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)

The N-myc proto-oncogene is amplified in 25% of neuroblastomas. Amplification is strongly correlated with advanced disease stage and rapid tumor progression. We have constructed a detailed restriction map of the amplified core region in neuroblastomas which will allow the identification of structural features such as joint fragments, rearrangements and CpG islands. Using probes that had been obtained previously, twenty YACs were isolated from a library constructed from a double-minute-containing neuroblastoma cell line with 150-fold amplification of N-myc. Twenty-one YACs also were isolated from two normal human libraries. Normal and neuroblastoma YAC contiguous arrays (contigs), each spanning over 1 Mb of DNA, have been assembled (Molec Cell Biol 12:5563, 1992). A high-resolution restriction map of over 200 kb of contiguous DNA containing N-myc has been generated by subcloning YACs into cosmids. Using cosmids from this region plus additional amplified probes, we have determined that the amplicons from 33 neuroblastomas range in size from 350 kb to over 1 Mb. Rearrangements and deletions were identified in both tumors and cell lines. However joint fragments were not always amplified to the same level as the major amplicon, and may therefore represent a subset of amplicons. We have defined a 130 kb region which was amplified in 32 of the 33 tumors, and one additional tumor had deleted 65 kb of this region from its amplicon. The only CpG island found in this region was within the N-myc gene. Cosmids were screened with radiolabeled total cDNA probes and no highly expressed genes other than N-myc were found in the amplicon.
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PMID:High-resolution mapping of the N-myc amplicon core domain in neuroblastomas. 797 37

N-myc oncogene amplification in neuroblastoma has been found to be significantly associated with advanced stage disease and tumor progression. However, there is a lack of data on tumors, regarding the relationship between N-myc gene amplification and proliferation activity. Proliferating cell nuclear antigen (PCNA) is a proliferation-induced 36 kD nuclear protein that is the auxiliary component of DNA polymerase delta. PCNA levels in tissues have been found to correlate with proliferative activity. We have examined PCNA levels in neuroblastomas in relation to N-myc gene amplification and tumor stage. Statistically, significantly higher levels of PCNA were observed in tumors with an amplified N-myc gene relative to tumors with a single gene copy. The highest levels of PCNA were observed in advanced stage tumors with an amplified N-myc gene. Treatment of neuroblastoma cells in culture with retinoic acid, which induces differentiation, resulted in a substantial decrease in PCNA. Our results suggest that PCNA levels may reflect differences in proliferative activity between neuroblastomas, related to stage of the disease and to N-myc gene copy number.
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PMID:PCNA levels in neuroblastoma are increased in tumors with an amplified N-myc gene and in metastatic stage tumors. 809 85

We have investigated the frequency of p53 gene mutations in Ewing's sarcoma (ES) and neuroblastoma (NB) by using polymerase chain reaction-single strand conformation polymorphism analysis for genomic DNA or complementary DNA generated from total RNA. Mutations of the p53 gene were found in six of seven ES cell lines: a missense mutation of TGC (Cys)-->TAC (Try) at codon 141 in one, a missense mutation of CGT (Arg)-->TGT (Cys) at codon 273 in one, a missense mutation of TGC (Cys)-->TTC (Phe) at codon 176 in three, and one base deletion of CGC-->CG at codon 283 in one. Further analysis of 14 ES and related primary tumors showed mutations of the p53 gene in only two: one base insertion of CCG-->CCCG at codon 152 in one and a missense mutation of GGC (Gly)-->GTC (Val) at codon 154 in the other. Both of the two tumors were obtained from patients with an advanced stage disease. Three of the eight ESs with mutations of the p53 gene showed the same missense mutation at codon 176, suggesting the mutational hot spot of the p53 gene in ESs. In contrast to ES, none of 6 NB cell lines or 48 NB tumors including advanced-stage ones with or without N-myc amplification showed any aberration of the p53 gene. Our findings suggest that mutations of the p53 gene in ES might represent late genetic events related to tumor progression, and that aberrations of the p53 gene might not be involved in the development or the progression of NB.
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PMID:Mutations of the p53 gene are involved in Ewing's sarcomas but not in neuroblastomas. 822 63

Survival rate in neuroblastoma, a tumor of post-ganglionic sympathetic neuroblasts, correlates with disease stage, tumor histology, and N-myc gene amplification. N-myc amplification is associated with rapid tumor progression and poor survival, but is not present in all cases of poor prognosis neuroblastoma. Moreover, overexpression of N-myc is not sufficient to cause cellular transformation. These data suggest that other genetic factors are important for neuroblastoma development. We investigated the expression of the, bcl-2 proto-oncogene in untreated cases of neuroblastoma. bcl-2 is a novel proto-oncogene that promotes cell growth by inhibiting programmed cell death (apoptosis), a form of cellular demise common during normal neurogenesis. Immunocytochemical localization using a monoclonal anti-bcl-2 antibody revealed that 16 of 40 patient specimens stained positive for bcl-2. bcl-2 was strongly associated with unfavorable histology (P = 0.002) and N-myc gene amplification (P = 0.002) and marginally associated with poor stage disease (P = 0.06). A logistic regression model evaluating the simultaneous association of stage, histology, and N-myc revealed that bcl-2 was most associated with unfavorable histology and N-myc gene amplification. These results support the notion that bcl-2 may play an important role in the genesis or progression of malignant neuroblastoma.
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PMID:Expression of the apoptosis-suppressing protein bcl-2, in neuroblastoma is associated with unfavorable histology and N-myc amplification. 825 47

