Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Clin Exp Metastasis 1993 Jan
PMID:PCNA levels in neuroblastoma are increased in tumors with an amplified N-myc gene and in metastatic stage tumors. 809 85

The authors describe a case of disseminated neuroblastoma discovered as a paratesticular tumor in a 7-month-old boy. The ectopic adrenal tissues adjacent to the paratesticular tumor and multiple lesions in the adrenal gland and skin suggested the possibility of multifocal primary tumors. Although infantile neuroblastoma diagnosed at less than 1 year of age generally responds well to treatment irrespective of distant metastases, metastases developed, and the boy died of disease within 7 months. All multiple lesions had amplification and overexpression of the N-myc protooncogene, which might explain the aggressive phenotype of this rare case.
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PMID:Paratesticular neuroblastoma with N-myc activation. 830 10

The physiologically active metabolite of vitamin D3, 1,25-dihydroxycholecalciferol (D3), plays an important role in embryonic development and cell differentiation. Previously, we have demonstrated that D3 significantly induces differentiation and inhibits growth of LA-N-5 human neuroblastoma cells at concentrations of 24 nm and higher. In this study, we compared two D3 analogs, 20-epi-22oxa-25a,26a,27a-tri-homo-1,25-D3 (KH 1060) and 1,25-dihydroxy-22,24-diene, 24,26,27-trihomo (EB 1089), with D3 with respect to their effects on differentiation and growth inhibition. We report an inhibition of growth by 45-55% in cells treated with 0.24 nm EB 1089 and 0.24 nM KH 1060, similar to that seen in cells treated with 24 nM D3. At these concentrations, both EB 1089 and KH 1060 stimulate the differentiation of LA-N-5 neuroblastoma cells as shown by increased neurite outgrowth, decreased N-myc expression and decreased invasiveness in vitro. An increase in acetylcholinesterase activity, a functional measure of differentiation, was also exhibited. Previous reports have shown that treatment doses needed to achieve 24 nM serum concentrations of D3 in patients would result in hypercalcemia. EB 1089 and KH 1060 can cause the same in vitro effects on LA-N-5 human neuroblastoma cells at 1/100 of the concentration required of D3. These data suggest a potential clinical efficacy of EB 1089 and KH 1060 as biological response modifiers.
Clin Exp Metastasis 1996 May
PMID:Vitamin D3 analogs inhibit growth and induce differentiation in LA-N-5 human neuroblastoma cells. 867 78

Neuroblastoma (NB), a neural crest derived tumor in children, shows a characteristic pattern of dissemination that includes adrenal glands, local lymph nodes, bone, liver, skin, and bone marrow. We have reconstructed a similar metastatic pattern in SCID mice following tail vein injection of human NB cells. HTLA230, an NB cell line isolated from a patient with advanced disease, and its NGF receptor (trkA) expressing derivative (18-10) cells, consistently disseminated to the liver, the adrenal gland, and the bone marrow, but not the lungs. Metastases in the different organs showed a characteristic hemorrhagic histopathology, and tumors in the bone marrow presented as syncytia-like cell aggregates, typically seen in patients. Cell lines reestablished from 18-10 derived liver and bone marrow metastases maintained their cellular morphology, growth behavior, N-myc overexpression, trkA expression, and functionally responded to NGF treatment, leading to growth arrest and neurite outgrowth. Hence circulating human NB cells in SCID mice show a similar organ-specific metastatic potential as seen in patients, independent of trkA expression.
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PMID:A metastatic neuroblastoma model in SCID mice. 870 12

We investigated the structure and the expression of various oncogenes in three of the most common human bone tumors-osteosarcoma (36 samples from 34 patients), giant cell tumor (10 patients), and chondrosarcoma (18 patients)-in an attempt to identify the genetic alterations associated with these malignancies. Alterations of RB and p53 were detected only in osteosarcomas. Alterations of c-myc, N-myc, and c-fos were detected in osteosarcomas and giant cell tumors. Ras alterations (H-ras, Ki-ras, N-ras) were rare. Chondrosarcomas did not contain any detectable genetic alterations. Our results suggest that alterations of c-myc, N-myc, and c-fos oncogenes occur in osteosarcomas, in addition to those previously described for the tumor suppressor genes RB and p53. Moreover, statistical analyses indicate that c-fos alterations occur more frequently in osteosarcoma patients with recurrent or metastatic disease.
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PMID:Oncogene alterations in primary, recurrent, and metastatic human bone tumors. 889 2

N-myc oncogene expression plays a pivotal role in the biology of neuroblastoma, a common childhood tumor. High N-myc expression is associated with advanced disease stage, and in animal models, increased expression results in increased metastatic potential. In normal embryologic development, N-myc expression is associated with neuroblast migration out from the neural crest. To further define the relationship between N-myc and metastasis, an in vitro assay was adapted to measure tumor cell attachment, motility, and proteolytic ability in neuroblastoma cell lines. These parameters were examined in a non-amplified, uniformly N-myc overexpressing cell line and its anti-sense N-myc expressing clones. These lines have been characterized previously, and have a decrease in N-myc expression, growth rate, and tumorigenicity relative to the parent line and vector-only control transfectant. Decrease in N-myc expression resulted in a non-proportional increase of tumor cell attachment, and a proportional decrease in both tumor cell motility and proteolytic ability. In further experiments, assay of a N-myc-amplified overexpressing cell line with an intrinsic heterogeneous pattern of expression demonstrated that motile cells expressed higher amounts of N-myc relative to the general population. Together these relationships indicate that N-myc plays a causative role in the invasive phenotype, and suggest that metastasis may, in part, result from the disruption of a developmentally important normal process.
Clin Exp Metastasis 1997 Mar
PMID:Modulation of N-myc expression alters the invasiveness of neuroblastoma. 906 89

