Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One of the morphologic hallmarks of human gliomas are inflammatory infiltrates with accumulation of macrophages in the tumor site. The signals leading to the macrophage response are only at the beginning of being understood. Novel chemotactic factors that have recently been characterized as secretory products of glioblastoma cells may attract mononuclear cells from the blood. Within the tumor tissue blood-derived monocytes and macrophages of the brain tissue, the microglial cells, may increase in cell numbers due to tumor-derived growth factors. Both astrocytoma cell lines and cultured astrocytes have been shown recently to produce granulocyte-macrophage (GM)-CSF. We show that in vitro not only astrocytoma but also glioblastoma cell lines secrete GM-CSF when stimulated with TNF-alpha or IL-1. However, there is no evidence for GM-CSF production by glioblastoma cells in vivo: fresh tumor samples lack the mRNA for GM-CSF and the protein is not detectable in the tumor cyst fluids or the cerebrospinal fluids of glioblastoma patients. This contrasts IL-1 and IL-6 that are detectable in the tumor cyst fluids and IL-6 also in the cerebrospinal fluids of the patients. Unlike GM-CSF, transforming growth factor-beta 2 mRNA is expressed in ex vivo tested glioblastoma tissues. Absence of GM-CSF in vivo may be explained by the presence of tumor-derived inhibitory factors, such as transforming growth factor-beta 2 and PGE which suppress GM-CSF production by glioblastoma cells in vitro. The accumulation of macrophages at the tumor site may be due to local elaboration of chemoattractants and/or not yet defined growth factors rather than due to GM-CSF production.
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PMID:Granulocyte-macrophage colony-stimulating factor (GM-CSF) production by glioblastoma cells. Despite the presence of inducing signals GM-CSF is not expressed in vivo. 131 29

In order to determine the in vivo immune response in glioblastoma, monoclonal and polyclonal antibodies specific for inflammatory leukocytes and immunoregulatory products were utilized to stain tissue from four surgical specimens. The more activated the inflammatory cells, the more activated the tumors appeared to be. In the tumor with the largest infiltration (Case 3), inflammatory cells were stained for interferon-gamma, interleukin-2, interleukin-1 beta, lymphotoxin, tumor necrosis factor-alpha, and transforming growth factor-beta. The tumor cells also expressed interleukin-1 beta, interleukin-6, transforming growth factor-beta, tumor necrosis factor-alpha, and prostaglandin E. In contrast, in the tumor with the least inflammatory response (Case 1), the tumor cells did not express any cytokines. Expression of cytokines by glioma cells was modest in the two cases with modest inflammatory responses. Cellular inflammation, primarily consisting of T cells and macrophages with few or no B cells or natural killer cells, was two- to 15-fold greater outside the tumor than within. In contrast to leukocytes outside the tumor, which were activated and expressing class II major histocompatibility antigens, leukocytes within the tumor parenchyma or at the tumor's edge were negative for these antigens. In the four specimens studied here, the tumor cells themselves were also negative for class II major histocompatibility antigens. These findings, although preliminary, suggest that inflammatory cells within gliomas are inactivated and that glioma cells may increase the expression of immunosuppressive cytokines in response to an increased lymphocyte infiltrate. This observation, if corroborated by more extensive studies, may help to explain the failure of immune treatments in glioblastoma multiforme.
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PMID:Inflammatory leukocytes associated with increased immunosuppression by glioblastoma. 131 61

Protein kinase C (PKC), an enzyme involved in signal transduction, responds to diacyl glycerol and also to phorbol ester, a ligand analogous to diacyl glycerol. We have studied the expression of the major isoforms (alpha, beta I, beta II, and gamma) in eight human glioblastoma cell lines. In all eight lines, PKC-alpha mRNA and protein were expressed. In none of the eight did a probe for PKC-beta I and -beta II mRNA give positive results nor were Western blots for PKC-beta II positive. The half-life for PKC alpha mRNA was approximately 16 h and levels of the mRNA were increased slightly following addition of phorbol myristate acetate (PMA) or transforming growth factor-beta (TGF beta). PKC-gamma was present in most of the glioblastomas. In cell line A172, 82% of the PKC-alpha was present in the cytosol with the remainder evenly divided between plasma membrane and nucleus. Thirty minutes after addition of PMA, 33% of the total original protein was in the plasma membrane and 48% in the nuclear fraction. By 21 h, no PKC-alpha was recovered from any fraction. PKC-gamma was also down-regulated in the presence of PMA, but there was no evidence for translocation to the plasma membrane or nuclear fraction. In a more detailed study, translocation of PKC-alpha in the presence of PMA was complete by 10 min, and a major decrease in the PKC translocated to the plasma-membrane fraction occurred some time between 2 and 4 h after PMA addition, while a major decrease in the translocated nuclear fraction occurred some time after 6 h. cAMP alone had no effect on the PKC alpha protein level or distribution, nor did it alter the translocation and down-regulation due to PMA exposure. In these studies the level of PKC-alpha mRNA in tumors was similar to that in normal glial cells.
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PMID:Protein kinase C isoforms in human glioblastoma cells. 133 68

Glioblastomas are malignant brain tumors that are attended by an immunosuppressed state. The authors have studied the expression of transforming growth factor-beta 2, which is known to have potent immunosuppressive and angiogenic properties. Transforming growth factor-beta 2 messenger ribonucleic acid and its protein product are both found to be greatly overexpressed in these tumors and are absent from normal brain tissue. The overexpression of this growth factor may contribute to the escape of neoplastic astrocytes from immune surveillance and, furthermore, to the immunosuppressed state that is characteristic of many of these patients.
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PMID:Effect of the expression of transforming growth factor-beta 2 in primary human glioblastomas on immunosuppression and loss of immune surveillance. 137 42