Neuroblastoma (NB) is a childhood cancer of the autonomic nervous system. The molecular pathology of NB is not yet well understood. Both amplification of the proto-oncogene N-myc and loss of heterozygosity of several chromosomal loci occur in NB, representing genetic instability. In this study, we examined another type of genetic instability, microsatellite instability. Five chromosomal loci known to exhibit this alteration in colon, gastric, and pancreatic cancers were used in a PCR-based assay to examine 30 matched normal and tumor DNAs, which included all stages of tumor progression. Among these 30, only 2 (7%) manifested microsatellite instability. There was no correlation between the occurrence of microsatellite instability and the amplification of the N-myc gene. These data show that microsatellite instability is infrequent in neuroblastoma tumors.
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PMID:Microsatellite instability is infrequent in neuroblastoma. 863 65

Multifactorial resistance is the main mechanism of chemotherapy failure in cancers. Multidrug resistance (MDR) is related to the expression of a 170 kDa membrane glycoprotein, the so-called P-glycoprotein (P-gp). This protein is able to extrude drugs of various structures and mechanisms out of the cytoplasm. P-gp is a pronostic value in hemopathy as well as in child sarcoma, osteosarcoma and neuroblastoma. Modulator agents of different generations are capable of inhibiting P-gp. MDR modulation is obtained in hemopathies and is associated with an eradication of the P-gp (+) cell clones. In solid tumors, clinical trials using verapamil or cyclosporin are not so convincing. It is likely that other mechanisms of resistance are responsible for tumor progression, such as the MRP system, glutathion and topoisomerases. A better knowledge of multifactorial resistance and drug synthesis counteracting these resistance mechanisms will allow to elaborate new therapeutic basis for cancer therapy.
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PMID:[MDR (Multiple Drug Resistant) type of resistance to chemotherapy in clinical practice]. 886 40

Gangliosides, sialic acid-containing glycosphingolipids, enhance tumor formation in experimental animals and are associated with tumor progression and metastasis in humans. The mechanism(s) for this activity is (are) unknown. One possibility is enhanced platelet activation, since the interaction of platelets with tumor cells contributes to tumor cell arrest in the vascular compartment. We have previously shown that neuroblastoma tumor gangliosides (NBTG) enhance platelet adenosine triphosphate (ATP) secretion, aggregation, and adhesion. We determined that these NBTG effects are specific for collagen and are mediated through an alpha2 beta1 integrin-dependent mechanism. This report describes the effects of NBTG on a physiologically relevant model of collagen-alpha2 betal interaction. Platelet adhesion to immobilized native collagen fibers similar to those found in the extracellular matrix of blood vessels was determined. Platelet adhesion is enhanced by NBTG in a concentration-dependent manner. Incubation with concentrations of 1 and 10 microM NBTG increased platelet adhesion by 9% and 52%, respectively, compared to less than 1% in controls not incubated with gangliosides (P = 0.001 and P < 0.0001, respectively). In addition to increasing the number of adherent platelets, NBTG promoted more rapid attachment. In NBTG-incubated platelets, platelet adhesion began after a 5-min lag phase and was maximal at 30 min compared to a 20-min lag phase and maximal adhesion at 60 min for control platelets. At 30 min this difference was significant (P = 0.017); however, by 120 min there was no difference between NBTG and controls (P = 0.259). NBTG also induces platelet adhesion at collagen concentrations (0.1 microg) that failed to support adhesion of control platelets. These effects of NBTG require Mg2+ or Mn2+ ions but are not supported by Zn2+ or Ca2+ ions. Furthermore, preincubation of platelets with a blocking antibody (6F1) to the integrin collagen receptor alpha2 beta1 abrogates all of the effects of NBTG. These results indicate that tumor gangliosides enhance platelet adhesion to extracellular matrix collagen and promote rapid stabilization of the collagen-alpha2 beta1 interaction, the initial steps in platelet activation.
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PMID:Effects of neuroblastoma tumor gangliosides on platelet adhesion to collagen. 900 4

