UMLS:C0027819 - FACTA Search

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Query: UMLS:C0027819 (neuroblastoma)
27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Paraneoplastic syndromes such as the subacute sensory neuronopathy (SSN) and paraneoplastic cerebellar degeneration (PCD) are associated with autoantibodies directed against various neural antigenic structures. SSN is characterised by autoantibodies against a neuronal intranuclear component called Hu (M. W. 35 to 40 kD), whereas in PCD these antibodies are directed against a Purkinje cell cytoplasmic component called (M. W. 34 and 65 kD). Neuroblastoma cell lines maintained in culture have been shown to contain neuronal antigens. We have demonstrated the presence of the Hu antigen in neuroblastoma cell lines such as SKN-SH, LAN-1 and IMR-32 by both immunocytochemistry and immunoblots of nuclear extracts. The Yo paraneoplastic antigen has been found to be expressed in HeLa cells. These methods may be used for screening of patients with suspected paraneoplastic disease and/or malignancy. Western blot analysis appears to be superior to immunohistochemistry alone. In our experience only 11 out of 122 SCLC patients were positive for the anti-Hu antibody, whereas 5 out of 5 patients with SSN/SCLC were positive, and all of the neurological controls were negative. The availability of cell lines expressing paraneoplastic antigens offers an easy diagnostic assay which may complement or replace conventional immunohistochemistry.
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PMID:Autoantibodies in neurological paraneoplastic diseases. 753 34

We showed earlier that interferon-gamma is a powerful inducer of differentiation of human neuroblastoma (NB) cells. Although 2',5' oligo-adenylate synthetase (2,5 OAS) may play a role in mediating the anti-proliferative and/or differentiative effects of interferons (IFNs), direct evidence is lacking. We have investigated gene and protein expression of the 4 different 2,5 OAS isoforms and their cumulative enzymatic activity in a previously characterized IFN-gamma-sensitive human NB cell line, LAN-5. Analysis of total and poly(A)+ RNA by Northern blot and RT-PCR indicated that expression of the mRNA coding for the 40-, 46-and 69-kDa isoforms was induced in a time- and dose-dependent manner, reaching a maximum after a 36-hr treatment with 1000 IU/ml of IFN-gamma. In the absence of treatment, only the mRNA for the 69-kDa isoform was detectable by RT-PCR. Inhibition of transcription with actinomycin D showed that 2,5 OAS mRNA was quite stable, with a half-life of about 4 hr. With respect to the protein content, no 2,5 OAS isoform was present in proliferating LAN-5 cells; following IFN-gamma treatment, the 100-, 69-and 46-kDa isoforms became detectable. Accordingly, 2,5 OAS enzymatic activity, virtually undetectable in untreated LAN-5 cells, increased up to 132 pmol oligoadenylate/micrograms protein/hr after 48 hr of treatment, then slowly decreased, remaining detectable up to 96 hr. However, the 2,5 OAS proteins required an exogenous activation by synthetic dsRNA to exert enzymatic activity. It is therefore conceivable that they do not play a biological role in NB cell functions. Moreover, an increase in 2,5 OAS enzymatic activity was also observed in NB cells resistant to the differentiation-promoting activity of IFN-gamma, further suggesting that 2,5 OAS induction was not sufficient to trigger IFN-gamma-dependent neuronal maturation. Furthermore, other differentiation-inducing agents, such as retinoic acid and cytosine arabinoside, or complete proliferative arrest produced by serum deprivation, failed to enhance 2,5 OAS activity, thus indicating that the 2,5 OAS system is not directly involved in mediating other differentiative pathways of NB cells.
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PMID:Induction of 2.5 OAS gene expression and activity is not sufficient for IFN-gamma-induced neuroblastoma cell differentiation. 762

