Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tenascin, an extracellular matrix protein that modulates cell adhesion, exists as a unique six-armed structure called a hexabrachion. The human hexabrachion is composed of six identical 320 kDa subunits and the structure is stabilized by inter-subunit disulfide bonds between amino-terminal segments. We have examined the biosynthesis of tenascin and its assembly into hexabrachions using pulsechase labeling of U-138 MG human glioma cells. Newly synthesized tenascin hexamers are secreted within 60 minutes of translation initiation. Intracellularly, as early as full length tenascin can be detected in pulse-labeled cell lysates, it is already in hexameric form. No precursors, such as monomers, dimers, or trimers, were identified that could be chased into hexamers. This lack of assembly intermediates suggests that nascent tenascin polypeptides associate prior to completion of translation. In contrast, fibronectin monomers in the same lysates are gradually formed into disulfide-bonded dimers. Although hexamer assembly is rapid, the rate-limiting step in secretion appears to be transport to the medial Golgi as endoglycosidase H-resistance was not detected until after a 30 minute chase. These results provide evidence for a novel co-translational mechanism of tenascin assembly which would be facilitated by its length and by the amino-terminal location of the assembly domain.
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PMID:Rapid intracellular assembly of tenascin hexabrachions suggests a novel cotranslational process. 754 60

The imaging of cerebral gliomas with radiolabelled monoclonal antibodies (MoAbs) has been previously reported. However, previous studies have been hampered by the drawback of a low tumour to non-tumour ratio. In order to overcome this problem we have developed a three-step pre-targeting method using the avidin-biotin system. The rationale of this technique consists in vivo labelling of biotinylated MoAbs targeted onto tumour deposits, when most of the unbound antibodies have been cleared from the bloodstream as avidin-bound complexes. The anti-tenascin MoAb BC2, specific for the majority of gliomas, was biotinylated and 1 mg was administered i.v. in 20 patients with histologically documented cerebral lesions. After 24-36 h, 5 mg avidin was injected i.v. followed 24 h later by a third i.v. injection of 0.2 mg PnAO-biotin labelled with 15-20 mCi technetium-99m. No evidence of toxicity was observed. Whole-body biodistribution was measured at 20 min, 3 h and 5 h post-injection. [99mTc]PnAO-biotin had a fast blood clearance and was primarily excreted through the biliary system. A dedicated single-photon emission tomography system was used to acquire brain tomographic images 1-2 h after the administration of [99mTc]PnAO-biotin. Tumours were detected in 15/18 glioma patients with a tumour to non-tumour ratio of up 14:1. This three-step method, based on the sequential administration of anti-tenascin MoAb BC2, avidin and [99mTc]PnAO-biotin, can support computed tomography or magnetic resonance imaging for the diagnosis and follow-up of patients with glioma. Further studies are required to evaluate the potential of this technique for therapeutic application.
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PMID:Pre-targeted immunodetection in glioma patients: tumour localization and single-photon emission tomography imaging of [99mTc]PnAO-biotin. 800 55

The potential utility of N-succinimidyl 5-iodo-3-pyridinecarboxylate (SIPC) for the radioiodination of monoclonal antibodies was investigated. Paired-label studies were performed using the anti-tenascin antibody 81C6 in athymic mice bearing subcutaneous D-54 MG human glioma xenografts. Radiolabeling was also done using N-succinimidyl 3-iodobenzoate (SIB). Radioiodination of SIPC and SIB both proceeded in 60-80% yield, but protein coupling efficiencies with SIB were higher (76 +/- 16 vs 60 +/- 7%). Immunoreactivity and affinity of both preparations were similar. Using SIPC, thyroid uptake was quite low, decreasing from 0.3% at day 1 to 0.05% at day 8. Tumor uptake reached 46 +/- 11% injected dose/g at day 1 but declined gradually thereafter. This apparent decline reflected the rapid growth of these xenografts since tumor accumulation expressed as percentage of injected dose remained nearly constant up to day 9. These results suggest that SIPC, like SIB, offers significant advantages for labeling antibodies when compared with conventional protein iodination methods.
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PMID:Radioiodination of a monoclonal antibody using N-succinimidyl 5-iodo-3-pyridinecarboxylate. 824 95

