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

Gain of chromosome 17q material is the most frequent genetic abnormality in neuroblastomas. The common region of gain is at least 375 cR large, which has precluded the identification of genes with a role in neuroblastoma pathogenesis. Neuroblastoma also frequently show amplification of the N-myc oncogene, which correlates closely with 17q gain. Both events are strong predictors of unfavorable prognosis. To identify genes that are part of the N-myc downstream pathway, we constructed SAGE libraries of an N-myc transfected and a control cell line. This identified the chromosome 17q genes nm23-H1 and nm23-H2 as being 6-10 times induced in the N-myc expressing cells. Northern and Western blot analysis confirmed this up-regulation. Time-course experiment shows that both genes are induced within 4 h after N-myc is switched on. Furthermore, we demonstrate also that c-myc can up-regulate nm23-H1 and nm23-H2 expression. Neuroblastoma tumor and cell line panels reveal a striking correlation between N-myc amplification and mRNA and protein expression of both nm23 genes. We show that the nm23 genes are located at the edge of the common region of chromosome 17q gain previously described in neuroblastoma cell lines. Our findings suggest that nm23-H1 and nm23-H2 expression is increased by 17q gain in neuroblastoma and can be further up-regulated by myc overexpression. These observations suggest a major role for nm23-H1 and nm23-H2 in tumorigenesis of unfavorable neuroblastomas.
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PMID:The N-myc and c-myc downstream pathways include the chromosome 17q genes nm23-H1 and nm23-H2. 1196 Mar 82

The thyroid hormone (T3) blocks proliferation and induces differentiation of neuroblastoma N2a-beta cells that overexpress the beta 1 isoform of the T3 receptor. An element in the region responsible for premature termination of transcription mediates a rapid repression of c-myc gene expression by T3. The hormone also causes a decrease of cyclin D1 gene transcription, and is able to antagonize the activation of the cyclin D1 promoter by Ras. In addition, a strong and sustained increase of the levels of the cyclin kinase inhibitor (CKI) p27(Kip1) are found in T3-treated cells. The increased levels of p27(Kip1) lead to a marked inhibition of the kinase activity of the cyclin-CDK2 complexes. As a consequence of these changes, retinoblastoma proteins are hypophosphorylated in T3-treated N2a-beta cells, and progression through the restriction point in the cell cycle is blocked.
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PMID:Cell cycle control by the thyroid hormone in neuroblastoma cells. 1250 6

In the present study we review ENT tumor pathology in childhood. Only the most salient aspects are emphasized and the variety of entities reviewed was restricted. Molecular biology techniques reveal infection by human papilloma virus (types 6 and 11) in 50 % of papillomas, while immunohistochemical techniques are less effective in papilloma virus detection. The myofibroblastic nature of nasal angiofibroma has been demonstrated and its incidence is 25 times more frequent in patients with familial polyposis of the colon. Overexpression of p53 occurs in the initial stages of nasopharyngeal carcinoma, while overexpression of c-myc is correlated with an unfavorable prognosis. Recently, olfactory neuroblastoma has been shown not to express the protein product of the MIC-2 gene (antibody 12E7), thus the hypothesis that it could be a member of the Ewing tumor family (neuroectodermal peripheral tumors) has not been confirmed, although it is a primitive neural tumor. The head and neck rhabdomyosarcoma with the best prognosis is that located in the orbit, and cytogenetic studies have shown chromosomic translocation t(2;13) in 50 % of these childhood tumors when they are of the alveolar-type, while trisomy of chromosome 2 or 20 is more characteristic of the embryonic-type. Currently, any classifying features of ENT lymphomas must be based on the Revised European-American Classification of Lymphoid Neoplasms (REAL). Papillary and medullary carcinomas are the most common histological types of thyroid carcinoma in childhood. Alterations in ret/PTC play a significant role in the pathogenesis of both.
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PMID:[Advances in the diagnosis of ENT tumors in childhood]. 1272 79

Neuronal differentiation implies morphological and biochemical changes to generate a specialized neuron. N2A neuroblastoma cells can be promoted to undergo differentiation associated to neurites outgrowth, a process linked to the arrest of cell division. Using N2A cells as a model, we investigated the detailed molecular aspects on the involvement of p27 in dibutyryl cAMP-induced neuronal differentiation. In the undifferentiated N2A phenotype, an unusually high level of accumulated p27 protein mass was evidenced. Data suggest that in proliferating cells, p27 could be sequestered by direct interaction with cyclin D1, thus preventing its inhibitory action on cell cycle Cdks. Studies also indicate that p27 is functionally active and that its loss of action on Cdks in proliferating cells is due to its strong association with cyclin D1. Therefore, when cell differentiation is triggered, the action of p27 on Cdks seems to depend on both p27 and cyclin D1 degradation during the early steps of differentiation followed by late events of re-synthesis of active p27. In this context, an overexpression of p27 after N2A transfection with a mouse p27 clone induces the outgrowth of neurites associated with a decrease in cyclin D1 expression. On the other hand, treatment of N2A undifferentiated cells with c-myc antisense oligonucleotides led to a decrease in p27 and cyclin D1 levels, similar events as those in early stages of cell differentiation. Studies suggest that blockage in c-myc expression triggers early events in neuronal differentiation. These studies are of the utmost importance to elucidate regulatory mechanisms of molecules that play a critical role in the transition from a proliferating phenotype to differentiated cells.
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PMID:Regulation of p27 in the process of neuroblastoma N2A differentiation. 1276 87

