Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Somatostatin and other neuropeptides are expressed in tumors originating from neuronal precursors and paraganglia, namely medulloblastoma, central Primitive Neuro-Ectodermal Tumors (cPNETs), neurocytoma, gangliocytoma. olfactory neuroblastoma, paraganglioma. In medulloblastoma, the most common malignant tumor in childhood, there is an extensive expression of somatostatin in addition to somatostatin receptors (SSTR) type 2. Although density of SSTR-2 and intensity of expression of somatostatin genes have no prognostic significance in medulloblastoma. their presence may bring along important information on oncogenesis and relate medulloblastoma to cPNETs. Radio-labeled octreotide scintigraphy may be useful in the follow-up of these patients. allowing differentiation between scar and tumoral tissue. Moreover, on the basis of octreotide-induced inhibition of cell proliferation in medulloblastoma, a trial with octreotide in patients with recurrent or high-risk tumor is warranted. Meningiomas and low-grade astrocytic gliomas, even if not displaying a clear neuroendocrine phenotype, have high levels of SSTR-2. In meningiomas, SSTRs-scintigraphy is not part of the routine pre-operative assessment; moreover, a therapeutic trial with somatostatin-analogues in patients with recurrent or inoperable meningiomas should be carried-out with great caution, because somatostatin and octreotide slightly increase cell proliferation in cultured meningiomatous cells. Low-grade gliomas (WHO grade 2), and a smaller fraction of anaplastic astrocytomas, express SSTR-2, while glioblastomas usually do not. Unfortunately, radiolabeled-octreotide scintigraphy is not useful in the differential diagnosis of gliomas, because the results are altered by the disruption of the blood brain barrier (BBB); in addition, radionuclide-labeled somatostatin analogues are not useful in the therapy of low-grade gliomas, because the intact BBB prevents them from reaching the target SSTR-2. Recently, a pilot study in gliomas, has proposed the use of a radio-labeled somatostostatin analogue with a loco-regional approach in order to overcome the intact BBB.
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PMID:Neuroendocrine tumors in the brain. 1176 40

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

B -Catenin is closely associated with carcinoma invasion/metastasis and poor survival. Recent studies have demonstrated that abnormal expression of B -catenin, especially its nuclear accumulation, also plays an important role in wingless/Wnt signaling pathway. In this study, we evaluated immunohistochemically the nuclear localization of B -catenin in a total of 93 human-endocrine-related tumors including 1 medullary carcinoma (thyroid gland), 12 parathyroid tumors, 22 carcinoid tumors (digestive tract and liver), 7 islet cell tumors, 26 adrenocortical tumors, 13 neuroblastoma (adrenal gland), and 12 pheochromocytoma (adrenal gland), and also studied genetic alterations of the B -catenin gene. Nuclear accumulation of B -catenin was frequently detected in 8 of 22 (36%) carcinoid tumors and 2 of 7 (29%) islet cell tumors. No genetic alteration in exon 3 of the B -catenin gene encoding serine/threonine rich domain, which was phosphorylated by GSK-3 B, was detected in any groups of the endocrine tumors. However, nuclear accumulation of B -catenin in carcinoid tumors was significantly correlated with the proliferative marker Ki-67 (MIB-1) labeling index (p <0.001). Our findings suggest that nuclear transfer and accumulation of the B -catenin may contribute in the tumorigenesis of carcinoid tumor as an oncoprotein.
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PMID:Nuclear Accumulation of B-Catenin in Human Endocrine Tumors: Association with Ki-67 (MIB-1) Proliferative Activity. 1211 96

Clues to mechanisms regulating development and tumorigenesis may be provided by studies of unusual diseases. Beckwit-Wiedemann syndrome (BWS) is a rare congenital disorder apparently related to abnormal regulation of insulin-like growth factor-2 (IGF-2) production. IGF2 mRNA has been previously localized to the chief cells of extra-adrenal paraganglia and to adult, but not fetal, adrenal medulla. Expression of IGF-2 by neuroblastomas has been hypothesized to reflect extra-adrenal paraganglionic differentiation. In the adrenals of a fetus with 8W5, we have observed both increased numbers of chromaffin cells and organoid nodules resembling extra-adrenal paraganglia. Immunoreactive IGF-2 was observed in both cell types, but was also observed in chromaffin cells in the normal fetal adrenal. The findings suggest autocrine or paracrine influences of IGF-2 in regulating the number and phenotype of cells derived from sympathoadrenal precursors in the developing adrenal medulla as well as in extra-adrenal paraganglia. These results have implications for the interpretation of data from neuroblastoma studies.
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PMID:Adrenal Medullary Nodules in Beckwith-Wiedemann Syndrome Resemble Extra-Adrenal Paraganglia. 1211 97

