Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autocrine stimulation of the type I insulin-like growth factor receptor (IGF-IR) by IGF-II is one mechanism that allows cancer cells to maintain unregulated growth and to resist programmed cell death (PCD). SH-SY5Y and SHEP cells are cloned human neuroblastoma (NBL) lines originating from a single primary tumor. SH-SY5Y cells, which express abundant cell surface IGF-IR and produce IGF-II, exhibit serum independent growth and resist PCD due to hypoxia and hyperosmolar conditions. In contrast, SHEP cells, which produce no IGF-II and express five-fold fewer IGF-IRs, die in serum-free media or following exposure to metabolic stressors. To better understand the roles of IGF-IR and its ligand, IGF-II, in NBL carcinogenesis, we stably transfected SHEP cells with either IGF-II or IGF-IR. Unregulated expression of IGF-II did not alter the growth characteristics of SHEP/human IGF-II transfectants. In contrast, overexpression of IGF-IR allowed SHEP/IGF-IR transfectants to survive in media supplemented only by IGF-II. IGF-IR abundance correlated in a graded fashion with resistance to PCD in response to three different death-inducing paradigms: mitogen withdrawal, hyperosmolar metabolic stress, and treatment with etoposide. Our results suggest that adjuvant therapy aimed at reducing IGF-IR abundance may enhance chemotherapy-coupled apoptosis in the treatment of NBL.
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PMID:Insulin-like growth factor I receptor prevents apoptosis and enhances neuroblastoma tumorigenesis. 881 51

Insulin-like growth factor (IGF) binding proteins (IGFBPs) modulate IGF action at cellular level through inhibition or, alternatively, potentiation, where their limited proteolysis is a contributory mechanism. Under basal conditions, neuroblastoma cells secrete IGFs (essentially IGF-II), IGFBPs (IGFBP-4 and predominantly IGFBP-2 that is partially proteolysed), and proteases, including tissue-type plasminogen (PLG) activator, whose activity is inhibited by PLG activator inhibitor-1. Neuroblastoma cells were used to investigate the influence of the plasmin system, transforming growth factor-beta retinoic acid on cell growth and the IGF system. In cells treated with 5 micrograms/ml PLG, proliferation was stimulated, an effect that was inhibited in the presence of either alpha IR-3 (which blocks the type 1 IGF receptor) or anti-IGF-II antibodies. There was a parallel increase in IGFBP-2 proteolysis, which resulted in a 5-fold loss of affinity for IGF-II. In the presence of 1 ng/ml transforming growth factor-beta, PLG-induced mitogenesis and IGFBP-2 proteolysis were reduced, and Northern blot analysis revealed increased PLG activator inhibitor-1 mRNA. Conversely, with 2 microM retinoic acid, the mitogenic effect of PLG, IGFBP-2 proteolysis, and tissue-type PLG activator mRNAs were increased. Therefore, IGF-II mediates autocrine proliferation in neuroblastoma cells under the control of IGFBPs secreted by the cells, its bioavailability being enhanced as a result of plasmin-induced IGFBP-2 proteolysis.
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PMID:Role of insulin-like growth factor binding protein-2 and its limited proteolysis in neuroblastoma cell proliferation: modulation by transforming growth factor-beta and retinoic acid. 900 3

Suramin, traditionally used in the treatment of trypanosomiasis, is under investigation in the treatment of cancer. One side effect that limits its use is the onset of a sensorimotor polyneuropathy. In order to investigate the mechanism by which suramin induces polyneuropathy, we examined its effects on SH-SY5Y human neuroblastoma cells, an in vitro model of neuronal growth and differentiation. Addition of 50-400 micrograms/ml suramin to SH-SY5Y cells grown in 0.6% CS inhibited [3H]thymidine ([3H]TdR) incorporation and cell growth. Upon removal of suramin, [3H]TdR incorporation increased, demonstrating that levels of suramin used were cytostatic and not cytotoxic. Analysis of suramin-treated SH-SY5Y cells by flow cytometry revealed growth arrest in the G1/G0 phase of the cell cycle. IGF-II-induced SH-SY5Y growth is mediated by the type I IGF receptor (IGF-IR). Therefore, we examined its effect on IGF-IR tyrosine phosphorylation. Suramin prevented IGF-II-stimulated IGF-IR tyrosine phosphorylation. These results indicate that in SH-SY5Y cells, suramin acts as a cytostatic agent and can block IGF-II-dependent cell growth by preventing IGF-IR activation. Thus, suramin toxicity in the peripheral nervous system may be due, in part, to preventing IGF and other growth factors from activating their receptors.
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PMID:Suramin disrupts insulin-like growth factor-II (IGF-II) mediated autocrine growth in human SH-SY5Y neuroblastoma cells. 902 79

