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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oncogenes represent altered versions of cellular genes instrumental for control of cell proliferation and differentiation. Several oncogenes have been implicated in glial cell transformation and immortalization in culture (myc, src, mos, ras, and SV40 large T antigen). The purpose of this study is to further our understanding of glial cell neoplasia by investigating the effect of oncogenes on the growth and differentiation of central nervous system glial progenitor cells from the oligodendrocyte type 2 astrocyte (O-2A) lineage. This progenitor cell differentiates into an oligodendrocyte or a type-2 astrocyte according to environmental cues. Drug-selectable retroviral vectors were used to introduce oncogenes either alone or in combination into primary cultures of rat O-2A cells. Established O-2A progenitor cell lines were only obtained after infection with c-myc or SV40 large T antigen, suggesting that among the oncogenes tested only these were capable of immortalizing O-2A progenitor cells. The O-2A/c-myc and O-2A/temperature-sensitive SV40 large T antigen cell lines retained the capacity to differentiate into oligodendrocytes and type-2 astrocytes, thereby providing an opportunity to study the effects of oncogene cooperation on the phenotype of O-2A lineage cells. Superinfection of these cells lines with retroviruses encoding ras or src led to abnormalities of differentiation whose nature and severity depended on the combination of cooperating oncogenes and/or the levels of expression obtained. This study demonstrates that oncogene-modified glial cell lines provide an amenable and unique model system to study differentiation in the central nervous system and the genetic changes involved in the development of glioma.
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PMID:The effect of oncogenes on the growth and differentiation of oligodendrocyte type 2 astrocyte progenitor cells. 771 86

Multiple basic fibroblast growth factor (bFGF) mRNAs are transcribed in rat brain at 6.0, 3.7, 2.5, 1.8, 1.6, 1.4, and 1.0 kb. These seven transcripts are also seen in Rat-1 fibroblasts and ras-transformed Rat-1 fibroblasts in culture. However, only a single bFGF transcript at 6.0 kb is detectable in the rat astrocytoma cell line, C6, and this mRNA is identical to that seen in a primary culture of cortical astrocytes. C6 glioma cells also transcribe message for FGF receptor 1 (FR1), suggesting possible autocrine growth by these cells. Growth factor activity in a C6 cell lysate was characterized by heparin affinity chromatography and Western blot analysis using an anti-bFGF antibody. Proteins of 18, 21.5, and 22 kDa were detected in C6 cells, indicating that the 6.0-kb mRNA is translated into the three characteristic bFGF proteins. Rat-1 fibroblasts also synthesize bFGF proteins of identical molecular weight. The small transcripts detected in brain probably represent bFGF or FGF-related mRNAs in cell types other than glia, such as fibroblasts, endothelial cells, or neurons. In cultured C6 cells, bFGF protein levels are highest in confluent, quiescent cells, whereas mRNA levels are low. Addition of serum, phorbol ester, or cycloheximide to both C6 cells and fibroblasts induces the level bFGF mRNA transcripts 10-fold after 1-4 h. This rapid induction after cell activation indicates that bFGF is an early response gene. Therefore, even though there are abundant intracellular stores of the factor, the transcriptional activation seen after mitogenic activation of cells implies that de novo bFGF mRNA synthesis is an important part of the mitogenic response.
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PMID:Regulation of basic fibroblast growth factor mRNA expression in rat C6 glioma cells. 826 39

The incidence of primary brain tumors has increased dramatically among elderly North Americans during the past two decades. Numerous chromosomal abnormalities have been associated with these tumors; various subsets of these abnormalities are specific to certain types of brain tumors. Astrocytic gliomas may exhibit losses of genetic information from chromosomes 9p, 10q, 11p, 13q, 17p, or 22. Mutations of the p53 gene are found mostly in the malignant astrocytic forms and have been linked to malignant tumor transformation and progression. Functional and structural abnormalities of the neurofibromatosis 1 (NF1) gene and overexpression of the epidermal growth factor receptor have been associated with expression of the malignant glioma phenotype. Other less clearly defined abnormalities in astrocytomas include mutations of the retinoblastoma (RB) gene and overexpression of platelet-derived growth factor; transforming growth factor-alpha and -beta; the c-erb B-1, c-myc, ras, c-fos, and ros oncogenes; and insulin-like growth factor I and II. In other glioma tumors, p53 mutations are either infrequent, as in oligodendrogliomas, or absent, as in ependymomas. Occasionally, medulloblastomas exhibit p53 mutations and loss of genetic information from chromosomes 6q and 16q or expression of the c-erb B-2 oncogene. Loss of heterozygosity in chromosome 22 is the most frequent event in meningiomas, suggesting the presence of a tumor-suppressor gene in this chromosome.
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PMID:Epidemiology, cytogenetics, and molecular biology of brain tumors. 849 8