The universal deregulation of c-myc gene expression in tumor cells suggests that this oncogene represents an attractive target for cancer therapeutic purposes. The same applies to the N-myc gene, which has a more restricted tissue specificity. Translocation (e.g., c-myc in Burkitt's lymphoma), or amplification (e.g., N-myc in neuroblastoma) of myc genes has been causally linked to tumor formation. Furthermore, the c-myc promoter integrates diverse mitogenic signalling cascades, which are constitutively activated in tumor cells, and translates them into expression of the c-MYC transcription factor, which promotes cell proliferation by regulating the expression of numerous target genes. Recent experimental data suggest, that even a brief inhibition of c-myc expression may be sufficient to permanently stop tumor growth and induce regression of tumors. Attempts to identify specific inhibitors of c-MYC/MAX dimerization have yielded promising results. In addition, downstream-target genes of c-MYC represent attractive targets for tumor therapy. Tumor cells expressing c-MYC at elevated levels are sensitized to treatment with DNA-damaging drugs. In mice and presumably also in human patients, the successful treatment of c-myc-induced tumors with conventional chemotherapy depends on the presence of functional p53. Therefore, restoration of this pathway, which is commonly lost in cancer cells, may enhance therapy of c-myc-induced tumors. These and other recent developments, which address the use of myc genes as therapeutic targets for cancer treatment, are discussed in this review.
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PMID:The MYC oncogene as a cancer drug target. 1276 86

N-myc gene amplification is the most characteristic feature of neuroblastoma. c-myc oncogene, another member of myc gene family, plays an important role in cell proliferation and differentiation. Both of them may contribute to tumorigenesis of neuroblastoma. In this study we use the in situ hybridization and immunocytochemical methods to test the frequencies of N-myc and c-myc expressions in 20 cases of human neuroblastoma at mRNA and protein levels. The positive rates of the expression of N-myc are 90% and 100% detected by in situ hybridization and immunocytochemical methods respectively. The positive rates of c-myc are 80% and 85% respectively. Sixty percent of the 20 specimens tested by in situ hybridization and 55% by immunocytochemistry show an inverse relationship between the expressions of these two oncogenes and this may indicate that there are different gene expression controlling mechanisms in different cases.
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PMID:The relationship between expressions of N-myc and c-myc oncogenes in neuroblastoma: an in situ hybridization and immunocytochemical study. 1290 18

A major prognostic marker for neuroblastoma (Nb) is N-myc gene amplification, which predicts a poor clinical outcome. We sought genes differentially expressed on a consistent basis between multiple human Nb cell lines bearing normal versus amplified N-myc, in hopes of finding target genes that might clarify how N-myc overexpression translates into poor clinical prognosis. Using differential display, we find the previously described growth-inhibitory gene Ndrg1 is strongly repressed in all tested Nb cell lines bearing N-myc amplification, as well as in a neuroepithelioma line with amplified c-myc. Overexpression of N-myc in non-amplified Nb cells leads to repression of Ndrg1, as does activation of an inducible c-myc transgene in fibroblasts. Conversely, N-myc downregulation in N-myc-amplified Nb cells results in re-expression of the Ndrg1, and stimuli known to induce Ndrg1 do so in Nb cells while simultaneously down-regulating N-myc. Relevant to these results, we demonstrate an in vitro interaction of Myc protein with the Ndrg1 core promoter. We also find that Ndrg1 levels increase dramatically during in vitro differentiation of two cell lines modeling neural and glial development, while c- and N-myc levels decline. Our results combined with previous information on the Ndrg1 gene product suggest that downregulation of this gene is an important component of N-Myc effects in neuroblastomas with poor clinical outcome. In support of this notion, we find that re-expression of Ndrg1 in high-Myc Nb cells results in smaller cells with reduced colony size in soft-agar assays, further underscoring the functional significance of this gene in human neuroblastoma cells.
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PMID:The growth-inhibitory Ndrg1 gene is a Myc negative target in human neuroblastomas and other cell types with overexpressed N- or c-myc. 1296 47

