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)

We have examined the expression of 72-kDa gelatinase/type IV collagenase or matrix metalloproteinase-2 (MMP-2) and its inhibitor, tissue inhibitor of metalloproteinase-2 (TIMP-2), in various cell lines derived from paediatric tumours. In a neuroblastoma model system of tumour progression, the expression level of MMP-2 mRNA was higher in the more malignant cell line. Surprisingly, MMP-2 was not expressed in the highly malignant rhabdomyosarcoma A-204 cell line. TIMP-2 showed higher expression levels in the 007 and U-2OS tumour cell lines than in the more malignant ones, WAC2 and A-204 cells. We have also determined the effect of some tumour cell proliferation modulators on gelatinolytic activity. While basic fibroblast growth factor and retinoic acid produced no apparent change in gelatinolytic activity, genistein induced in partial inhibition of gelatinolytic activity.
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PMID:Matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 expression in paediatric tumour cells. Effects of tumour cell proliferation modulators on gelatinolytic activity. 776 64

We have identified and characterized a novel human tissue inhibitor of metalloproteinase (TIMP). It is found exclusively in the extracellular matrix of a large number of cultured human cells, including: primary embryonal kidney (293), neuroblastoma (SK-N-SH), normal whole embryo (FHs 173We), cervical carcinoma (HeLa S3), colon adenocarcinoma (Caco-2), ileocecal adenocarcinoma (HCT-8), fibrosarcomas (SW 684 and Hs 913T) and normal gingival fibroblasts (GF11 and 1292). It was not detected in the conditioned media from any of these cell lines. Its apparent molecular mass of 24-25 kDa, as determined by its migration on protease-substrate gels, is intermediate between TIMP-1 (28.5 kDa) and TIMP-2 (21 kDa). Like the latter two proteins, human TIMP-3 contains intrachain disulfide bonds and displays altered electrophoretic mobility in the presence of beta-mercaptoethanol. The N-terminal, amino acid sequence of the protein is identical to that of chicken TIMP-3 (ChIMP-3), and its amino acid composition is similar. The protein is not N-glycosylated, as determined by treatment with N-glycosidase-F. Finally, it is recognized by antisera raised against pure ChIMP-3 but not by anti-human TIMP-1 or anti-human TIMP-2 antibodies. Based on these properties, we propose that this protein is TIMP-3 and is the human counterpart of ChIMP-3 (Pavloff et al., J. Biol. Chem. 267: 17321-17326, 1992). Two additional inhibitors detected in the matrix of human cell lines, designated inhibitor of metalloproteinase (IMP)-a and IMP-b, migrate with apparent masses of 29 kDa and 30 kDa. Both are N-glycosylated. A fourth inhibitor activity, which is smaller in mass than TIMP-3 and is also pecifically located in the matrix, is detectable in some cell lines.
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PMID:Identification and characterization of human tissue inhibitor of metalloproteinase-3 and detection of three additional metalloproteinase inhibitor activities in extracellular matrix. 779 86

The ets transcription factor E1AF can activate several matrix-degrading metalloproteinase (MMP) genes and is implicated in enhancement of tumor cell invasion. Here we compared the invasive activity of five human neuroblastoma cell lines (TGW, GOTO, SK-N-BE, SK-N-SH and SK-N-AS), which exhibit distinct levels of N-myc amplification, together with the expression of E1AF. Extracellular matrix-degrading proteases and their inhibitor proteins, which play an important role in local invasion, were also analyzed. The activity to invade through reconstituted basement membrane was high in cells (TGW, GOTO, and SK-N-BE) with N-myc amplification, and these cells produced relatively large amounts of E1AF mRNA, correlating with the invasive activities. Of several matrix metalloproteinases (MMPs) and a tissue inhibitor of MMPs (TIMP), only membrane-bound type 1 MMP (MT1-MMP) was specifically detected in N-myc-amplified cells, suggesting a role of MT1-MMP in neuroblastoma cell invasion. MMP-2 (72 kD type IV collagenase), TIMP-1 and TIMP-2 were expressed in all five cell lines. Urokinase-type plasminogen activator was undetectable. These findings indicate that the transcription factors E1AF and N-myc are related to malignant phenotypes of neuroblastoma.
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PMID:Two transcription factors, E1AF and N-myc, correlate with the invasiveness of neuroblastoma cell lines. 919 32

