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)

Through the technical advances in molecular biology during the past decade, important new insights into the fundamental chromosomal changes associated with brain tumors have been gained. The pace of such research is accelerating, and most of the published reports have appeared outside the neurosurgical literature. Furthermore, many neurosurgeons may not be sufficiently familiar with the terminology and techniques involved to remain abreast of the field. In this review, we discuss through specific examples of recent work on brain tumors the basic techniques of molecular biology, including the Southern and Northern blots, restriction enzyme digestion of DNA, molecular cloning of genes, and mapping of chromosomal deletions. Gene amplification and rearrangements are discussed through review of recent work on the N-myc gene in neuroblastoma and the epidermal growth factor receptor (EGFR) gene in glioblastoma. The molecular cloning of the gli gene from a glioblastoma illustrates the powerful analytic nature of these laboratory techniques and the investigative potential of a cloned gene. The concept of the "recessive oncogene" is discussed through a summary of recent work analyzing restriction fragment length polymorphisms (RFLPs) in families of patients with meningioma, acoustic neurinoma, and bilateral acoustic neurofibromatosis (BANF; NF-2). Throughout this article, emphasis is placed on ways in which molecular biology may soon affect clinical practice.
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PMID:Molecular biology of brain tumors. 305 15

Northern blot analysis has shown that the human neurofibromatosis type 2 (NF2) cDNA hybridizes to multiple RNA species. To examine whether these hybridizing RNA species represent NF2 transcripts, we cloned the complete NF2 cDNA by a combination of techniques: 5' and 3' rapid amplification of cDNA ends, RT-PCR, and searching and sequencing the NF2-related cDNA clones from the IMAGE consortium. We showed that human NF2 transcripts initiate at multiple positions. Analogous to those reported previously, NF2 transcripts undergo alternative splicing in the coding exons. We isolated eight alternatively spliced NF2 cDNA isoforms, including one that contains a new exon termed exon 2', which potentially could encode proteins of different sizes. We assembled the overlapping cDNA fragments, and the longest NF2 cDNA, containing all 17 exons, consists of 6067 nucleotides, which is consistent with the size of the major RNA species hybridized to the NF2 probe. The cDNA has a 425-nucleotide 5' untranslated region upstream from the ATG start codon, and a long 3' untranslated region of 3869 nucleotides. We also isolated two shorter NF2 cDNAs that were terminated by different polyadenylation signal sequences, which indicates that differential usage of multiple polyadenylation sites also contributes to the complexity of human NF2 transcripts. By reference to the transcription initiation site mapped, we analyzed the 5' flanking sequence of the human NF2 gene. Transient transfection analysis in human 293 kidney, SK-N-AS neuroblastoma, and NT2/D1 teratocarcinoma cells with NF2 promoter-luciferase chimeric constructs revealed a core promoter region extending 400 base pairs from the major transcription initiation site. Although multiple regions are required for full promoter activity, a site-directed mutagenesis experiment identified a GC-rich sequence (position -58 to -46), which could be bound by transcription factor Sp1, as a positive cis-acting regulatory element. Cotransfection studies in Drosophila melanogaster SL2 cells showed that Sp1 could activate the NF2 promoter through the GC-rich sequence.
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PMID:Multiple transcription initiation sites, alternative splicing, and differential polyadenylation contribute to the complexity of human neurofibromatosis 2 transcripts. 1182 59

Neuroblastoma (NB) is the most common malignant solid tumor in early childhood. Amplification of the MYCN oncogene is associated with a more malignant course of disease and poor outcome. The role that MYCN plays in the regulation of angiogenesis in NB remains unclear. To better elucidate this matter, fresh biopsy samples from 21 patients, 10 with MYCN-amplified tumors (defined as having >10 copies of the oncogene) and 11 with nonamplified tumors, were tested for their angiogenic capacity using the chick embryo chorioallantoic membrane assay, a useful model for such investigation. Moreover, using the same experimental model, conditioned media obtained from 5 different human NB cell lines MYCN-amplified (HTLA-230, LAN-5 and GI-LI-N) or nonamplified (ACN and SH-SY5Y) and biopsy fragments obtained from xenografts derived from 4 NB cell lines (HTLA-230, GI-LI-N, ACN and SH-SY5Y) injected in nude mice were assayed for angiogenic potential. Our results clearly demonstrated that MYCN amplification parallels angiogenesis in NB. When fresh biopsy samples from patients, CM derived from NB cell lines and biopsy fragments derived from xenografts of the same cell lines injected in nude mice were tested, the response was univocal: the angiogenic response, evaluated both macroscopically and microscopically, was significantly higher in the MYCN-amplified specimens compared to the nonamplified ones.
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PMID:In vivo angiogenic activity of neuroblastoma correlates with MYCN oncogene overexpression. 1240 4