Preliminary data have shown that IL-6 may act as an autocrine growth factor to control proliferation. We further characterised the role of IL-6 in tumour growth as an autocrine/paracrine growth factor in neuroectodermal tumours. We evaluated the production and secretion of IL-6 by seven human melanoma, five neuroblastoma and one glioblastoma cell lines. Moreover, we determined their IL-6-dependent growth in serum free-medium or under minimal growth-supplement conditions: IL-6 dependent growth was observed in two non-IL-6 producing melanoma and in one neuroblastoma cell lines. In addition, expression of IL-6 mRNA and peptide was increased by retinoic acid. The data support the hypothesis that IL-6 contributes to neuroectodermal tumour growth, even though it shows a less potent effect than other reported growth factor such as IGF-II.
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PMID:A possible growth factor role of IL-6 in neuroectodermal tumours. 904 37

The IGF system is involved in the growth and differentiation of neuroblastoma cells, but the precise roles played by the IGF-binding proteins (IGFBPs) remain unknown. We have examined the expression and functions of IGFBPs produced by the neuroblastoma cell line, SH-SY5Y, in the presence of: insulin, IGF-I, IGF-II, des(1-3)IGF-I (an IGF-I analogue with weak affinity for IGFBPs), acidic fibroblast growth factor, basic fibroblast growth factor, or nerve growth factor. Under basal conditions, SH-SY5Y cells in serum-free medium secreted IGF-II, and traces of IGF-I, IGFBP-2 and IGFBP-4. After 24 h of culture, comparative mitogenic potencies were: des(1-3)IGF-I > IGF-I > IGF-II > insulin. After 48 h, when IGFBP-2 and IGFBP-4 concentrations in the culture media had increased, des(1-3)IGF-I remained the most active, but the activity of insulin now equalled or exceeded that of IGF-I and IGF-II. This suggests a negative feedback mechanism involving partial sequestration of IGF-I and IGF-II by IGFBP-2 and IGFBP-4. At high cell density and with high concentrations of IGF-I, des(1-3)IGF-I (40 ng/ml) or IGF-II (80 ng/ml), the mitogenic activities of the IGFs diminished concomitantly with the appearance in the culture medium of an additional IGFBP identified as IGFBP-6, whose production depended on activation of the type 1 IGF receptor. These findings suggest that IGFBP-6 contributes as an autocrine inhibitor in the regulation of growth by the IGF system in these neuroblastoma cells.
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PMID:IGF-binding protein-6 is involved in growth inhibition in SH-SY5Y human neuroblastoma cells: its production is both IGF- and cell density-dependent. 907 79

