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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor cells of a particular tissue may show a pattern of gene expression characteristic of the precursor cells of this tissue. To test this proposition for tumors of the central nervous system (CNS) we have used immunohistochemistry to analyze the expression of nestin in primary human CNS tumors and corresponding nonneoplastic brain tissue. Nestin defines a recently discovered sixth class of intermediate filament proteins and in the rat is expressed predominantly in CNS stem cells. In the adult nonneoplastic human brain we have detected only nestin expression in occasional endothelial cells. In contrast, a variety of primary CNS tumors contained substantially elevated nestin levels. The nestin-positive cells in the tumor tissue were tumor cells and/or endothelial cells. Glioblastomas expressed higher nestin levels than less malignant gliomas. This may indicate a correlation between nestin expression and malignancy within the glioma tumor group. In the primitive neuroectodermal class of tumors we observed both nestin-expressing and nonexpressing tumors, suggesting that nestin expression could be used to further characterize this complex and heterogeneous tumor group. Nine metastatic carcinomas were studied, and none showed nestin immunoreactivity in tumor cells. In conclusion, our data support the notion that primary CNS tumors share gene expression patterns with primitive, undifferentiated CNS cells and that nestin, like other intermediate filaments, may be useful in tumor diagnosis.
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PMID:Expression of the class VI intermediate filament nestin in human central nervous system tumors. 138 41

Various growth factors and basement membrane proteins have been implicated in the pathobiology of astrocytomas. The goal of this study was to determine the relative contribution of these two factors in modulating the phenotype of U-373 MG glioblastoma cells as determined by the expression of the intermediate filament proteins glial fibrillary acidic protein, vimentin, and nestin. For these determinations, cells plated in serum-free medium were treated either with growth factors binding to tyrosine kinase receptors including transforming growth factor-alpha, epidermal growth factor, platelet-derived growth factor-AA, basic fibroblast growth factor, and insulin-like growth factor-1 or with basement membrane proteins including collagen IV, laminin, and fibronectin. The changes in the expression levels of intermediate filament proteins in response to these treatments were analyzed by quantitation of immunoblots. The results demonstrate that collagen IV and growth factors binding to tyrosine kinase receptors decrease the glial fibrillary acidic protein content of U-373 MG cells. Growth factors binding to tyrosine kinase receptors also decrease the vimentin content of these cells but do not affect their nestin content. On the other hand, basement membrane proteins decrease the nestin content of U-373 MG cells but do not affect their vimentin content. The significance of these results with respect to the role played by different factors in modulating the phenotype of neoplastic astrocytes during tumor progression is discussed.
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PMID:Effects of growth factors and basement membrane proteins on the phenotype of U-373 MG glioblastoma cells as determined by the expression of intermediate filament proteins. 977 47

To begin understanding the regulation and biological significance of changes in the expression of intermediate filament proteins in astrocytic tumors, we have recently shown that TGF-alpha alters the protein level of glial fibrillary acidic protein (GFAP), nestin, and vimentin in U-373 MG glioblastoma cells. Here, we have determined the molecular mechanisms regulating these changes. In addition, to evaluate the significance of these changes we have examined whether TGF-alpha affects various cellular properties related to differentiation. Our results show that, in U-373 MG cells treated with TGF-alpha, GFAP gene transcription, mRNA level, and specific protein synthesis decrease by approximately 50%. This suggests that, in U-373 MG cells, TGF-alpha down-regulates the expression of this marker of astrocytic differentiation at the transcriptional level, resulting in decreased GFAP mRNA level and specific protein synthesis. In contrast, TGF-alpha does not change vimentin gene transcription, but increases by about 50% the transcription of the gene for nestin, a marker for undifferentiated astrocytic precursors. This differential regulation of GFAP, nestin, and vimentin gene expression indicates that TGF-alpha induces further dedifferentiation of U-373 MG cells. This notion is also supported by our findings that TGF-alpha increases the motility of U-373 MG cells and induces a less stellate morphology.
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PMID:TGF-alpha differentially regulates GFAP, vimentin, and nestin gene expression in U-373 MG glioblastoma cells: correlation with cell shape and motility. 1064 Apr 25