The cytotoxicity of two compounds described as anti-angiogenic, the isoflavone genistein and the oestrogen metabolite 2-methoxyestradiol, has been studied in different human tumour cell lines. Since the degradation of the extracellular matrix is one of the essential steps in angiogenesis, the potential modulatory effects of both compounds on the proteolytic balance in media conditioned by different human tumour cells have been also investigated. The IC50 values for 2-methoxyestradiol were lower than those for genistein on all the cell lines tested. In all the cell lines expressing measurable amounts of active enzymes, genistein induced a shift towards antiproteolysis in both matrix metalloproteinase/tissue inhibitor of metalloproteinase and urokinase/plasminogen activator inhibitor proteolytic balances. On the other hand, 2-methoxyestradiol did not produce any clear net shift of the proteolytic balance, with the significant exception of the matrix metalloproteinase/tissue inhibitor of metalloproteinase balance in WAC-2 cells, a neuroblastoma cell line with enhanced expression of the N-myc oncogene.
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PMID:A comparative study of the effects of genistein and 2-methoxyestradiol on the proteolytic balance and tumour cell proliferation. 1038 72

The amyloid precursor protein (APP) is proteolytically processed predominantly by alpha-secretase to release the ectodomain (sAPPalpha). In this study, we have addressed the cellular location of the constitutive alpha-secretase cleavage of endogenous APP in a neuronal cell line. Incubation of the neuroblastoma cell line IMR32 at 20 degrees C prevented the secretion into the medium of soluble wild-type APP cleaved by alpha-secretase as revealed by both immunoelectrophoretic blot analysis with a site-specific antibody and immunoprecipitation following metabolic labeling of the cells. No sAPPalpha was detected in the cell lysates following incubation of the cells at 20 degrees C, indicating that alpha-secretase does not cleave APP in the secretory pathway prior to or within the trans-Golgi network. Parallel studies using an antibody that recognizes specifically the neoepitope revealed on soluble APP cleaved by beta-secretase indicated that this enzyme was acting intracellularly. alpha-Secretase is a zinc metalloproteinase susceptible to inhibition by hydroxamate-based compounds such as batimastat [Parvathy, S., et al. (1998) Biochemistry 37, 1680-1685]. Incubation of the cells with a cell-impermeant, biotinylated hydroxamate inhibitor inhibited the release of sAPPalpha by >92%, indicating that alpha-secretase is cleaving APP almost exclusively at the cell surface. The observation that alpha-secretase cleaves APP at the cell surface, while beta-secretase can act earlier in the secretory pathway within the neuronal cell line indicates that there must be strict control mechanisms in place to ensure that APP is normally cleaved primarily by alpha-secretase in the nonamyloidogenic pathway to produce the neuroprotective sAPPalpha.
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PMID:Cleavage of Alzheimer's amyloid precursor protein by alpha-secretase occurs at the surface of neuronal cells. 1042 52

ADAM 23 (a disintegrin and metalloproteinase domain)/MDC3 (metalloprotease, disintegrin, and cysteine-rich domain) is a member of the disintegrin family of proteins expressed in fetal and adult brain. In this work we show that the disintegrin-like domain of ADAM 23 produced in Escherichia coli and immobilized on culture dishes promotes attachment of different human cells of neural origin, such as neuroblastoma cells (NB100 and SH-S(y)5(y)) or astrocytoma cells (U373 and U87 MG). Analysis of ADAM 23 binding to integrins revealed a specific interaction with alphavbeta3, mediated by a short amino acid sequence present in its putative disintegrin loop. This sequence lacks any RGD motif, which is a common structural determinant supporting alphavbeta3-mediated interactions of diverse proteins, including other disintegrins. alphavbeta3 also supported adhesion of HeLa cells transfected with a full-length cDNA for ADAM 23, extending the results obtained with the recombinant protein containing the disintegrin domain of ADAM 23. On the basis of these results, we propose that ADAM 23, through its disintegrin-like domain, may function as an adhesion molecule involved in alphavbeta3-mediated cell interactions occurring in normal and pathological processes, including progression of malignant tumors from neural origin.
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PMID:ADAM 23/MDC3, a human disintegrin that promotes cell adhesion via interaction with the alphavbeta3 integrin through an RGD-independent mechanism. 1074 42

Neuroblastomas are biologically heterogeneous tumors that consist of two main cell populations: neuroblastic/ganglionic cells and Schwann cells. The amount of Schwannian stroma strongly impacts prognosis, and favorable outcome is associated with tumors that are Schwannian stroma rich/stroma dominant. At the present time, there is controversy regarding the origin of Schwann cells in neuroblastoma tumors. However, recent studies have suggested that the Schwann cells in mature neuroblastoma tumors may be normal cells that produce soluble substances that enhance the survival and differentiation of neuroblastoma cell lines. Previously, we reported that in neuroblastoma, high vascular index correlated with clinically aggressive disease. In contrast, tumors with favorable histology and abundant Schwannian stroma had low tumor vascularity. As a first step toward investigating whether Schwann cells also play a role in inhibiting angiogenesis in neuroblastoma tumors, we examined the ability of conditioned medium collected from normal human Schwann cells to affect basic fibroblast growth factor- and vascular endothelial growth factor-induced endothelial cell proliferation and migration and in vivo angiogenesis. In vitro angiogenesis assays were also performed with conditioned medium collected from Schwann cells derived from a Schwannian stroma-dominant neuroblastoma tumor. Our results indicate that Schwann cells derived from either adult nerve or tumor tissue produce a potent inhibitor(s) of angiogenesis. Expression studies revealed tissue inhibitor of metalloproteinase (TIMP)-2 in conditioned medium collected from both normal and tumor-derived Schwann cells. In addition, TIMP-2 was detected in the cytoplasm of Schwann cells and ganglion cells in stroma-rich/stroma-dominant neuroblastoma tumors by immunohistochemistry studies. We postulate that the low level of vascularity and more benign clinical behavior of Schwannian stroma-rich/stroma-dominant neuroblastoma tumors result from the Schwann cell production of TIMP-2 and/or other inhibitors of angiogenesis.
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PMID:Schwann cell-conditioned medium inhibits angiogenesis. 1108 14