Neuroblastoma cells are thought to depend upon autocrine stimulation by IGF-II but not by IGF-I. We have studied the expression of IGF, IGFBP and IGF receptor mRNA in two human neuroblastoma cell lines, SK-N-MC and CHP, and asked whether or not the expression of the IGF system in these malignant cells determines their growth pattern. SK-N-MC cells grow with a cell doubling time of 36 hours in medium supplemented with 10% fetal calf serum whereas CHP cells only grow with a doubling time of 72 h. In addition, the SK-N-MC cell line has a plating efficiency ten times greater than the CHP cell line. RNase protection assays were performed using (32)P-labelled riboprobes and RNA that had been purified from SK-N-MC and CHP cells respectively. A 520 bases human IGF-I, a 556 bases human IGF-II, a 480 bases human IGF-I receptor and a 250 human IGF-II/mannose-6-phosphate (M6P) receptor probe were radiolabelled as were human IGFBP-1, -2, -3, -4, -5 and -6 probes. While both SKNMC and CHP neuroblastoma cells expressed mRNAs for IGFBP-2, -4, and -6 no signal was detected for IGFBP-1, and -3 and only SK-N-MC cells expressed IGFBP-5 mRNA. In addition, a 400 bases protected band was seen with the IGF-I receptor probe and a 260 bases protected band with the IGF-IIM6P receptor probe in either cell line. Interestingly, a 300 bases protected species was detected with the IGF-II probe in CHP cell RNA whereas SK-N-MC cells did not express IGF-II transcripts. Conversely, SK-N-MC cells expressed a 520 bases IGF-I transcript while CHP cells did not show IGF-I mRNA expression. As determined by specific radioimmunoassays SK-N-MC cells secreted 0.75+/-0.02 ng/ml IGF-I, 1.2+/-0.04 ng/ml IGF-II and 149+/-2.1 ng/ml IGFBP-2 within 24 h, whereas CHP cells secreted 0.1+/-0.01 ng/ml IGF-I, but 6.2+/-0.1ng/ml IGF-II and 254.8+/-5.5 ng/ml IGFBP-2 (N=5). IGFBP-2 secretion correlated positively with IGF-II secretion in CHP cells (r=0.85, P=0.05) and negatively with IGF-I (r= -0.9, P<0.01) in SK-N-MC cells. In conclusion, SK-N-MC cells which grow rapidly and have a high plating efficiency, express IGF-I, while CHP cells that grow more slowly express IGF-II. We hypothesize that neuroblastoma cells depend upon autocrine stimulation by either IGF-I or IGF-II. Variable sensitivity to growth inhibitors or apoptotic processes may be related to the differential expression of the IGF system.
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PMID:Human neuroblastoma cells use either insulin-like growth factor-I or insulin-like growth factor-II in an autocrine pathway via the IGF-I receptor: variability of IGF, IGF binding protein (IGFBP) and IGF receptor gene expression and IGF and IGFBP secretion in human neuroblastoma cells in relation to cellular proliferation. 940 29

Insulin-like growth factors I and II (IGF-I and IGF-II) are actively involved in neuroblastoma cell growth. In all biological fluids, they are noncovalently bound to high-affinity binding proteins. At least six species of these IGF-binding proteins (IGFBPs) have been identified, but their precise roles remain unclear. One of them, IGFBP-6, is produced by neuroblastoma cells in culture under certain experimental conditions and seems to be associated with the arrest of cell growth. We stably transfected IGR-N-91 and SK-N-SH neuroblastoma cells with an expression vector comprising IGFBP-6 cDNA, whose expression was placed under the control of the constitutive and ubiquitous cytomegalovirus promoter. Analyses of the cell cycle (flux cytofluorometry), mitogenic activity (radiolabeled thymidine incorporation), and the number of viable cells (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test) showed that the mitogenic effects of serum, IGF-I, IGF-II, and des (1-3) IGF-I, a truncated IGF-I analogue with no affinity for IGFBP-6, were depressed in both transfected cell lines. With s.c. injection of transfected IGR-N-91 cells into nude mice, tumors developed in only 50-70% of cases, 1 or 2 weeks after those in controls, and were 60-90% smaller. Our findings show that IGFBP-6 influences neuroblastoma cell growth, both in vitro and in experimental xenograft development.
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PMID:Expression of insulin-like growth factor-binding protein 6 complementary DNA alters neuroblastoma cell growth. 956 81