For glioma- and glioblastoma-specific gene expression, we utilized a nestin regulatory element whose activity was evaluated by the reporter gene lacZ. Nestin is a 38-kDa intermediate filament protein, and is expressed specifically in the neuroepithelial stem cells. Nestin is detected in gliomas and glioblastomas, but not in normal brain tissue. We constructed a nestin gene regulator by placing nestin's second intron before the 5' upstream region (2iNP). To obtain enhanced expression of this tissue-specific regulator, we utilized the adenovirus double-infection method with a Cre-loxP on/off switching system. We constructed a 'regulator' vector, Ax2iNPNCre, which expresses Cre recombinase under the control of the nestin regulatory element, 2iNP. A 'reporter' vector, AxCALNLNZK, expresses lacZ under the control of a strong CAG promoter when the stuffer sequence has been removed by Cre recombinase at a pair of loxP sites. We used seven human glioma/glioblastoma cell lines: U251, KG-1C, NGM5, U87 MG, LN-Z308, NP-2 and T98G. Of these, nestin was expressed highly in U251 and KG-1C, less in NGM5, and undetectably in the other four lines. With the use of the two adenovirus vectors, we found X-gal staining and high nestin regulator-promoted beta-galactosidase activities in four of the seven glioma/glioblastoma cell lines. Staining was strong in U251, KG-1C and NGM5, and less in U87 MG. LacZ expression was nearly undetectable in the non-glioma cell line, HeLa, but a little in COS-7. The adenovirus double-infection method, which uses a nestin regulator, is applicable for glioma/glioblastoma-specific expression.
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PMID:Glioma/glioblastoma-specific adenoviral gene expression using the nestin gene regulator. 1080 92

Deletion of the INK4a-ARF locus is found in the majority of human malignant gliomas. However, the role of INK4a-ARF loss in gliomagenesis is unclear. Animal modeling has shown that mice with targeted deletions in the Ink4a-Arf gene do not develop spontaneous gliomas. We have previously reported that combined KRas and Akt signaling could induce glioblastoma (GBM) formation from neural progenitor cells but had no effect in differentiated astrocytes. In this investigation, we have studied the effects of Ink4a-Arf loss on the formation of GBM induced by KRas and Akt gene transfer into neural progenitor cells and astrocytes. We show here that Ink4a-Arf deficiency allows for GBM formation from astrocytes and that it enhances tumor incidence in neural progenitor cells. Furthermore, KRas alone can cooperate with deletion of the Ink4a-Arf locus in tumor formation from both neural progenitor cells and astrocytes. The resulting tumors were nestin positive and resembled a spectrum of glioma morphologies ranging in astrocytic character depending on cell-of-origin and presence of activated Akt. Our data strongly supports the view that one role of loss of Ink4a-Arf in gliomagenesis could be to sensitize astrocytes to transformation through dedifferentiation in response to the appropriate oncogenic stimuli.
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PMID:Ink4a-Arf loss cooperates with KRas activation in astrocytes and neural progenitors to generate glioblastomas of various morphologies depending on activated Akt. 1235 67

The ability of herpes simplex virus type 1 thymidine kinase (HSV-tk)-expressing cells incubated with ganciclovir (GCV) to induce cytotoxicity in neighboring HSV-tk-negative (bystander) cells has been well documented. Although it has been suggested that this bystander cell killing occurs via the transfer of phosphorylated GCV, the mechanism(s) of this bystander effect and the importance of gap junctions for the effect of prodrug/suicide gene therapy in primary human glioblastoma cells remains elusive. Surgical biopsies of malignant gliomas were used to establish explant primary cultures. Proliferating tumor cells were characterized immunohistochemically and found to express glial tumor markers including nestin, vimentin, glial fibrillary acidic protein (GFAP), S-100, and gap junction protein connexin 43 (Cx43). Western blot analysis revealed the presence of phosphorylated isoforms of Cx43 and Calcein/DiI fluorescent dye transfer showed evidence of efficient gap junction communication (GJC). In order to study the effect(s) of prodrug/suicide gene therapy in these cultures, human glioblastoma cell cultures were transfected with the HSVtk gene for transient or stable expression. Ganciclovir treatment of these cultures led to >90% of cells dead within 1 week. Eradication of cells could be inhibited by the addition of alpha-glycyrrhetinic acid (AGA), a GJC inhibitor. In parallel experiments, AGA decreased the immunodetection of phosphorylated Cx43 as analyzed by Western blot and inhibited fluorescent dye transfer. In conclusion, these observations are consistent with GJC as the mediator of the bystander effect in primary cultures of human glioblastoma cells by the transfer of phosphorylated GCV from HSVtk gene transfected cells to untransfected ones.
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PMID:Gap junction-mediated bystander effect in primary cultures of human malignant gliomas with recombinant expression of the HSVtk gene. 1265 Nov 52