Constitutive expression of the cellular proto-oncogenes c-fos and c-jun, and in a lesser extent ras, was demonstrated in the glioma cell line C-6 by flow cytometry analysis using specific mono and polyclonal antibodies. Basal expression of the products of the early response genes c-fos and c-jun were increased 66 and 50% when Theiler's murine encephalomyelitis virus (TMEV) infected these cells. No increase in ras transcription could be demonstrated after infection. This activation follows a kinetic reaching maximum values after 60 min and was proportional to the multiplicity of infection used. The described effect was completely abrogated by rabbit antibodies to TMEV but was not altered by normal rabbit serum. Furthermore, an intact infectious virion is needed to detect this effect. Fetal calf serum and lipopolysaccharide stimulation slightly increases c-fos and c-jun expression following a slower kinetics. Cytokine treatment (IL-1 alpha, IL-6, IFN-gamma and TNF alpha), did not induce oncogene over-expression. Therefore, this stimulation seems to be linked to the TMEV infectious process.
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PMID:Overexpression of basal c-fos and c-jun but not of ras oncogenes after Theiler's murine encephalomyelitis virus infection of glial cells. 879 9

It has been well established that patients with malignant glioblastomas exhibit T cell anergy. In this report, we further investigate the nature of this T cell anergy. The results demonstrate that tumor size but not location correlates with decreased mitogen or anti-CD3 mAb responsiveness of T cells obtained from patients. Stimulation of the TCR/CD3 complex on these patients' T cells revealed defects in early transmembrane signaling. Both PHA and anti-CD3 mAb activated PBL and T cells obtained from patients exhibited a marked decrease in the tyrosine phosphorylation of a number of proteins. In particular, decreased phosphorylation of pp100 and phospholipase Cgamma1 (PLCgamma1) was observed. In addition, PLCgamma1 and p56(lck) protein levels were dramatically reduced in T cells obtained from patients harboring a glioma. In contrast, the protein levels of p59(fyn) were normal or only slightly reduced in T cells obtained from patients with gliomas. Quantitation of free intracellular calcium concentrations ([Ca2+]i) after mitogen (PHA) stimulation or ionomycin treatment of T cells obtained from patients revealed that they mobilize less calcium than do T cells obtained from normal subjects. Stimulation of T cells obtained from patients with PMA and ionomycin, which should bypass the requirement for PLCgamma1 activation as well as directly activate the p21(ras) signaling pathway, did not restore the proliferative capacity of these T cells to normal levels. These results indicate that the anergy observed in T cells obtained from these patients is a consequence of one or more defects in the early transmembrane signaling events associated with TCR/CD3 stimulation.
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PMID:T cell receptor-mediated signaling is defective in T cells obtained from patients with primary intracranial tumors. 937 40

Malignant gliomas are thought to be highly dependent on the mevalonate pathway for cell growth. Lovastatin, a cholesterol-lowering drug, inhibits not only the rate-limiting step in the mevalonate pathway (hepatic hydroxymethyl glutaryl coenzyme A reductase), but also the prenylation of several key regulatory proteins including ras and the small guanosine triphosphate binding proteins. Therefore, from August 1994 through March 1996, 18 patients with either anaplastic glioma or glioblastoma multiforme were entered into a trial testing the safety of high-dose lovastatin with or without radiation. Although the response data is too premature to evaluate activity, the fact that high doses of lovastatin are well tolerated with concurrent radiation suggests that central nervous system toxicity will not be a significant limiting toxicity as more selective farnesyltransferase inhibitors are brought into the clinic as radiation sensitizers.
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PMID:A phase I-II trial of lovastatin for anaplastic astrocytoma and glioblastoma multiforme. 985 59

To prevent neoplasia, cells of multicellular organisms activate cellular disposal programs such as apoptosis in response to deregulated oncogene expression, making the suppression of such programs an essential step for potentially neoplastic cells to become established as clinically relevant tumors. Since the mutation of ras proto-oncogenes, the most frequently mutated proto-oncogenes in human tumors, is very rare in some tumor types such as glioblastomas and gastric cancers, we hypothesized that mutated ras genes might activate a cell death program that cannot be overcome by these tumor types. Here we show that the expression of oncogenically mutated ras gene induces cellular degeneration accompanied by cytoplasmic vacuoles in human glioma and gastric cancer cell lines. Cells dying as a result of oncogenic Ras expression had relatively well-preserved nuclei that were negative for TUNEL staining. An immunocytochemical analysis demonstrated that the cytoplasmic vacuoles are derived mainly from lysosomes. This oncogenic Ras-induced cell death occurred in the absence of caspase activation, and was not inhibited by the overexpression of anti-apoptotic Bcl-2 protein. These observations suggested that oncogenic Ras-induced cell death is most consistent with a type of programmed cell death designated 'type 2 physiological cell death' or 'autophagic degeneration', and that this cell death is regulated by a molecular mechanism distinct from that of apoptosis. Our findings suggest a possible role for this non-apoptotic cell death in the prevention of neoplasia, and the activation of the non-apoptotic cell death program may become a potential cancer therapy complementing apoptosis-based therapies. In addition, the approach used in this study may be a valuable way to find genetically-regulated cell suicide programs that cannot be overcome by particular tumor types.
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PMID:Oncogenic Ras triggers cell suicide through the activation of a caspase-independent cell death program in human cancer cells. 1032 74

