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)

Phosphatidylinositol (PI) breakdown represents a powerful system participating in the transduction mechanism of some neurotransmitters and growth factors and producing two second messengers, diacylglycerol and inositol trisphosphate. The transformation of PC12 neuroblastoma cells into neuron-like cells induced by nerve growth factor (NGF) is preceded by a rapid stimulation of PI breakdown; however, it was not known whether PI breakdown mediates actions of other members of the neurotrophin family. The present study analyzed the effects of NGF, brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) on PI breakdown in primary cultures of embryonic rat brain cells. Cultures were grown for 7 days; PI was then labeled by incubating cultures with myo-[3H]inositol, which then were exposed acutely to growth factors. BDNF and NT-3, but not NGF, elevated the levels of labeled inositol phosphates within 10-15 min after addition to the cultures in a dose-dependent manner. ED50 values for BDNF and NT-3 were 12.4 and 64.5 ng/ml, respectively. Comparable effects were found in cultures of cortical, striatal, and septal cells. The actions of BDNF and NT-3 probably reflect actions on neurons, because no effects were seen in cultures of nonneuronal cells. In contrast, basic fibroblast growth factor induced a marked stimulation of PI breakdown in cultures of nonneuronal cells. K252b, which selectively blocks neurotrophin actions by inhibiting trk-type receptor proteins, prevented the PI breakdown mediated by BDNF and NT-3. The findings suggest that rapid and specific induction of PI breakdown is involved in the signal transduction of BDNF and NT-3, and they provide evidence that cortical neurons are functionally responsive to BDNF and NT-3 during development.
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PMID:Stimulation of phosphatidylinositol hydrolysis by brain-derived neurotrophic factor and neurotrophin-3 in rat cerebral cortical neurons developing in culture. 143 96

Trk receptors are a family of genes implicated in the survival, differentiation, and growth of certain neurons and tumors of the nervous system. A better understanding of the regulation of Trk receptors is relevant for developmental and oncological studies. Human neuroblastoma (NB) cell lines constitutively express low levels of TrkA mRNA, while TrkB mRNA is not readily detectable. Differentiation of NB cells is accompanied by a differential modulation of Trk expression in human NB cells. Nanomolar concentrations of RA induce a stable increase of TrkB mRNA. A transient induction of TrkA mRNA levels requires micromolar concentrations of RA. Induction of both TrkA and TrkB mRNA does not require new protein synthesis. However, RA-induced TrkB mRNA expression is transcriptionally regulated, while the transient RA-induced increase of TrkA mRNA is a consequence of extended mRNA stability. Interferon gamma (IFN-gamma) selectively increases TrkA mRNA without affecting TrkB mRNA levels. Similar to RA, IFN-gamma does not modify the transcriptional rate of TrkA mRNA, but rather increases TrkA mRNA stability. Thus, RA and IFN-gamma differentially regulate TrkA or TrkB expression in the same cell type by predominantly transcriptional (TrkB) or post transcriptional (TrkA) mechanisms. Such experiments indicate the complexity of Trk mRNA regulation and also indicate compounds that may affect neurotrophin responsiveness in developing neural cells.
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PMID:Selective regulation of TrkA and TrkB receptors by retinoic acid and interferon-gamma in human neuroblastoma cell lines. 755 88

Interactions of the trk family of tyrosine kinase receptors with neurotrophins result in growth and maturational changes in neuronal cells. The continued progression, maturation, or regression of neuroblastoma, an embryonal, sympathetic nervous system-derived tumor of infants and children, might be governed by neurotrophic influences. Immunocytochemistry was utilized to evaluate TrkA, TrkB, and TrkC protein expression at the cellular level in the developing human fetal sympathetic nervous system and in a selection of neuroblastoma tumor specimens. TrkA and TrkC expression was identified in sympathetic ganglia and within the adrenal medulla, with intense TrkB expression restricted to paraganglia, of the normal developing human sympathetic nervous system. In neuroblastoma, pp140trkA expression correlated positively with favorable tumor stage (P = 0.0027) and favorable outcome (P = 0.026). No statistically significant correlation of TrkC expression with outcome was evident; however, both TrkA and TrkC expression was most apparent in tumor cells of increased differentiation. TrkB expression was primarily localized to cells within the fibrovascular tumor stroma. A model of neurotrophin receptor expression and neurotrophin reactivity with differentiation is proposed. The existence and spatial distribution of neurotrophin receptors in neuroblastoma lend supportive evidence that neurotrophic influences may be involved in tumor persistence or regression.
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PMID:Association of neurotrophin receptor expression and differentiation in human neuroblastoma. 760 72