Midkine (MK) is a developmentally regulated, secreted growth factor homologous to pleiotrophin (PTN). To investigate the potential role of MK in tumor growth, we expressed MK in human SW-13 cells and studied receptor binding, signal transduction, and activity of MK. The MK protein stimulates soft agar colony formation in vitro and tumor growth of SW-13 cells in athymic nude mice, as well as proliferation of human endothelial cells from brain microvasculature and umbilical vein (HUVEC) in the low ng/ml range. MK binds to anaplastic lymphoma kinase (ALK), the receptor for PTN, with an apparent K(d) of 170 pm in intact cells, and this receptor binding of MK is competed by PTN with an apparent K(d) of approximately 20 pm. Monoclonal antibodies raised against the extracellular ligand-binding domain of ALK inhibit ALK receptor binding of MK as well as MK-stimulated colony formation of SW-13 cells. Furthermore, MK stimulates ALK phosphorylation in WI-38 human fibroblasts and activates PI3-kinase and MAP kinase signal transduction in WI-38, HUVEC, neuroblastoma (SH SY-5Y) and glioblastoma (U87MG) cells that express the ALK protein. We conclude that MK can act as a growth, survival, and angiogenic factor during tumorigenesis and signals through the ALK receptor.
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PMID:Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types. 1212 9

Testicular germ cell tumours (TGCTs) are histologically heterogeneous neoplasms with variable malignant potential. Previously, we demonstrated frequent 3p allele loss in TGCTs, and recently we and others have shown that the 3p21.3 RASSF1A tumour suppressor gene (TSG) is frequently inactivated by promoter hypermethylation in a wide range of cancers including lung, breast, kidney and neuroblastoma. In order to investigate the role of epigenetic events in the pathogenesis of TGCTs, we analysed the promoter methylation status of RASSF1A and nine other genes that may be epigenetically inactivated in cancer (p16(INK4A), APC, MGMT, GSTP1, DAPK, CDH1, CDH13, RARbeta and FHIT) in 24 primary TGCTs (28 histologically distinct components). RASSF1A methylation was detected in four of 10 (40%) seminomas and 15 of 18 (83%) nonseminoma TGCT (NSTGCT) components (P=0.0346). None of the other nine candidate genes were methylated in seminomas, but MGMT (44%), APC (29%) and FHIT (29%) were frequently methylated in NSTGCTs. Furthermore, in two mixed germ cell tumours, the NSTGCT component for one demonstrated RASSF1A, APC and CDH13 promoter methylation, but the seminoma component was unmethylated for all genes analysed. In the second mixed germ cell tumour, the NSTGCT component was methylated for RASSF1A and MGMT, while the seminoma component was methylated only for RASSF1A. In all, 61% NSTGCT components but no seminoma samples demonstrated promoter methylation at two or more genes (P=0.0016). These findings are consistent with a multistep model for TGCT pathogenesis in which RASSF1A methylation occurs early in tumorigenesis and additional epigenetic events characterize progression from seminoma to NSTGCTs.
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PMID:Frequent epigenetic inactivation of the RASSF1A tumour suppressor gene in testicular tumours and distinct methylation profiles of seminoma and nonseminoma testicular germ cell tumours. 1254 68

Cyclin D1 regulates G1 cell cycle progression by controlling the phosphorylation of the retinoblastoma protein. This pathway is frequently deregulated in many malignancies. In neuroblastoma, however, no consistent G1 cell cycle checkpoint aberrations have been found. We examined the possible deregulation of cyclin D1 (CCND1) in this tumor. mRNA expression profiles of neuroblastoma generated by SAGE (Serial Analysis of Gene Expression) revealed a high expression of CCND1 in a subset of neuroblastoma cell lines and tumors. The CCND1 expression level can be 0.3% of the total cellular mRNA. Northern blot analysis of CCND1 expression showed a relative overexpression in 16 of 23 neuroblastoma cell lines and 10 of 15 tumor samples. In the majority of cases, the high CCND1 mRNA levels also led to high CCND1 protein levels. In the search for mechanisms causing this relative overexpression, we screened for amplifications and rearrangements of CCND1. Five amplifications were found in 202 neuroblastoma tumors and cell lines. Analysis of the 3'-UTR of CCND1 showed a rearrangement in 1 of 96 tumors. These clonal aberrations of CCND1 together with the high expression suggest a role for deregulated CCND1 activity in neuroblastoma tumorigenesis.
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PMID:Rearrangements and increased expression of cyclin D1 (CCND1) in neuroblastoma. 1255 24

