF-beta1 mRNA production and increased TGF-beta1 activity. 5-HT also increased collagen biosynthesis at the dosages studied. Furthermore, TGF-beta1 added to SAVIC cultures increased the production of sulfated glycan and hyaluronic acid. In addition, overexpression of Galphaq using an adenoviral expression vector for a constitutively active Galphaq mutant (Q209L-Galphaq) resulted in increased phospholipase C activity as well as up-regulation of TGF-beta expression and activity. These results strongly support the view that G-protein-related signal transduction is involved in 5-HT up-regulation of TGF-beta1. In conclusion, 5-HT-associated valve disease may be, in part, because of TGF-beta1 mechanisms.
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PMID:Serotonin mechanisms in heart valve disease I: serotonin-induced up-regulation of transforming growth factor-beta1 via G-protein signal transduction in aortic valve interstitial cells. 1246 27

Serotonin [5-hydroxytryptamine (5-HT)]-mediated cardiac valvular disease has been commonly observed in patients with carcinoid tumors. Previous research by others using reverse transcriptase-polymerase chain reaction demonstrated that aortic valve cells expressed predominantly 5-HT(2A/2B) receptors (5-HT(2A)R). Related investigations by our group using sheep aortic valve interstitial cell (SAVIC) cultures demonstrated that 5-HT both up-regulates transforming growth factor (TGF)-beta1 expression and activity, and also results in increased phospholipase C (PLC) activity. Thus, the present study investigated the hypothesis that the 5-HT signaling pathway in SAVICs involves 5-HT(2)Rs with associated G-protein signal transduction. The objectives were to functionally characterize in SAVIC cultures the native serotonin receptor subtypes using specific agonists and antagonists, and to delineate the serotonin-signaling pathway. 5-HT administration caused a marked stimulation of PLC activity. SAVIC studies of specific agents that target the 5-HT(2)R subtypes indicate that this response seemed to be mediated predominantly by 5-HT(2A)Rs. Furthermore, the sheep 5-HT(2A)R was identified by reverse transcriptase-polymerase chain reaction with sequence confirmation including comparisons to pig and human 5-HT(2A)R. Extracellular signal-regulated kinase (Erk 1/2) is a signaling molecule downstream from the 5-HT(2A)R. Both a protein kinase C inhibitor, GF109203X, and a Src inhibitor, PP1, attenuated 5-HT-stimulated Erk 1/2 activation. However, a 5-HT(2A)R antagonist, MDL 100907, inhibited 5-HT up-regulation of PLC and TGF-beta1, while having far less pronounced effects on Erk 1/2. In conclusion, these studies of the signal transduction activity of SAVICs in response to 5-HT have demonstrated that the 5-HT(2A)Rs are the most functionally active of the 5-HT(2)Rs in this cell type. Furthermore, 5-HT(2A)Rs are also involved in 5-HT up-regulation of active TGF-beta. 5-HT also mediated strong Erk 1/2 signaling via the MAP-kinase pathway, which was only in part because of 5-HT(2A)R activity. Thus, major 5-HT Erk 1/2 signaling beyond that controlled by 5-HT(2)Rs must involve other serotonin receptor types and/or secondary signaling events.
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PMID:Serotonin mechanisms in heart valve disease II: the 5-HT2 receptor and its signaling pathway in aortic valve interstitial cells. 1246 35

Carcinoids of the intestine are the most common gastrointestinal carcinoid tumors. Therapeutic options to treat patients with these tumors are limited. There are very few ileal carcinoid cell lines available for in vitro studies to analyze new drugs that could be effective in treating patients with metastatic tumors. A replication defective recombinant adenovirus with an SV40 early T-antigen insert was used to infect two intestinal carcinoid tumors to create carcinoid cell lines. The cell lines were studied by cell culture, reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry. Both cell lines expressed SV40 large T antigen and receptors for TGFbeta1, TGFbeta2, EGFR, and somatostatin receptors. Treatment with TGFbeta1 led to growth inhibition and increased apoptosis in the cultured cells. Octreotide inhibited cell growth of both cell lines while stimulating apoptosis. Treatment of the HC45 cells with gefitinib also inhibited cell growth in a concentration-dependent manner. TGFbeta treatment stimulated chromogranin A expression while expression of two other granins, chromogranin B and 7B2, did not change significantly. RNA profiling of cells treated with TGFbeta1 showed increased expression of vitamin D3 receptor. This finding was validated by real-time quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. These results indicate that these carcinoid cell lines can be used to study the proliferative and apoptotic mechanisms involved in intestinal carcinoid tumor growth regulation.
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PMID:Characterization of the functional and growth properties of cell lines established from ileal and rectal carcinoid tumors. 1824 65