Immunohistochemical expression of tenascin (TN) and glial fibrillary acidic protein (GFAP) was investigated in 9 human malignant gliomas with leptomeningeal dissemination. In these patients intracerebral glioma tissues obtained at operation and/or autopsy displayed localized expression of TN in tumor vessels and stroma. In contrast, TN was expressed in the tumor vessels, tumor stroma, and the cytoplasm of tumor cells to a high degree throughout all the leptomeningeal tumor tissues obtained at autopsy, whereas there was much less expression of GFAP in these tissues than at the primary site. These findings suggest that TN expression and decrease of GFAP expression in glioma tissue may be involved in the development of leptomeningeal dissemination.
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PMID:Leptomeningeal dissemination of malignant glioma: immunohistochemical analysis of tenascin and glial fibrillary acidic protein. 852 26

Gliomas affect 15,000 to 17,000 Americans every year and carry a dismal prognosis. The potential of immunologically mediated diagnosis and therapy, although greatly enhanced since the advent of monoclonal antibodies, has not been fully realized due to significant problems, most especially the challenge of identifying antigenic molecules specific to glial tumors. Other problematic issues include antigen-associated factors such as heterogeneity, modulation, shedding, and cross-reactivity with normal cells, and factors associated with therapeutic agent delivery, typically variable tumor perfusion and unfavorable diffusional forces in tumor microenvironment. An understanding of these problems called for the delineation of operationally specific antigens (tumor-associated antigens not expressed by the normal central nervous system) combined with the use of compartmental therapeutic approaches to increase the specificity of therapy. Numerous antigens have been identified and are classified as extracellular/matrix-associated, membrane-associated, and intracellular antigens. Nevertheless, only a few have been demonstrated to be of significant therapeutic and diagnostic utility. These few include the extracellular matrix-associated antigens tenascin and GP 240, defined by the monoclonal antibodies 81C6 and Mel-14, both of which are now in Phase I clinical trials, and membrane-associated ganglioside molecules, primarily 3', 6'-isoLD1, defined by the antibody DMAb-22. Recent identification of the overexpression of a deletion variant of the epidermal growth factor receptor (EGFRvIII) in up to 50% of the more malignant glial tumors and the subsequent creation of monoclonal antibodies that are specific to this molecule and do not recognize the wild-type EGFR provide the most exciting development yet in the design of specific antiglioma immunoconjugates. In addition, the tumor-specific nature of EGFRvIII combined with improved knowledge of immune mechanisms, especially in the context of the central nervous system, will facilitate the design of highly selective cell-mediated therapeutic approaches with a view toward obtaining tumor-specific immunity.
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PMID:Tumor antigens in astrocytic gliomas. 858 61

Using a monoclonal antibody specific for human tenascin (TN), 180 intracranial growths were immunohistochemically studied. In 69 cases of meningioma, neoplastic cells were negative, with some positivity being observed only in the perivascular and the supporting stroma, especially in anaplastic meningiomas. In 57 cases of glioma different degrees of reactivity occurred in both the cellular conglomerates and the stromal components of the tumours. A higher variability in reactivity was observed in anaplastic astrocytomas and glioblastomas. The most constant finding of the study was the staining of the stroma, which was observed in all types of growths, including metastasis, abscess and tuberculoma. The results are consistent with the hypothesis that tenascin is a stromal marker rather than a true marker of malignant tumours. The heterogeneous distribution of TN in anaplastic gliomas may be a factor in the variable response to treatment with radiolabelled anti-TN monoclonal antibodies.
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PMID:Tenascin distribution in human brain tumours. 874 26

When labeled using the Iodogen method, a chimeric antibody composed of the human IgG2 constant region and the variable regions of murine anti-tenascin 81C6 exhibited superior uptake in human glioma xenografts compared with its murine parent. In the current study, three paired-label experiments were performed in athymic mice with subcutaneous D-54 MG human glioma xenografts to evaluate further the properties of radioiodinated chimeric 81C6. These studies demonstrated that (a) the enhanced tumor uptake of chimeric 81C6 is specific; (b) when labeling was performed using N-succinimidyl 3-iodobenzoate, chimeric 81C6 again showed preferential accumulation in tumor compared with murine 81C6; and (c) the tumor uptake advantage observed previously with murine 81C6 for N-succinimidyl 3-iodobenzoate compared with Iodogen labeling did not occur with chimeric 81C6.
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PMID:Chimeric anti-tenascin antibody 81C6: increased tumor localization compared with its murine parent. 883 99