As concerns human adult brain neoplasms, the biological behaviour of glioblastoma, a high-grade neuro-ectodermal tumour, is among the most disadvantageous. Glioblastoma may develop either as a primary tumour without clinical and histological evidence of a prior precursor lesion, or as the final stage of malignant transformation of a low-grade or anaplastic astrocytoma. There are conflicting reports in connection with the association of the p53 tumour suppressor gene mutation with the clinical and histological progression of gliomas. Previous studies likewise led to contradictory results concerning the significance of ras oncogenes in different histological malignancies, and especially in neuro-epithelial tumours. The possible roles of p53 and ras gene alterations in the development of "primary" and "transformed" glioblastomas were studied in this work. Eighteen tumours were investigated by means of immunohistochemistry and polymerase chain reaction-assisted-single strand conformation polymorphism (PCR-SSCP) sequence analysis in a search for molecular genetic differences between primary and transformed glioblastomas. An increased incidence of p53-immunopositive cells was observed in both types of glioblastomas but there was no significant difference between the transformed tumours and the primary form. All samples were screened for point mutation in codons 12 and 61 of the H-, K-, and N-ras oncogenes and exons 5-8 of the p53 gene. No aberrant band or mutation was found in the H-, K- and N-ras oncogenes. Aberrant bands were seen in only 2 (11%) of the 18 tumours in the SSCP analyses of exons 6 and 8. Sequence analysis of the 2 abnormal cases revealed G --> C transmission in the second nucleotide of codon 280 on exon 8, which resulted in a change in the encoded amino acid from arginine to threonine (case 15). A ttagtct --> ttggtct transmission on intron 5 (case 8) was also found. No genetic difference could be identified between the primary and the transformed glioblastoma forms as concerns their p53 and ras oncogenes. There are two possible explanations for these findings: (a) The p53 and ras gene mutations were not primary events in the morphological transformations. Alterations in these genes may therefore take place at an early stage in glioma progression. (b) The different genetic changes may accumulate during glioblastoma development. These specific genetic events may additionally play a role in multistep tumourigenesis.
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PMID:Sporadic p53 mutations and absence of ras mutations in glioblastomas. 1092 24

Oncostatin M (OSM) and other members of the interleukin-6 cytokines, like ciliary neurotrophic factor and leukemia inhibitory factor, can induce differentiation of glial cells. We have recently described that OSM inhibited the growth of human glioma cells in vitro and induced a cell morphology resembling that of mature astrocytes. Using the glioblastoma cell line 86HG39, we demonstrated that treatment of the glioma cells with OSM also leads to a differentiation of the malignant glioma cells as judged by a strong increase in glial fibrillary acidic protein expression. The differentiation and the growth inhibition were not significantly blocked by expression of a dominant-negative (dn) signal transducer and activator of transcription (Stat) 3 protein. OSM exerted a reduction in DNA synthesis even in the presence of a high expression level of dnStat3. Moreover, inhibition of the ras-raf-mitogen-activated protein kinase (MAPK) pathway by the MAPK kinase 1 inhibitor PD98059 resulted in a synergistic enhancement of the OSM effect, indicating that the activation of this pathway counteracts the activity of the cytokine.
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PMID:Oncostatin M-mediated growth inhibition of human glioblastoma cells does not depend on stat3 or on mitogen-activated protein kinase activation. 1093 78

Malignant tumors are characterized by their great heterogeneity and variability. There are hundreds of different types of malignant tumors that harbour many oncogenic alterations. The tumor heterogeneity has important morphological, molecular and clinical implications. Except for some hematopoietic and lymphoproliferative processes and small cell infant tumors, there are not specific molecular alterations for most human tumors. In this review we summarize the most important aspects of carcinogenesis and chemoradiosensitivity of malignant cells. In this regard, some oncogenes such as neu, ras and bcl-2 have been associated with cellular resistance to treatment with anticancer agents. The knowledge of oncogenic alterations involved in each tumor can be important to correlate the morphological features, the genetic background, the prognosis and the clinical response to treatment with anticancer agents. Based on the molecular background of the tumor there are new cancer gene therapy protocols. For example using adenovirus Ela in tumors with overexpression of neu oncogene, inhibitors of tyrosine kinase specific for the PDGF receptor in glioma, inhibitors of farnesil transferase to prevent ras activity in tumors with mutations in the ras gene.
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PMID:Tumor heterogeneity: morphological, molecular and clinical implications. 1096 32


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