Two human neuroblastoma cell lines, LAN-5 and GI-CA-N, have been analyzed for their capability to adhere to different extracellular matrix (ECM) components. The GI-CA-N cells adhered to all the tested substrates: laminin (LN), type I and type IV collagen (Coll I, Coll IV), vitronectin (VN), and fibronectin (FN). Conversely LAN-5 cells weakly attached to FN and VN, whilst adhesion on LN and Coll I and IV was strong and induced a rapid elongation of cell processes. By means of RT-PCR and immunoprecipitation we showed that the integrin pattern of these two lines was different and could explain their diversity in adhesion capability. Both cell lines express a large amount of the beta 1 integrin subunit, associated with different alpha chains, probably responsible for their adhesion to some ECM proteins. After treatment of LAN-5 cells with biological differentiating agents, such as gamma-interferon, alone or in combination with tumour necrosis factor-alpha (TNF-alpha), or retinoic acid, the levels of alpha 1 beta 1, alpha 2 beta 1, and alpha 3 beta 1 integrin expression were enhanced, while the amount of alpha v remained constant. In contrast, treatment of LAN-5 cells with TNF-alpha, that did not induce any maturation, or starvation in 2% foetal calf serum, that inhibited cell proliferation without affecting neural differentiation, did not induce any change in the integrin assessment. Messenger-RNAs for the two alpha 6 isoforms, A and B, were present in both cell lines. However, in LAN-5 cells, the protein product was neither detectable nor inducible by differentiation. Our results confirm the specific modulation of the alpha 1 beta 1 integrin expression in human neuronal development, and show, for the first time, the involvement of alpha 2 beta 1 and alpha 3 beta 1 heterodimers in this maturational process.
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PMID:Modulation of alpha 1 beta 1, alpha 2 beta 1 and alpha 3 beta 1 integrin heterodimers during human neuroblastoma cell differentiation. 769 64

Human neuroblastoma cells, LAN, were used to study the phosphorylation and dephosphorylation of tau proteins. These cells contained mainly a form of tau comparable to fetal brain tau in molecular weight (55 kDa). Neuroblastoma tau reacted with antibodies that recognize epitopes spanning the whole tau molecule (E-1, Alz50, Tau-1, and Tau46), and antibodies (PHF-1, NP8, and T3P) that recognize hyperphosphorylated tau (PHF-tau) in Alzheimer's disease (AD) brains. Exposure of the cells to 45 degrees C heat stress resulted in dephosphorylation of the epitopes recognized by PHF-1, NP8, and T3P. Transfer of the heat-stressed cells to 37 degrees C led to rephosphorylation of the dephosphorylated epitopes. Cells that had been treated with okadaic acid (OA), regardless of whether they were subsequently subjected to heat stress or heat stress and recovery, all contained tau with a molecular weight similar to that of control cells. These tau proteins, similar to tau in control cells, also reacted with antibodies to phosphorylated epitopes. However, unlike the tau from control or heat-stressed cells, the OA-treated and heat-stressed tau had decreased reactivity with Tau-1. Alteration of Tau-1 immunoreactivity has been reported to be an early event in AD neurodegeneration. The reduction of Tau-1 immunoreactivity observed in OA-treated samples could be restored by incubation of electroblots of isolated tau with alkaline phosphatase, indicating an induction of the Tau-1 epitope phosphorylation by OA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reversible heat stress-related loss of phosphorylated Alzheimer-type epitopes in Tau proteins of human neuroblastoma cells. 769 94