The HLA class II expression is controlled by the transcriptional activator CIITA. The transcription of CIITA is controlled by different promoters, among which promoter-IV is inducible by IFN-gamma. We analysed the regulation of HLA class II molecules by IFN-gamma in a large series of human neuroblastoma cell lines. No induction of surface or intracellular HLA class II molecules and of specific mRNA was observed, in all neuroblastomas, with the exception of a nonprototypic cell line, ACN. In a large subset of neuroblastomas IFN-gamma induced expression of CIITA mRNA, derived from promoter-IV, which was not methylated. In contrast, in another subset of neuroblastomas, CIITA was not inducible by IFN-gamma and CIITA promoter-IV was either completely or partially methylated. Interestingly, the use of DNA demethylating agents restored CIITA gene transcriptional activation by IFN-gamma, but not HLA class II expression. The defect of HLA class II was not related to alterations in RFX or NF-Y transcription factors, as suggested by EMSA or RFX gene transfection experiments. In addition, the transfection of a functional CIITA cDNA failed to induce HLA class II expression in typical neuroblastoma cells. Confocal microscopy and Western blot analysis suggested a defective nuclear translocation and/or reduced protein synthesis in CIITA-transfected NB cells. Altogether, these data point to multiple mechanisms preventing HLA class II expression in the neuroblastoma, either involving CIITA promoter-IV silencing, or acting at the CIITA post-transcriptional level.
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PMID:Different levels of control prevent interferon-gamma-inducible HLA-class II expression in human neuroblastoma cells. 1458 11

Interferon-gamma (IFN-gamma) directs T helper-1 cell differentiation and mediates antitumour effects in preclinical models. However, high-dose IFN-gamma is toxic in vivo, and IFN-gamma-transfected neuroblastoma (NB) cells secreting high amounts of the cytokine may be lost due to cell apoptosis or differentiation. Two human NB cell lines (ACN and SK-N-BE2(c)) differing as to genetic and phenotypic features were transfected with the human IFN-gamma gene and selected on the grounds of the low concentrations of IFN-gamma produced. In both IFN-gamma-transfected cell lines, autocrine and paracrine activation of IFN-gamma-mediated pathways occurred, leading to markedly reduced proliferation rate, to increased expression of surface HLA and CD40 molecules and of functional TNF binding sites. ACN/IFN-gamma cells showed a significantly delayed tumorigenicity in nude mice as compared to parental cells. ACN/IFN-gamma tumours were smaller, with extensive necrotic area as a result of a damaged and defective microvascular network. In addition, a significant reduction in the proliferation index was observed. This is the first demonstration that IFN-gamma inhibits in vivo proliferation of NB cell by acting on the tumour cell itself. This effect adds to the immunoregulatory and antiangiogenic activities operated by IFN-gamma in syngeneic tumour-bearing hosts.
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PMID:Low-dose interferon-gamma-producing human neuroblastoma cells show reduced proliferation and delayed tumorigenicity. 1515 May 52

Pediatric neurogenic tumors include primitive neuroectodermal tumors (PNETs), especially medulloblastoma; ependymomas and choroid plexus papillomas; astrocytomas; retinoblastoma; and sympathetic neuroblastoma. Meningiomas and nerve sheath tumors, although uncommon in childhood, are also significant because they can result from exposures of children to ionizing radiation. Specific chromosomal loci and specific genes are related to each of these tumor types. Virtually all these genes appear to act as tumor suppressor genes, which are inactivated in tumor cells by mutations or by chromosomal loss. In genetically engineered mice, some genes that are clearly associated with specific human tumors (e.g., RB1 in retinoblastoma and NF2 in meningiomas and schwannomas) have no such effect. Other genetic constructs in mice involving the genes p53, ptc1, and Nf1 have produced tumors remarkably similar to some of the human pediatric neoplasms. Some of these tumors become clinically apparent after only a few weeks, while the mice are still juveniles, especially when two or more tumor suppressor genes are inactivated in the same genetic construct. Conversely, at least one genetic pathway in rodents involving point mutation in the coding region of a transforming gene (neu in malignant schwannomas) does not appear to operate in any human tumors. The nervous system is markedly susceptible to experimental carcinogenesis during early life in rodents, dogs, primates, and other nonhuman species, and there is no obvious reason why this generalization should not also apply to humans. However, except for therapeutic ionizing radiation, no physical, chemical, or biological cause of human pediatric nervous system tumors is known. The failure of experimental transplacental carcinogenesis to mirror human pediatric experience more closely may reflect the need for multiple mutational events in target cells, and for experimental carcinogens that are capable of causing the full spectrum of mutations that occur in cancer-related genes in pediatric neurogenic tumors.
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PMID:Causation of nervous system tumors in children: insights from traditional and genetically engineered animal models. 1531 89