Several genetic features have been identified that are characteristic of neuroblastomas. These include hyperdiploidy, deletion of 1p, amplification of N-myc, and expression of the neurotrophin receptor, TRK-A. These genetic characteristics allow neuroblastomas to be categorized into three subtypes, with distinct clinical features and behavior. In the past, neuroblastoma had been considered to be a disease with a better outcome if diagnosed early. However, it is now apparent that the tumors occurring in infants are genetically different than those in older children, and a genetically favorable subtype seldom, if ever, evolves into an unfavorable one. Different approaches may be necessary for each subtype, and the molecular pathology of the tumor may be better at predicting outcome than patient age and disease stage.
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PMID:Molecular pathology of human neuroblastomas. 780 5

Retinoic acid (RA) induces the neuronal differentiation of many human neuroblastoma cell lines. In this study, we show that RA treatment of neuroblastoma cells induces the expression of TrkB, the receptor for the neurotrophins BDNF, NT-3, and NT-4/5. BDNF addition to RA-treated SH-SY5Y neuroblastoma cells stimulated the tyrosine phosphorylation of TrkB and neuronal differentiation. RA treatment of KCNR neuroblastoma cells, which constitutively express BDNF mRNA, resulted in the expression of TrkB and differentiation in the absence of added BDNF. Finally, in 15N neuroblastoma cells, which express BDNF mRNA but do not differentiate in response to RA, RA induced only a truncated form of TrkB. 15N cells transfected with full-length TrkB differentiated in the absence of RA. These results indicate that RA induces the neuronal differentiation of neuroblastoma cells by modulating the expression of neurotrophin receptors.
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PMID:Induction of TrkB by retinoic acid mediates biologic responsiveness to BDNF and differentiation of human neuroblastoma cells. Eukaryotic Signal Transduction Group. 839 22

Human neuroblastomas have been found to express the neurotrophin receptors TrkA and TrkB. Expression of TrkA correlates with favorable outcome, while expression of full-length TrkB is associated with unfavorable, more aggressive, N-myc amplified tumors. In this study we have determined the expression of TrkC in neuroblastoma primary tumors and cell lines. Using probes for the extracellular domain and the tyrosine kinase domain of human TrkC, we found by Northern analysis that TrkC mRNA is expressed in 14 of 55 (25%) tumors from a representative panel of neuroblastomas. A 14 kb transcript was detected by both probes, indicating that it would encode the full-length TrkC protein. A significant association was found between TrkC mRNA expression detected by Northern analysis and lower stage tumors [stage 1, 2, 4S, 11 of 30 (37%); vs stage 3, 4, 3 of 25 (12%), chi2 = 4.4, P < 0.04]. Only one of eight primary tumors with N-myc amplification had detectable TrkC mRNA expression and none of the eight neuroblastoma cell lines expressed TrkC by Northern analysis. Our results suggest that TrkC is involved in the biology of favorable neuroblastomas.
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PMID:Expression of TrkC in favorable human neuroblastomas. 855 97

Immunotoxins have been used to study the targeting of biologically active substances at neurons in vivo and to make experimental neural lesions. OX7-saporin, directed against Thy 1, destroys any neuron. 192 IgG-saporin, directed against the 'low affinity' neurotrophin receptor (p 75NTR), selectively destroys neurons expressing this receptor (sympathetic, sensory, cholinergic basal forebrain, cerebellar Purkinje). Anti-D beta H-saporin, directed against dopamine beta-hydroxylase, the enzyme that converts dopamine to norepinephrine, selectively destroys noradrenergic neurons (sympathetic, CNS). These agents show that several types of neural antigens may prove useful in treating pain, and anti-D beta H-saporin may be active against pheochromocytoma or neuroblastoma.
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PMID:Targeting toxins to neural antigens and receptors. 874 May 62