Based on our previous observations that neuroblastoma (NB) cells express fibroblast growth factor-2 (FGF-2; basic FGF) and respond to it [Janet T. et al. (submitted); Wewetzer K. et al. (1993) J. Neurosci. Res. 36, 209-215), we attempted to find to what extent selected cytokines [interleukin (IL)-1 beta and interferon gamma (IFN gamma)] may modulate FGF-mediated proliferative activity and differentiation. The NB cell lines IMR-32, SH-SY5Y, GIMEN and LAN-1 and colorimetric assays were used for the determination of cell numbers. IL-1 beta (and several other ILs, including IL-1 alpha, -2, -3, and 6) per se did not affect proliferation of any cell line studied. IFN gamma inhibited growth of GIMEN and LAN-1 cells, but was uneffective on IMR-32 and SH-SY5Y cells. FGF-2 was antimitogenic for GIMEN cells. IFN gamma reversed and IL-1 beta enhanced this antimitogenic effect of FGF-2. FGF-2 per se did not affect LAN-1 cells and did not modulate the growth inhibitory actions of IFN gamma on these cells. FGF-2 induced proliferation of IMR-32 and SH-SY5Y cells. This effect was not modulated by IFN gamma or IL-1 beta. These results suggest a heterogeneous response pattern of human NB cell lines towards the cytokines studied and complex interactions of FGF-2, IL-1 beta and IFN gamma.
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PMID:Interleukin-1 beta and interferon gamma interact with fibroblast growth factor-2 in the control of neuroblastoma cell proliferation and differentiation. 781 83

The 3-5 year survival rates of patients with disseminated Ewing's sarcoma (ES) or the closely related peripheral primitive neuroectodermal tumors (PNET) remain low, even under aggressive treatment involving highly toxic multidrug chemotherapeutic regimens. ES and PNET are sensitive to doxorubicin, but may escape treatment by expression of the multidrug-resistant phenotype and/or other mechanisms. In this study, we have identified albumin as growth supporting factor for ES and PNET cells in IGF-I-supplemented serum-free tissue culture medium. To investigate the specificity and toxicity of albumin-based drug conjugates, doxorubicin was coupled to bovine serum albumin (BSA) by either a two step glutaraldehyde or carbodiimide-C4-spacer technique, yielding monomeric DOX-albumin conjugates with conjugation numbers ranging from 3-20 moles DOX/mole BSA. Cellular uptake of fluorescein-isothiocyanate-(FITC)-labeled albumin and DOX-albumin conjugates could be demonstrated by flow cytometric measurements of cell-associated fluorescence and confocal microscopy. The cytostatic activity of these conjugates against ES/PNET cell lines, a neuroblastoma (LAN-1) and prostate cancer carcinoma cell line (PC-3) and normal lymphoblasts was tested in short-term proliferation assays (48 h). The results show a high selectivity of the DOX-albumin conjugates for ES/PNET cell lines, with highest growth inhibition by conjugates with low DOX conjugation numbers (n = 3) in serum-supplemented medium (17-32 fold loss of activity compared to free DOX), followed by 20-DOX-C4-albumin in serum-free medium and low activity of the other conjugates. In conclusion, DOX-albumin conjugates inhibit the growth of ES/PNET cell lines selectively, showing low activity against the unrelated carcinoma line PC-3 and sparing normal lymphoblasts. The inverse correlation of activity and conjugation number demonstrates a low cytotoxic activity of DOX in acid-stable binding to monomeric albumin, pointing to a selective cytostatic activity of the modified albumin against ES and PNET cells, even in the presence of a 100 fold excess of unmodified serum albumin.
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PMID:In vitro antiproliferative effects of albumin-doxorubicin conjugates against Ewing's sarcoma and peripheral neuroectodermal tumor cells. 784 32