In this study, in an attempt to identify neuroblastoma-associated surface antigens, we generated mAbs against the ACN neuroblastoma cell line. A mAb was selected (5B14) that reacted with all neuroblastoma cell lines analyzed and allowed detection of tumor cell infiltrates in bone marrow aspirates from neuroblastoma patients. In cytofluorimetric analysis, unlike anti-disialoganglioside mAb, 5B14 mAb did not display reactivity with normal bone marrow hematopoietic cell precursors, thus representing a highly specific marker for identifying neuroblastoma cells. Molecular analysis revealed that the 5B14 mAb-reactive surface glycoprotein corresponded to the recently identified 4Ig-B7-H3 molecule. Remarkably, mAb-mediated masking of the 4Ig-B7-H3 molecule on cell transfectants or on freshly isolated neuroblastoma cells resulted in enhancement of natural killer-mediated lysis of these target cells. These data suggest that 4Ig-B7-H3 molecules expressed at the tumor cell surface can exert a protective role from natural killer-mediated lysis by interacting with a still undefined inhibitory receptor expressed on natural killer cells.
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PMID:Identification of 4Ig-B7-H3 as a neuroblastoma-associated molecule that exerts a protective role from an NK cell-mediated lysis. 1531 38

Subfrontal schwannoma is a rare disease, which can be mis-diagnosed as an olfactory meningioma or a neuroblastoma, because of similar clinical symptoms and signs and neuroradiological features. Especially for young subjects, olfactory neuroblastoma should be carefully differentiated, since the management strategies for those lesions are significantly different. The craniofacial approach is often needed for the resection of a neuroblastoma. We report a case of 14-year old boy in which olfactory neuroblastoma was suspected prior to surgery, but turned out to be a schwannoma histologically. Molecular genetic examination revealed neither NF2 gene mutation nor loss of heterozygosity of chromosome 22q, unlike common schwannomas.
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PMID:Subfrontal schwannoma. 1582 81

Tumour progression in neuroblastoma (NB) patients correlates with high vascular index. We have previously shown that the ACN NB cell line is tumorigenic and angiogenic in immunodeficient mice, and that interferon-gamma (IFN-gamma) gene transfer dampens ACN tumorigenicity. As IFN-gamma represses lymphocyte-induced tumour angiogenesis in various murine models and inhibits proliferation and migration of human endothelial cells, we have investigated the antiangiogenic activity of tumour-derived IFN-gamma and the underlying mechanism(s). In addition, we characterised the tumour vasculature of the ACN xenografts, using the chick embryo chorioallantoic membrane assay. We show that the ACN/IFN-gamma xenografts had a lower microvessel density and less in vivo angiogenic potential than the vector-transfected ACN/neo. The vascular channels of both xenografts were formed by a mixed endothelial cell population of murine and human origin, as assessed by the FICTION (fluorescence immunophenotyping and interphase cytogenetics) technique. With respect to ACN/neo, the ACN/IFN-gamma xenografts showed more terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling-positive human and murine endothelial cells, suggesting that inhibition of angiogenesis by IFN-gamma was dependent on the induction of apoptosis, likely mediated by nitric oxide. Once the dual origin of tumour vasculature is confirmed in NB patients, the xenograft model described here will prove useful in testing the efficacy of different antiangiogenic compounds.
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PMID:Angiogenesis in a human neuroblastoma xenograft model: mechanisms and inhibition by tumour-derived interferon-gamma. 1672 59

We report the effect of the stable expression of a 13 amino acid human fibronectin (FN) peptide (FN13) on the organization of the FN extracellular matrix (ECM) and of FN integrin receptors (FNRs), in relationship with the inhibition of cellular invasion, in three FN-ECM defective human tumor-derived cell lines: SK-Hep1C3, hepatoma, ACN, neuroblastoma, and SK-OV-3, ovary carcinoma. All these cell lines stably expressing the FN13 peptide, organized an FN-ECM, disorganized alpha v beta 1 integrins and inactivated the ILK pathway, with the loss of secretion of MMP-9. This was associated with the inhibition of cell invasion in Matrigel matrix only in SK-Hep1C3 and ACN, but not in SK-OV-3 cells. Analysis of the integrin receptors organization showed that the FN13 expressing cells SK-Hep1C3 and ACN organized alpha v beta 3 integrins, whereas SK-OV-3 organized alpha v beta 5 dimers. The functional block of alpha v beta 5 integrins, with an inactivating anti-alpha v beta 5 antibody, led to the induction of alpha v beta 3 integrins also in SK-OV-3 cells, and to the inhibition of cell invasion. These data show that in the human tumor cells studied FN13 inhibits the in vitro invasion through the dissociation of alpha v beta 1 dimers, leading to ILK pathway inactivation, only when the organization of alpha v beta 3 integrins is induced in the plasma membrane.
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PMID:The FN13 peptide inhibits human tumor cells invasion through the modulation of alpha v beta 3 integrins organization and the inactivation of ILK pathway. 1738 46


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