Tenascin, an extracellular matrix protein, is expressed in human gliomas in vitro and in vivo. The distribution of tenascin at the invasive edge of these tumors, even surrounding solitary invading cells, suggests a role for this protein as a regulator of glioma cell migration. We tested whether purified tenascin, passively deposited on surfaces, influenced the adhesion or migration of a human gliomaderived cell line, SF-767. Adhesion of glioma cells to tenascin increased in a dose-dependent fashion up to a coating concentration of 10 micrograms/ml. Higher coating concentrations resulted in progressively fewer cells attaching. Cell adhesion could be blocked to basal levels using anti-beta 1 integrin antibodies. In contrast, when anti-alpha v antibodies were added to the medium of cells on tenascin, cell adhesion was enhanced slightly. Using a microliter scale migration assay, we found that cell motility on tenascin was dose dependently stimulated at coating concentrations of 1 and 3 micrograms/ml, but migration was inhibited below levels of non-specific motility when tested at coating concentrations of 30 and 100 micrograms/ml. Migration on permissive concentrations of tenascin could be reversibly inhibited with anti-beta 1, while treatment with anti-alpha v antibodies increased migration rates. We conclude that SF-767 glioma cells express two separate integrin receptors that mediate contrasting adhesive and migratory responses to tenascin.
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PMID:Contrasting migratory response of astrocytoma cells to tenascin mediated by different integrins. 885 12

We have generated a monoclonal antibody (MAb) L1A3 directed to the alpha v integrin subunit as shown by competitive binding with other anti-alpha v-specific MAbs and immunodepletion. MAb L1A3 is a function-blocking antibody inhibiting cell adhesion to the extracellular matrix proteins, fibronectin and vitronectin. Adherence to vitronectin of all cells studied including normal dermal microvascular endothelial cells and three tumor cell lines was inhibited in the presence of MAb L1A3. However, the contribution of the alpha v integrin subunit in mediating adhesion to fibronectin was dependent on the cell line, as indicated by differences in the inhibition of cell adhesion with MAb L1A3 and alpha 5 beta 1 integrin subunit blocking MAb P1D6. Glioma U251.3 cell adhesion to fibronectin was blocked by either MAb L1A3 or MAb P1D6 while fibrosarcoma HT1080 cells were blocked with MAb P1D6 only. Tumor cell migration mediated by vitronectin and fibronectin is blocked by MAb L1A3 in the two-dimensional spheroid outgrowth assay. Microvascular endothelial cell transwell membrane migration onto the fibronectin was also blocked by MAb L1A3. Comparison of the integrins involved in U251.3 cell migration on fibronectin or tenascin using a panel of integrin blocking MAbs including MAb L1A3 showed that only a subset of integrins participating in cell adhesion is essential for cell migration and these integrins appear to be ligand specific. Fibronectin-mediated tumor cell migration was critically dependent on alpha v integrins as shown by L1A3 blocking of migration while the beta 1 integrins were absolutely necessary for tenascin-mediated cell migration.
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PMID:A novel monoclonal antibody, L1A3, is directed to the functional site of the alpha v integrin subunit. 888 Feb 15

The role of tenascin in mediating tumor cell migration was studied using two cell migration models. In migration/invasion Transwell assays U251.3 glioma cells rapidly migrated through the 8 mu m pore size membranes onto tenascin- and fibronectin-coated surfaces. In this assay the number of cells migrating onto tenascin was 52.2 +/- 9.6% greater than on fibronectin within 4 hours. To assess cell migration rates and cell morphology, U251.3 migration was examined in a two-dimension spheroid outgrowth assay. The radial distance migrated by U251.3 cells from tumor spheroids was found to be 53.8 +/- 4.9% greater on tenascin than on fibronectin. Cells migrating on tenascin display a very motile appearance, while cells migrating on fibronectin spread and maintain close intercellular contacts. Cell migration in the presence of integrin blocking antibodies demonstrated that migration on tenascin and fibronectin is mediated by distinct integrins, alpha2beta1 and alphavbeta5/alphavbeta3, respectively. Since tenascin is coexpressed in malignant tumor matrices with fibronectin, we assessed the effects of tenascin on U251.3 cell migration mediated by fibronectin. Tenascin was found to provide a positive effect on fibronectin-mediated migration by altering cell morphology and enhancing cell motility. These effects of tenascin on fibronectin-mediated cell migration were inhibited by blocking beta1 and alpha2beta1 integrins. The results suggest that tenascin may play a significant role in promoting tumor cell migration and invasiveness by modulating cell responses to normal matrix components.
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PMID:Tenascin mediates human glioma cell migration and modulates cell migration on fibronectin. 890 9


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