Neuroblastoma is characterized by several distinct genetic alterations including MYCN amplification, chromosome 1p deletion and gain of chromosome 17. Although these alterations are thought to play a crucial role in oncogenesis, to date little is known about their underlying mechanisms. In order to more precisely document these genetic alterations, we have performed a combined study of 27 neuroblastoma cell lines using 24-color karyotyping (24-CK) and comparative genomic hybridization (CGH). 24-CK detected balanced translocations in 13 cases with recurrent involvement of chromosome 8. More importantly, 144 nonreciprocal translocations were observed in the 27 cell lines, with chromosome 1 as the most frequent recipient and chromosome 17 the most frequent donor. Each cell line exhibited at least one unbalanced translocation involving 17q, with 14 cell lines demonstrating more than one such translocation. Other recurrent alterations were amplification of the 2p24 chromosome region, which encodes the MYCN oncogene, losses of 1p, 3p and 11q, and gains of 1q and 7. In most cases, CGH profiles were directly linked to the presence of unbalanced translocations with gain of the donor fragment and loss of the replaced region on the recipient chromosome. Strikingly, over 60% of the chromosome breakpoints mapped to early replicating chromosome bands, which represent around 13% of the genome. Altogether these data suggest that neuroblastoma is characterized by rearrangements that predominantly involve chromosome fragments replicating early in the S-phase.
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PMID:Combined 24-color karyotyping and comparative genomic hybridization analysis indicates predominant rearrangements of early replicating chromosome regions in neuroblastoma. 1258 96

Many distinct regions of 3p show frequent allelic losses in a wide range of tumour types. Previously, the BLU candidate tumour suppressor gene (TSG) encoded by a gene-rich critical deleted region in 3p21.3 was found to be inactivated rarely in lung cancer, although expression was downregulated in a subset of lung tumour cell lines. To elucidate the role of BLU in tumorigenesis, we analysed BLU promoter methylation status in tumour cell lines and detected promoter region hypermethylation in 39% lung, 42% breast, 50% kidney, 86% neuroblastoma and 80% nasopharyngeal (NPC) tumour cell lines. Methylation of the BLU promoter region correlated with the downregulation of BLU transcript expression in tumour cell lines. Expression was recovered in tumour cell lines treated with 5-aza 2-deoxycytidine. Exogenous expression of BLU in neuroblastoma (SK-N-SH) and NSCLC (NCI-H1299) resulted in reduced colony formation efficiency, in vitro. Furthermore, methylation of the BLU promoter region was detected in primary sporadic SCLC (14%), NSCLC (19%) and neuroblastoma (41%). As frequent methylation of the RASSF1A 3p21.3 TSG has also been reported in these tumour types, we investigated whether BLU and RASSF1A methylation were independent or related events. No correlation was found between hypermethylation of RASSF1A and BLU promoter region CpG islands in SCLC or neuroblastoma. However, there was association between RASSF1A and BLU methylation in NSCLC (P=0.0031). Our data suggest that in SCLC and neuroblastoma, RASSF1A and BLU methylations are unrelated events and not a manifestation of a regional alteration in epigenetic status, while in NSCLC there may be a regional methylation effect. Together, these data suggest a significant role for epigenetic inactivation of BLU in the pathogenesis of common human cancers and that methylation inactivation of BLU occurs independent of RASSF1A in SCLC and neuroblastoma tumours.
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PMID:Epigenetic inactivation of the candidate 3p21.3 suppressor gene BLU in human cancers. 1262 21

Neuroblastoma exhibiting deletion of a segment of the long arm of chromosome 11 represents a genetic subtype of tumor that is distinct from those exhibiting MYCN amplification or 1p deletion. The 11q- genetic subtype is further characterized by gain of 17q and loss of distal 3p material. Gain of 11p material has also been reported in neuroblastoma with 11q loss, but at a considerably lower frequency than gain of 17q or loss of the distal 3p region. Our results, however, indicate that gain of 11p may occur more frequently in 11q- neuroblastoma than what was previously realized. Comparative genomic hybridization analyses of neuroblastoma tissue from eleven patients indicated that six of 11 tumors (55%) with loss of 11q also possessed gain of 11p. The shortest region of 11p gain was 11p11.2-->p14. G-banding and fluorescence in situ hybridization analysis performed on tumor cells from primary and metastatic sites from one patient allowed us to infer that gain of 11p arose secondarily to the abnormality that led to the loss of 11q material. Gain of an entire chromosome 7 was detected in 17 of 43 (40%) tumors, whereas gain of 7q was detected in 5 of 43 (12%) tumors. Unlike gain of 11p, gain of an entire chromosome 7 appears to be prevalent in all tumor stages and is not limited to the 11q- tumor subtype. Gain of 7q, however, is more prevalent in higher stage tumors. G-band cytogenetic analysis indicated that an unbalanced t(3;7) was responsible for the gain of 7q and loss of 3p material in one case. We discuss the possibility that gain of 7/7q, and 11p material may contribute to either tumorigenesis or progression.
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PMID:Are gains of chromosomal regions 7q and 11p important abnormalities in neuroblastoma? 1264 51


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