Alterations in adhesion to the extracellular matrix mediated by integrin receptors are commonly observed in a wide variety of transformed/tumor classes. Reductions in the expression of several integrin subunits have been documented in human neuroblastoma cell lines that over-express the neuroblastoma-associated oncogene N-myc. Neuroblastoma cells transfected with a cDNA encoding N-myc on a high-expression plasmid exhibit greatly reduced levels of alpha2, alpha3 and beta1 integrin subunits with concomitant rounding of cells on substrata. In the current studies, we examined whether integrin downregulation by N-myc is cell-type specific by transfecting a human N-myc cDNA into Saos-2 human osteosarcoma cells and evaluating integrin expression. Several N-myc-expressing cell lines were isolated which exhibit reduced levels of beta1 integrin subunit protein and significant alteration in cell morphology - these cell lines resemble N-myc-over-expressing neuroblastoma cells. In addition to reduced beta1 subunit levels, the osteosarcoma-derived N-myc transfectants exhibit little or no alpha3beta1 integrin complexes, either intracellular or at the cell surface. Finally, reduced amounts of alpha3 integrin subunit in these cell lines occur at the level of alpha3 integrin mRNA, although post-transcriptional mechanisms may also be involved, particularly with inability of pre-beta1 protein to mature. These results confirm our previous studies demonstrating integrin downregulation by an N-myc-dependent process and, in addition, demonstrate lack of cell-type specificity in the action of N-myc on integrin extracellular matrix receptor expression when comparing neural precursor (neuroblastoma) cells with connective tissue (osteosarcoma) cells.
Clin Exp Metastasis 1997 May
PMID:N-myc over-expression downregulates alpha3beta1 integrin expression in human Saos-2 osteosarcoma cells. 917 24

The N-myc oncogene plays a key role in the biology of neuroblastoma and the differentiation process. N-myc expression is associated with metastatic disease, as well as the undifferentiated state of normal neuroblasts migrating from the neural crest during embryogenesis. Its down-regulation is a pivotal event in the differentiation of neuroblastoma cells by retinoic acid (RA). Our previous work has shown that RA works synergistically with other agents, such as interferon-gamma (IFN-gamma), to down-regulate N-myc expression and induce differentiation. The present study demonstrates that IFN-gamma, like RA, decreases N-myc transcription. However, functional analysis of N-myc upstream regulatory sequences using 5' deletion mutants of a promoter-CAT construct containing germ line sequences from nucleotide position -887 to +151 showed that IFN-gamma and RA act through different sites on the N-myc promoter. In addition to its transcriptional effect, IFN-gamma was also found to shorten the half-life of N-myc mRNA. Taken together, these findings provide a mechanistic basis for the synergistic action of IFN-gamma and RA in inducing neuroblastoma differentiation and a rationale for the possible development of combination differentiation therapy for clinical use.
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PMID:Interferon-gamma and retinoic acid down-regulate N-myc in neuroblastoma through complementary mechanisms of action. 957 Mar 57

Neuroblastoma is a very common solid tumor which arises in childhood and shows an extreme heterogeneity at the clinical, histological and genetic levels. Besides age and stage, N-myc amplification and 1p deletion are prognostic factors of the disease: in Europe, these genetic markers are used to conduct therapy. In France, N-myc amplification is a factor of bad prognosis which leads, in all forms of the disease including localised forms and metastatic forms of children aged of less than 1 year, to a myeloablative treatment with autologous hematopoietic stem cells transplantation. By contrast, N-myc amplification has no impact on the survival of children aged of more than 1 year with a poor prognosis (30% overall survival, 5 years) but this genetic abnormality is taken into account to treat primary tumor of these patients. In an attempt to find out prognostic factors of these aggressive forms of the disease, various pathways (apoptosis, differentiation angiogenesis, detoxication, immune response) have been recently surveyed, but studies have been carried out on a limited number of genes. Moreover, experimental models of human metastatic neuroblastoma have been obtained in which variations of genes transcript levels involved in these pathways, are observed. The current break-through of cDNA microarrays allows to develop a dynamic transcriptomic scanning of these models as well as of tumors and bone marrows from patients upon conventional chemotherapy. This technology will enable: i) to define molecular entities of the metastatic disease; ii) to apply adapted treatment; iii) to develop new therapeutic strategies.
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PMID:[A functional gene map is required to adapt therapy of metastatic neuroblastoma]. 1131 7

In spite of aggressive therapy, children suffering from neuroblastoma have a poor prognosis. Therapeutic failure is most often observed in neuroblastomas with unfavorable features, including amplification/over-expression of the N-myc oncogene, rapid growth, effective angiogenesis and/or the tendency to metastasize. Here, we have used cultured human neuroblastoma cells with such features and we have examined whether antiangiogenic agents alone or in combination with tumor irradiation inhibit their angiogenesis and growth in vivo. We report that antiangiogenic agents (arginine deiminase, SU5416 and DC101) inhibit in vivo growth of neuroblastomas with unfavorable properties and that these effects are potentiated by simultaneous irradiation. Combination of either agent with irradiation leads to a reduction in the absolute number of tumor vessels and of perfused tumor vessels. Combination of arginine deiminase or DC101 with irradiation does not increase tumor hypoxia. Our data demonstrate for the first time that arginine deiminase suppresses the growth of unfavorable experimental neuroblastomas and that this effect is potentiated by irradiation. We suggest that antiangiogenesis alone or in combination with established therapeutic regimen may improve the outcome of unfavorable neuroblastomas in a clinical setting.
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PMID:Arginine deiminase and other antiangiogenic agents inhibit unfavorable neuroblastoma growth: potentiation by irradiation. 1286 32


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