Insulin-like growth factors (IGF-I and IGF-II) stimulate proliferation and differentiation in many cell types. In biological fluids, they associate non-covalently with high-affinity binding proteins (IGFBPs) which control their bioavailability and modulate their action. We previously demonstrated that IGFBP-2, -4 and -6 are intimately involved in the growth of cells derived from human neuroblastomas. Here, we have investigated the effects of retinoic acid (RA), which induces differentiation in these cells, on the expression of IGFBPs secreted by SK-N-SH neuroblastoma cells. Analysis of transcriptional activity of the IGFBP-2, -4 and -6 genes in isolated nuclei (run-on experiments) showed that RA increased the transcriptional activity of the IGFBP-6 gene, reduced that of the IGFBP-4 gene and had no effect on that of the IGFBP-2 gene. Northern blot analysis following treatment with actinomycin D showed that RA increased the stability of IGFBP-6 mRNA by a factor of 2.6, decreased that of IGFBP-2 mRNA by a factor of 2.3 and failed to affect IGFBP-4 mRNA. Treatment of cells with cycloheximide indicated the involvement of labile proteins in the stabilization of these mRNAs the expression of which could be under the control of RA. The transcriptional and/or post-transcriptional mechanisms by which RA regulates each of the IGFBPs produced by SK-N-SH cells are therefore different. Such regulation may also reflect the state of differentiation of the neuroblastoma cells. With RA-induced differentiation, IGFBP-6 is strongly stimulated, whereas IGFBP-2 and IGFBP-4 are severely depressed, which would suggest that each IGFBP plays a specific role. Moreover, this regulation seems tissue-specific because it is different in other cell types.
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PMID:Retinoic acid stimulates IGF binding protein (IGFBP)-6 and depresses IGFBP-2 and IGFBP-4 in SK-N-SH human neuroblastoma cells. 979 62

Insulin-like growth factors I and II (IGF-I and IGF-II) stimulate proliferation and differentiation in many cell types, including cell lines derived from human neuroblastomas. Their effects are mediated via the IGF-I receptor (IGF-IR) that is essential for growth in these cells. Amplification of the N-myc oncogene is a marker for poor prognosis in neuroblastoma development, and it therefore seemed of interest to analyze the relationships that may exist between IGF-IR and N-myc. N-myc-deficient SK-N-SH neuroblastoma cells were used as an experimental model. After stable transfection with N-myc cDNA, Northern blotting revealed a marked increased in IGF-IR, IGF-II, IGF-binding protein (IGFBP)-2, and IGFBP-4 mRNA levels, whereas IGFBP-6 mRNA levels were clearly diminished. Western immunoblot analysis also demonstrated increased intact IGFBP-2 but decreased IGFBP-6 in the presence of N-myc oncogene. Parallel binding experiments using IGF-I missing the first 3 amino acids revealed a 47% increase in binding sites for IGF-I and an increase of at least 335% in DNA synthesis, as measured by labeled thymidine incorporation into DNA. s.c. injection of these cells into nude mice provoked xenograft development in 50-100% of cases (depending on the series of experiments). Control cells, in contrast, were not tumorigenic. In cells transfected with bp -420/+60 of the human IGF-IR promoter controlling expression of the luciferase reporter gene, promoter activity was stimulated by a factor of 3.8 +/- 0.6 (n = 6) in the presence of N-myc oncogene. This suggests transcriptional regulation of IGF-IR expression by N-myc. IGF-IR activity and N-myc amplification are two events that to date have been identified as independently instrumental in the etiology of human neuroblastoma. Our results provide the first evidence of a direct link between them and demonstrate the effects of the oncogene on components of the IGF system in neuroblastoma cell growth in vitro and in vivo.
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PMID:N-myc regulation of type I insulin-like growth factor receptor in a human neuroblastoma cell line. 1038 52

Embryonal tumors, such as neuroblastoma, medulloblastoma and Wilms' tumor, have their peak incidence in the first 4 years of life. These neoplasias exhibit genetic and clinical heterogeneity, but little is known about their molecular pathogenesis. Application of the differential-display PCR approach led to the identification of a gene, glypican 3 (GPC3), that is differentially expressed in cancer cells. Expression of this gene is usually limited to fetal mesodermal tissue, and its inactivation has been found to be responsible for the X-linked Simpson-Golabi-Behmel overgrowth syndrome. Here, we show that GPC3 mRNA is present in several neuroblastomas and all Wilms' tumors tested to date but not in medulloblastoma. GPC3 was not expressed in normal kidney tissues obtained from the corresponding Wilms' tumor patients, suggesting that in these cancer cells expression was not repressed (or was activated). No correlation was found between expression of GPC3 and the known indicator of neuroblastoma prognosis MYCN mRNA. However, all samples that expressed GPC3 also expressed IGF-II, coding for a growth factor important in the survival and growth of many cancer types. Although the biological significance of this relationship remains unclear, our results suggest that GPC3 may be implicated in the development of embryonal tumors through a signaling pathway that appears to involve IGF-II.
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PMID:Expression of glypican 3 (GPC3) in embryonal tumors. 1100 3


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