Tumor specimens of 203 infants with neuroblastomas of different clinical stages-registered in successive multicenter clinical trials of the German Society of Pediatric Oncology-could be examined for N-myc amplification, chromosome 1-ploidy and-structure, CD44 std. expression (in tumor tissue, and also in patient's sera). Eighty-seven (= 43%) of these infants had a non-localized, disseminated neuroblastoma, mainly involving sympathetic nerve tissue, lymph nodes, liver, skin, bone marrow and bones (46 patients were classified into the 4 group, 41 patients in the true 4 group). If the clinical classification between stage 4 and stage 4s was neglected, then 17 of these infants (= 20%) had N-myc amplification (4-64 copies) with 16 already dead. Seven of 9 examined patients with true stage 4- had chromosome 1p aberrations (with N-myc amplification in 5), and among the dead there were 2 with CD44 negative expression. In another series, serum CD44 std. was measured by ELISA, and the highest (significantly different) Kruskal-Wallis mean rank values (147.8) were found in infants (n = 6) with stage 4s compared to the low mean-rank-value of 71.9 in patients with stage 4 (n = 65). Stage 1-3 patients (n = 42) had values of 99.8-88.6. Thus, infants with disseminated neuroblastomas, showing non-diploidy, normal chromosome 1p structure, non-N-myc amplification and high CD44 std. expression in tumor tissue, and also high CD44 std. values in serum, will have the highest chance of survival due to tumor-non-progression. On the other hand, N-myc amplification in the tumor cells was found to be characteristic for stage 4s neuroblastoma patients with tumor progression (n = 6). Therefore, 4s neuroblastoma-patients with N-myc amplified tumors should be aggressively treated like true stage 4 tumor patients.
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PMID:Disseminated neuroblastomas under 1 year of age: cell biology and prognosis. 904 47

Although there is no definitive evidence of the association of human cytomegalovirus (HCMV) infection with human cancers, the oncogenic potential of HCMV has been well established by in vitro studies demonstrating the ability of UV-irradiated or infectious virus to transform a variety of cells. After prolonged passaging the transformed cell type was maintained while HCMV DNA sequences were no more detectable. Three morphological transforming regions (mtr) of HCMV have been identified. The effects of HCMV on cellular functions which may be associated with the malignant phenotype include the expression of oncogenes and transcriptional activation of growth factors and interleukin synthesis. In infected cells, HCMV induces cytoskeletal alterations and changes in expression of cell surface receptors for extracellular matrix proteins which could result in increased motility and dissemination of cancer cells. Several human neuroblastoma cell lines undergo maturation in different neural crest derived cell types upon treatment with oncogenic potential agents, i.e. retinoic acid. The persistent HCMV infection of neuroblastoma cells (> 1 year) is accompanied by the increased expression of oncoproteins (i.e. N-myc) and decreased expression of tyrosine hydroxylase and dopamine-beta-hydroxylase. The activation of the cellular metabolism is due to HCMV binding to cellular receptors (prior to virus gene expression) and to the activity of HCMV immediate early (IE) gene products. IE proteins act directly as transcriptional activators or their activity is mediated by a variety of cellular transcription factors. HCMV infection may result in activation of promoters of cellular genes coding for cytokines, replication enzymes, proto-oncogenes and viral promoters. Recently it has been demonstrated that HCMV IE proteins block apoptosis probably by suppressing the ability of the antioncogene p53 to activate a reporter gene. The interactions of HCMV with tumor suppressor proteins such as p53 or retinoblastoma (pRb) susceptibility protein are reminiscent of those mediated by the oncoproteins of DNA tumor viruses. The acquisition of a fully malignant phenotype by normal cells is thought to require several mutations in a number of cellular genes. In this connection, HCMV may play the role of a nonobligate either direct or indirect cofactor for tumor genesis, e.g. by blocking apoptosis, which may be an essential requirement for tumor progression. Due to the stimulation of growth factors and/or inhibition of antioncogenes by its gene products, HCMV may modulate the malignant potential for tumor cells.
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PMID:Modulatory effects of human cytomegalovirus infection on malignant properties of cancer cells. 907 67

Amplification of MYCN portends rapid tumor progression and poor prognosis in neuroblastoma. MYCN copy number has been described as homogeneous within a tumor and congruent in primary tumor and metastasis. We report a child with stage III favorable histology stroma-rich neuroblastoma (ganglioneuroblastoma) and a poor outcome with an apparent change in MYCN gene amplification by Southern blot. Initial biopsy revealed a ganglioneuroblastoma with predominance of differentiating cells designated as neuroblastoma, stroma-rich, intermixed (Shimada). Southern blot failed to demonstrate MYCN gene amplification. After front-line chemotherapy failed, a total resection was performed. In this specimen, Southern blot demonstrated MYCN amplification (15-20 copies) in the undifferentiated component and no amplification in the differentiated. Fluorescence in situ hybridization (FISH) analysis performed retrospectively on both tumor biopsies demonstrated MYCN amplification in the undifferentiated sections of both tumor specimens but not in the differentiated ones. This is the first well-documented case report of heterogeneous MYCN amplification in a child with neuroblastoma. Because key therapeutic decisions are based on the presence of MYCN amplification, physicians diagnosing and treating children with neuroblastoma need to be aware of the possibility that MYCN amplification may be heterogeneous within a tumor and may be missed using techniques based on pooled DNA such as Southern blotting. FISH may be a preferable method for determining MYCN amplification.
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PMID:Heterogeneity of MYCN amplification in a child with stroma-rich neuroblastoma (ganglioneuroblastoma). 935 27


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