Childhood neuroblastoma tumours of the sympathetic nervous system show a remarkable clinical heterogeneity ranging from spontaneous regression to unfavourable outcome despite intensive therapy. Favourable neuroblastomas often express high levels of trkA mRNA, encoding the tyrosine kinase receptor for nerve growth factor. We have investigated mRNA expression for the neurotrophin receptor trkC in 23 primary neuroblastomas using a sensitive RNAase protection assay. TrkC expression was detected in 19 of these tumours at highly variable levels with a 300-fold difference between the highest and lowest values. Significantly higher levels of trkC mRNA were found in tumours from patients with favourable features such as low age (P < 0.012), favourable tumour stage (P < 0.012) and favourable prognosis (P < 0.05). Children with intermediate or high trkC mRNA expression had better prognosis compared with those with low or undetectable levels (83.3% vs 20%, P = 0.005). Further characterisation of trkC mRNA expression by reverse transcriptase-polymerase chain reaction (RT-PCR) showed that mRNA encoding the full-length cytoplasmic tyrosine kinase domain of the receptor was only expressed in a subset of favourable tumours. These data show that favourable neuroblastomas may express the full trkC receptor while advanced tumours, in particular MYCN-amplified neuroblastoma, seem to either express no trkC or truncated trkC receptors of as yet unknown biological function. These data are suggestive of a role for trkC and its preferred ligand neutotrophin-3, NT-3, in neuroblastoma differentiation and/or regression.
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PMID:Expression of mRNA for the neurotrophin receptor trkC in neuroblastomas with favourable tumour stage and good prognosis. 879 81

The nerve growth factor receptor TrkA was initially isolated as a transforming oncogene, trk, in which most of the extracellular receptor part is replaced by the coding sequence for a tropomyosin-encoding gene. The impact that the identification of the first neurotrophin receptor has made on the entire field of developmental neurobiology cannot be overstated. Following a brief introduction to the biology of neurotrophins and their receptors, this review will focus on oncogenic Trk in human malignant disorders, discuss putative tumorigenic involvement of Trk family members in the childhood malignancy neuroblastoma, and point out potential neurotrophin-based treatment modalities for this and other neuroendocrine tumors.
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PMID:Neurotrophin receptors, tumor progression and tumor maturation. 889 38

In neuroblastoma, high levels of mRNA for p140trkA and p75LNGFR neurotrophin receptors are predictive of favorable outcome. Their evaluation by Northern blot, however, requires substantial amounts of tissue and this prevents their routine evaluation as well as the possibility for multicenter studies to be easily carried out. In an attempt to overcome these limitations, the feasibility and reliability of determining both neurotrophin receptors on cryostat sections by immunohistochemistry were assessed, and these findings were compared to those obtained from Northern blot analysis. Primary tumor samples from 28 untreated patients at all stages were evaluated by using H10 anti-p140trkA and ME20.4 anti-p75LNGFR mAbs. Although weak, positive immunostaining was found in 9 of 28 tumors for p140trkA and in 5 of 28 tumors for p75LNGFR. As compared to Northern blot, the concordance rate was 79% (22 of 28 cases) for p140trkA (p < 0.05) and 71% (20 of 28 cases) for p75LNGFR (p < 0.05). No case negative for Northern blot was found to be positive with immunohistochemistry. Since only high mRNA levels for both receptors have been shown to be clinically relevant, their immunohistochemical detection, although less sensitive than Northern blot, can be just as sufficient and reliable as a prognostic tool, and possibly with a better cost-benefit ratio.
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PMID:Immunohistochemical detection of p140trkA and p75LNGFR neurotrophin receptors in neuroblastoma. 904 31


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