Thioredoxin (Trx) inhibited tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 activity with an approximate IC50 of 0.3 microM, matrix metalloproteinase (MMP)-2 activity with an approximate IC50 of 2 microM but did not inhibit MMP-9 activity. This differential capacity of Trx to inhibit TIMP and MMP activity resulted in the promotion of MMP-2 and MMP-9 activity in the presence of molar TIMP excess. Inhibition of TIMP and MMP-2 activity by Trx was dependent upon thioredoxin reductase (TrxR), was abolished by Trx catalytic site mutation and did not result from TIMP or MMP-2 degradation. HepG2 hepatocellular carcinoma cells induced to secrete Trx inhibited TIMP activity in the presence of TrxR. SK-N-SH neuroblastoma cells secreted TrxR, which inhibited TIMP and MMP-2 activity in the presence of Trx. Trx stimulated SK-N-SH invasive capacity in vitro in the absence of exogenous TrxR. This study therefore identifies a novel extracellular role for the thioredoxin/thioredoxin reductase redox system in the differential inhibition of TIMP and MMP activity and provides a novel mechanism for altering the TIMP/MMP balance that is of potential relevance to tumor invasion.
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PMID:Thioredoxin alters the matrix metalloproteinase/tissue inhibitors of metalloproteinase balance and stimulates human SK-N-SH neuroblastoma cell invasion. 1116 76

Platelet Activating Factor (PAF), an inflammatory bioactive lipid, has been shown to be involved in the regulation of the activity of matrix metalloproteinases (MMPs). In view of the role played by MMPs in tumor cell invasiveness, we investigated whether PAF influences MMP activity in a system of neuroblastoma clones, the AA5 and AE12 cells, isolated from the human LaN1 neuroblastoma cell line. These clones were characterized by an inverse relationship between invasiveness and differentiative capacity and by the expression of specific cell surface PAF receptors. We found that the levels of mRNAs specific for MMP-2 and for MT1-MMP, the MMP-2 activator, were reduced in both clones treated with 300 nM PAF. These changes are consistent with the reduced secretion and activation of MMP-2 found in the neuroblastoma clones exposed to PAF. These effects were accompanied by an inhibition of invasiveness through Matrigel and by a promotion of differentiation, as revealed by an increased percentage of cells with neurites. The finding that both neuroblastoma clones exposed to the metalloproteinase inhibitors, BB3103 and 1,10-phenanthroline, increased their differentiative capacity and reduced their invasiveness through Matrigel, represents a further indication that PAF modulates differentiation and invasiveness by affecting the activity of MMPs.
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PMID:Platelet activating factor inhibits the expression of matrix metalloproteinases and affects invasiveness and differentiation in a system of human neuroblastoma clones. 1192 13

Neuroblastoma (NB), a common pediatric neoplasm, consists of two main cell populations: neuroblastic/ganglionic cells and Schwann cells. NB tumors with abundant Schwannian stroma display a more benign clinical behavior than stroma-poor tumors. Recent studies suggest that Schwann cells influence NB tumor growth via secreted factors that induce differentiation, suppress proliferation, and inhibit angiogenesis. Two angiogenesis inhibitors, pigment epithelium-derived factor and tissue inhibitor of metalloproteinase-2, have been detected in Schwann cell secretions. Here, we isolated another Schwann cell-derived secreted inhibitor of angiogenesis, a 43-kDa protein identified as SPARC (secreted protein acidic and rich in cysteine), an extracellular matrix protein. We found SPARC to be critical for the antiangiogenic phenotype of cultured Schwann cells. We also show that purified SPARC potently inhibits angiogenesis and significantly impairs NB tumor growth in vivo. SPARC may be an effective candidate for the treatment of children with clinically aggressive, Schwannian stroma-poor NB tumors.
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PMID:SPARC is a key Schwannian-derived inhibitor controlling neuroblastoma tumor angiogenesis. 1249 80


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