The effect of sequential stimulation of different inositol (1,4,5)-trisphosphate (IP3)-linked receptors on the functioning of intracellular Ca2+ stores was evaluated in single LAN-1 human neuroblastoma cells by means of fura-2 microfluorimetry. Homologous restimulation both in the absence and in the presence of extracellular Ca2+ with endothelin-1 (ET-1), Lys-bradykinin (BK), and ATP did not elicit an intracellular Ca2+ increase, whereas a [Ca2+]i elevation after carbachol (CCh) re-exposure was obtained only in the presence of extracellular Ca2+. Since thapsigargin and ionomycin, in the absence of extracellular Ca2+, were still able to release Ca2+ after ET-1, BK, and ATP but not after CCh, it can be argued that in the first case the stores were not completely depleted. This evidence was also confirmed by the fact that LAN-1 cells, sequentially exposed in different order to ET-1, BK, ATP, and upon extracellular Ca2+ removal, showed an increase of [Ca2+]i although progressively reduced in magnitude. By contrast, when CCh was perfused as the first agonist, it completely precluded any further Ca2+ mobilization by the other three agonists. In addition, the lack of potentiation of the Ca2+ response when BK and ET-1 were superfused together and the potentiation of Ca2+ response elicited by ET-1 after BK, when the plasma membrane Ca2+ efflux pathways were blocked by lanthanum during the first agonist exposure, indicated that LAN-1 cells can recycle cytoplasmic Ca2+ when exposed to ET-1, BK, ATP but not when exposed to CCh. This inhibitory effect of CCh (perfused for 90 s) on Ca2+ refilling was strictly dependent on the time of receptor occupancy since the exposure to CCh for a shorter period (15 s) produced the same effect on Ca2+ refilling when ET-1, BK, and ATP were perfused, as first agonist, for 90 s. Furthermore, the entity of Ca2+ refilling after 15 s of BK receptor occupancy was similar to that observed after 90 s. This seems to suggest that the receptors for ET-1, BK, and ATP maintain the transductional mechanisms in an activated state for a time shorter than the time of receptor occupancy. This was confirmed by the fact that IP3 levels during a 90-s BK exposure fell to prestimulated value within 30 s, whereas after CCh they reached a sustained plateau phase, after the peak.
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PMID:Relationship between time of activation of phospholipase C-linked plasma membrane receptors and reloading of intracellular Ca2+ stores in LAN-1 human neuroblastoma cells. 802 61

Recombinant gamma-interferon (IFN-gamma) has recently been shown to be one of the most effective inducers of neuroblastoma (NB) cell differentiation. Since increasing evidence indicates that expression of MHC class-I and class-II antigens by tumour cells is important for immunorecognition and cell targeting, we tested whether induction of NB cell differentiation by IFN-gamma is followed by expression of HLA class-I and class-II molecules. LAN-5 human NB cell line completely lacks HLA class-I antigens. Their expression was induced in a dose-dependent manner by IFN-gamma. HLA class-II molecules are also absent on LAN-5 cells, but only DP antigens were dose-dependently induced by IFN-gamma, while DR and DQ molecules were unaffected by the treatment. To confirm and extend the immunological data to all the class-II molecules, we performed Northern blot analysis, observing that DP alpha mRNA was induced in a dose- and time-dependent manner. DO beta and DZ alpha genes were also induced peaking after 3 days of IFN-gamma treatment. DR beta and DQ beta genes, which were not induced by IFN-gamma, gave a normal pattern of enzyme restriction by Southern blot. To get an insight into the regulation of HLA class-II gene expression in the neuronal model, we measured the decline of the steady-state HLA class-II mRNA. DO beta mRNA rapidly returned to baseline level after removing IFN-gamma, while the decay rates of DP alpha and DZ alpha mRNA were very slow. This might indicate different regulation at the post-transcriptional level for DO beta mRNA with respect to DP alpha and DZ alpha mRNA. To strengthen these findings we evaluated the half-lives of the mRNA after IFN-gamma induction by means of actinomycin D treatment. HLA-DO beta mRNA had a shorter half-life, while DZ alpha and DP alpha had a longer decay rate. Finally, we report that treatment of LAN-5 cells with cycloheximide did not alter the rate of transcription of the HLA-DP alpha gene, suggesting that no protein factor(s) is/are needed to maintain DP alpha gene expression.
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PMID:Uncoordinate induction and differential regulation of HLA class-I and class-II expression by gamma-interferon in differentiating human neuroblastoma cells. 824 79