Pediatric brain tumors may originate from cells endowed with neural stem/precursor cell properties, growing in vitro as neurospheres. We have found that these cells can also be present in adult brain tumors and form highly infiltrating gliomas in the brain of immunodeficient mice. Neurospheres were grown from three adult brain tumors and two pediatric gliomas. Differentiation of the neurospheres from one adult glioblastoma decreased nestin expression and increased that of glial and neuronal markers. Loss of heterozygosity of 10q and 9p was present in the original glioblastoma, in the neurospheres and in tumors grown into mice, suggesting that PTEN and CDKN2A alterations are key genetic events in tumor initiating cells with neural precursor properties.
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PMID:Genetic alterations and in vivo tumorigenicity of neurospheres derived from an adult glioblastoma. 1546 6

Nestin is a member of intermediate filaments abundantly expressed in neural stem cells and glioblastomas. The nestin gene has four exons and three introns, and neural cell-specific expression is regulated by the second intron. We previously reported that nestin was invariably detected in the tumor endothelium in gliomas even though tumor cells were negative for nestin. In the present study, we further confirmed nestin immunostaining in tumor endothelium of a variety of common cancers, including lung, stomach, colon, and cervical carcinomas. We examined an endothelium-specific regulator using human umbilical vein endothelial cells (HUVECs) and human glioblastoma-derived U251 cells. In a luciferase reporter assay, the first intron plus 5' upstream promoter (5'UP) gave the highest activity, followed by 5'UP, and the second intron plus 5'UP. However, the assay values were much lower by HUVEC extracts than by U251 cell extracts. Although green fluorescent protein expression was positive over all U251 cells under either the first intron, second intron, or ubiquitously active CAG promoter, the fluorescence in HUVECs was limited to a few cells even under the first intron. This difference came from the growth feature of HUVECs which exhibit growth arrest by contact inhibition. We found that the nestin expression was specific to proliferative endothelium, by using proliferation markers in hemangioblastomas and in situ hybridization. Using an endothelial tube formation assay, tyrosine kinase domain-deleted VEGF receptor KDR effectively abolished the tube formation under the first intron. We suggest that the nestin expression in tumor endothelium is enhanced by the first intron.
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PMID:Angiogenic endothelium-specific nestin expression is enhanced by the first intron of the nestin gene. 1550 61

Neural precursor cells contribute to adult neurogenesis and to limited attempts of brain repair after injury. Here we report that in a murine experimental glioblastoma model, endogenous neural precursors migrate from the subventricular zone toward the tumor and surround it. The association of endogenous precursors with syngenic tumor grafts was observed, after injecting red fluorescent protein-labeled G261 cells into the caudate-putamen of transgenic mice, which express green fluorescent protein under a promoter for nestin (nestin-GFP). Fourteen days after inoculation, the nestin-GFP cells surrounded the tumors in several cell layers and expressed markers of early noncommitted and committed precursors. Nestin-GFP cells were further identified by a characteristic membrane current pattern as recorded in acute brain slices. 5-bromo-2-deoxyuridine labeling and dye tracing experiments revealed that the tumor-associated precursors originated from the subventricular zone. Moreover, in cultured explants from the subventricular zone, the neural precursors showed extensive tropism for glioblastomas. Tumor-induced endogenous precursor cell accumulation decreased with age of the recipient; this correlated with increased tumor size and shorter survival times in aged mice. Coinjection of glioblastoma cells with neural precursors improved the survival time of old mice to a level similar to that in young mice. Coculture experiments showed that neural precursors suppressed the rapid increase in tumor cell number, which is characteristic of glioblastoma, and induced glioblastoma cell apoptosis. Our results indicate that tumor cells attract endogenous precursor cells; the presence of precursor cells is antitumorigenic; and this cellular interaction decreases with aging.
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PMID:Glioblastoma-induced attraction of endogenous neural precursor cells is associated with improved survival. 1575 74

Homozygous deletion of the INK4a-ARF locus is one of the most frequent mutations found in human glioblastoma. We have previously shown that combined Ink4a-Arf loss can increase tumor incidence in both glial progenitor cells and astrocytes during mouse gliomagenesis. Here we have investigated the separate contribution of loss of each of the tumor suppressor genes in glial progenitor cells and astrocytes in Akt + Kras-induced gliomagenesis. We show that Arf is the major tumor suppressor gene in both cell types. Arf loss generated glioblastomas from both nestin-expressing glial progenitor cells and glial fibrillary acidic protein-expressing astrocytes, with a significantly higher incidence in astrocytes. Ink4a loss, on the other hand, could only significantly contribute to gliomagenesis from glial progenitor cells and the induced tumors were of lower malignancy than those seen in Arf-deficient mice. Thus, Ink4a and Arf have independent and differential tumor suppressor functions in vivo in the glial cell compartment.
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PMID:Cell type-specific tumor suppression by Ink4a and Arf in Kras-induced mouse gliomagenesis. 1578 13


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