Peripheral primitive neuroectodermal tumour (PNET)/Ewing's sarcoma (ES) and neuroblastoma (NB) are related tumours of neural crest origin with primitive neural characteristics. Fibroblast growth factor 2 (FGF2) is a critical signalling molecule for primitive neural crest cells. The treatment of NB cells with FGF2 variably affects biological characteristics such as growth and differentiation, while in PNET/ES, FGF2 predominantly induces apoptosis. The JK-GMS Askin tumour cell line can be induced to differentiate upon treatment with nerve growth factor (NGF), indicating the integrity of the cellular machinery necessary for differentiation. The present study assesses whether FGF2 can induce differentiation in JK-GMS cells. JK-GMS cells expressed high-affinity FGF receptors (FGFRs), and treatment with FGF2 induced phosphorylation of FGFR1 together with activation of extracellular signal-regulated kinases (ERK1/ERK2) and c-Jun N-terminal kinase (JNK). Subsequent biological effects were growth inhibition, neuronal differentiation, and apoptosis, and these changes were associated with increased expression of neurofilaments, reduction of c-myc and bcl-2 expression, and activation of caspase 3. Treatment of the cells with a specific inhibitor of the MAPK/extracellular signal-regulated kinase (MEK)-1, PD98059, predominantly inhibited the effects of FGF2 on growth, differentiation, and apoptosis, while an inhibitor of JNK reduced apoptosis, indicating that the ERK1/2 and JNK pathways are critical components of FGF2-mediated effects in JK-GMS cells. Additional comparative analyses of FGF2-mediated effects in two ES cell lines (CADO-ES, RD-ES) and a PNET cell line (SK-N-MC) showed pronounced differentiation in SK-N-MC, but not in CADO-ES or RD-ES cells. This study demonstrates that FGF2 can induce neuronal differentiation of PNET including Askin tumour. These findings clearly indicate that the FGF2-mediated signalling pathway plays a critical role in controlling the major properties of PNET cells and may provide a potential therapeutic target for PNET.
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PMID:Fibroblast growth factor 2 induces differentiation and apoptosis of Askin tumour cells. 1469 27

Neuroectodermal tumors are highly malignant and increasingly common tumors. Because the cure rate of these neoplasias by conventional treatment is very low, new therapeutic approaches are needed. Entrapping high concentrations of cytotoxic drugs and/or oligonucleotides within stabilized liposomal formulations represents an emerging modality of antitumor treatment. Here, we tested the in vitro and in vivo antitumor effects of a novel antisense oligodeoxynucleotide (asODN) liposomal formulation, the coated cationic liposomes (CCL), by targeting the c-myc and the c-myb oncogenes on melanoma and neuroblastoma, respectively, through the use of a monoclonal antibody against the disialoganglioside GD2, selectively expressed by neuroectoderma-derived tumors. Our methods produced GD2-targeted liposomes that stably entrapped 90 percent of added asODNs. These liposomes showed selective binding for GD2-positive tumor cells in vitro. Neuroblastoma cells treated with free myb-as or nontargeted CCL-myb-as showed the same level of c-myb protein expression as control cells. In contrast, c-myb protein expression of cells treated with aGD2-CCL-myb-as was inhibited by approximately 70 percent. Melanoma and neuroblastoma cell proliferation was inhibited to a greater extent by GD2-targeted liposomes containing c-myc or c-myb asODNs than by nontargeted liposomes or free asODNs. Mice bearing established subcutaneous human melanoma xenografts treated with aGD2-CCL-myc-as exhibited significantly reduced tumor growth and increased survival. The mechanism for the antitumor effects appears to be downregulation of the expression of the c-myc protein, induction of p53, and inhibition of Bcl-2 proteins, leading to extensive tumor cell apoptosis. In contrast, the increased life span obtained in a neuroblastoma pseudometastatic mouse model with the liposomal c-myb asODNs seems to be due to a synergistic mechanism: specific targeting to neuroblastoma cancer cells, downmodulation of c-myb protein expression, and stimulation of the innate immune system. These results suggest that inhibition of c-myc or c-myb proto-oncogenes by GD2-targeted antisense therapy could provide an effective approach for the treatment of neuroectodermal tumors in an adjuvant setting.
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PMID:Targeted delivery of oncogene-selective antisense oligonucleotides in neuroectodermal tumors: therapeutic implications. 1565 Feb 35

c-myc and N-myc belong to the myc family of proteins that plays an important role in cell proliferation, differentiation and apoptosis. The N-myc gene is amplified in aggressive neuroblastoma and c-myc is overexpressed in many lymphomas and cancers. However, c-myc has not been implied in tumorigenesis or progression of neuroblastoma. We therefore investigated the so far unknown effects of c-myc overexpression on the aggressiveness of neuroblastoma cells with single copy N-myc. c-myc overexpression in serum-deprived murine NXS2 neuroblastoma cells led to cell cycle progression and massive apoptosis, causing a net decrease of viable cells. In serum-replete medium c-myc caused NXS2 cells to arrest in G2/M. Furthermore, c-myc decreased clonogenic growth of neuroblastoma cells. Taken together, these data suggest that c-myc attenuates the malignant phenotype of NXS2 neuroblastoma cells. Thus, although c-myc increased NXS2 tumor mass in vivo, c-myc appears to have decreased malignant potency in neuroblastoma cells compared to N-myc. This may be one reason why c-myc does not play a role in neuroblastomagenesis.
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PMID:Growth inhibition of murine neuroblastoma cells by c-myc with cell cycle arrest in G2/M. 1568 16


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