The anti-Hu antibody is associated with a paraneoplastic subacute sensory neuronopathy (SSN) described in cases of small cell lung cancer (SCLC). The Hu antigen is a pan-neuronal nuclear antigen with a molecular weight of 35-40 kDa. In this study we demonstrated the presence of the paraneoplastic Hu antigen in different neuroblastoma cell lines. We showed that by indirect immunocytochemistry the serum of patients with SSN and SCLC reacts with the nuclei of neuroblastoma cell lines SKN-SH and LAN-1. Western blot analysis of nuclear extracts from neuroblastoma cell lines SKN-SH, IMR-32 and LAN-1 confirmed the presence of the Hu antigen in these neuroblastoma cell lines. By comparing the immunocytochemical method and the Western blot analysis we were able to determine that the Western blot analysis was a more sensitive test. Screening of the sera of a large population (a total of 122 patients with SCLC, 17 with paraneoplastic disorders as well as 121 controls with other neurological disorders) was performed and showed all 5 of the patients with SSN and SCLC to be positive for the anti-Hu antibody, whereas only 11 of the 122 SCLC patients and none of the controls were positive, thereby suggesting that this test has a very high degree of sensitivity.
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PMID:Sensory neuronopathy and small cell lung cancer: antineuronal antibody reacting with neuroblastoma cells. 839 93

Interferon-gamma (IFN-gamma) is a potent growth-inhibitory cytokine also endowed with differentiating activity on neural cells. Binding of IFN-gamma to its high-affinity receptor induces a rapid and transient activation of phospholipase A2 (PLA2). The mechanism coupling the IFN-gamma receptor (IFN-gamma-R) to PLA2 activation is not clearly defined, and no information is available on this mechanism in neuroblast cells. We have tested the hypothesis that GTP-binding proteins (G-proteins) may couple the IFN-gamma-R to PLA2 in the human neuroblastoma (NB) cell line LAN-5. Incubation of NB cells with IFN-gamma resulted in a rapid increase in [3H]arachidonic acid (AA) release, and this effect was blocked by pretreatment with anti-IFN-gamma antibodies. IFN-gamma-stimulated AA release was still observed in permeabilized cells that were blocked by pretreatment with anti-IFN-gamma-R antibodies. Exposure of permeabilized LAN-5 cells to guanosine 5'-[gamma-thio]triphosphate (GTP[S]), a non-hydrolysable GTP analogue, induced a dose-dependent release of [3H]AA. A non-specific nucleotide effect was excluded, since similar stimulatory effects on AA mobilization were not observed by GTP, ATP, CTP, ADP and GDP. IFN-gamma-stimulated AA release was completely blocked by the guanine nucleotide analogue that inhibits G-protein function, guanosine 5'-[beta-thio]diphosphate (GDP[S]). A role for G-proteins in IFN-gamma-R coupling to PLA2 was further supported by the inhibition of IFN-gamma-induced [3H]AA release by treatment of permeabilized cells with pertussis toxin and with the antiserum against the common alpha-subunits of G-proteins. To determine a possible contribution to AA mobilization by the phospholipase C and diacyglycerol lipase pathway or by protein kinase C activation, the effects of neomycin, a phospholipase C inhibitor, and PMA (phorbol 12-myristate 13-acetate), a direct activator of protein kinase C, were investigated. Neither neomycin nor PMA affected either basal or IFN-gamma-stimulated AA release. Ca2+ concentration, which has been shown to regulate the activity of some PLA2s, does not appear to play an important role in the regulation of the IFN-gamma-stimulated PLA2 activity, since incubating permeabilized cells in different concentrations of Ca2+ induced AA release without affecting the IFN-gamma response. Altogether, these findings suggest the existence of IFN-gamma-R, which couples a Ca(2+)-independent PLA2 activation via pertussis-toxin-sensitive G-proteins.
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PMID:Interferon-gamma-stimulated and GTP-binding-proteins-mediated phospholipase A2 activation in human neuroblasts. 839 12

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