Tumor cells have been reported to exert inhibitory effects on the activation of T lymphocytes in vitro. We show that the IL-2-stimulated proliferation of a Th cell line is suppressed when the T cells are cocultured with human glioblastoma and melanoma cell lines. The use of two Th cell clones that differ in their responsiveness to growth-inhibition by transforming growth factor-beta (TGF-beta) and the analysis of tumor cell-derived supernatants as well as of TGF-beta 1/TGF-beta 2 gene expression allowed to distinguish two pathways of tumor-induced immunosuppression. Glioblastoma cells exert their immunosuppressive effects by producing biologically active TGF-beta 2, whereas the immunosuppressive state induced by melanoma cells is TGF-beta-independent and requires direct contact between tumor cell and T cell. The TGF-beta-dependent immunosuppression is down-regulated by various protease inhibitors and up-regulated by estradiol via modulation of the production of biologically active TGF-beta 2 by glioblastoma cells leaving total activatable TGF-beta 2 unaffected. No such modulation is functional for the TGF-beta-independent pathway of immunosuppression. We conclude that the production of active TGF-beta by tumor cells is regulated at a posttranslational level by the coordinated action of several proteolytic enzymes.
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PMID:Protease inhibitors interfere with the transforming growth factor-beta-dependent but not the transforming growth factor-beta-independent pathway of tumor cell-mediated immunosuppression. 172 72

To study the regulation of major histocompatibility complex class II antigen by central nervous system cells, the expression of one of these antigens, human leukocyte antigenDR (HLADR) in three human glioblastoma cell lines (HTB14, 16 and 17) and a neuroblastoma cell line (HTB11) was determined. Interferon-gamma (IFN gamma) induced HTB16 and HTB17 cells to express HLADR, and enhanced the antigen expression in HTB14 cells, but it failed to induce HLADR expression in HTB11 cells. Tumor necrosis factor-alpha amplified and accelerated the expression of HLADR induced by IFN gamma in HTB16 cells. Interleukin-1 beta, prostaglandin E2 and transforming growth factor-beta suppressed IFN gamma-induced HLADR expression in HTB16 cells. Several other substances tested did not affect HLADR expression or IFN gamma-induced HLADR. These findings confirm that IFN gamma plays a role in the regulation of HLADR expression in cells derived from the brain and that some other cytokines modify IFN gamma-HLADR interactions.
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PMID:Modulation of human leukocyte antigenDR expression in glioblastoma cells by interferon gamma and other cytokines. 195 63

Human glioblastoma cells secrete a peptide termed glioblastoma-derived T cell suppressor factor (G-TsF) which inhibits T cell activation. Recently, purification and cloning of G-TsF revealed that G-TsF is identical to transforming growth factor-beta 2. As shown here, G-TsF suppresses the growth of an ovalbumin-specific mouse T helper cell clone (OVA-7T) independently of the stimulus used being either (a) antigen in the presence of antigen-presenting cells, or (b) interleukin 2 (IL2) or (c) phorbol ester and calcium ionophore. Furthermore, in the presence of antibodies against IL2 receptors, G-TsF was able to suppress the residual proliferation still observed when OVA-7T were stimulated with phorbol ester/ionophore. G-TsF failed to inhibit the release of IL3 from OVA-7T activated with IL2. Taken together, the data provide evidence that G-TsF does not directly interfere with interactions of IL2 with its receptor but rather inhibits T cell activation by interfering with an as yet unidentified pathway used by both IL2 and phorbol ester/ionophore. When analyzing different monokines and lymphokines for its effect on G-TsF-induced suppression of T cell growth the only factor found to partially neutralize the effect of G-TsF was tumor necrosis factor-alpha.
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PMID:The glioblastoma-derived T cell suppressor factor/transforming growth factor-beta 2 inhibits T cell growth without affecting the interaction of interleukin 2 with its receptor. 245 45

Human glioblastoma cells secrete a peptide, termed glioblastoma-derived T cell suppressor factor (G-TsF), which has suppressive effects on interleukin-2-dependent T cell growth. As shown here, complementary DNA for G-TsF reveals that G-TsF shares 71% amino acid homology with transforming growth factor-beta (TGF-beta). In analogy to TGF-beta it is apparently synthesized as the carboxy-terminal end of a precursor polypeptide which undergoes proteolytic cleavage to yield the 112 amino-acid-long mature form of G-TsF. Comparison of the amino-terminal sequence of G-TsF with that of porcine TGF-beta 2 and bovine cartilage-inducing factor B shows complete homology, which indicates that we have cloned the human analogue of these factors. It is tempting to consider a role for G-TsF in tumor growth where it may enhance tumor cell proliferation in an autocrine way and/or reduce immunosurveillance of tumor development.
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PMID:Complementary DNA for human glioblastoma-derived T cell suppressor factor, a novel member of the transforming growth factor-beta gene family. 332 13

T cell suppressor factor produced by human glioblastoma cells inhibits T cell proliferation in vitro and more specifically interferes with interleukin-2 (IL-2)-dependent T cell growth. Here we report the purification of this factor from conditioned medium of the human glioblastoma cell line 308. Amino-terminal sequence analysis of the 12.5-kd protein demonstrates that eight out of the first 20 amino acids are identical to human transforming growth factor-beta. Purified glioblastoma-derived T cell suppressor factor and transforming growth factor-beta from porcine platelets inhibit both IL-2-induced proliferation of ovalbumin-specific T helper cells and lectin-induced thymocyte proliferation with similar specific activities. If released by glioblastoma cells in vivo, the factor may contribute to impaired immunosurveillance and to the cellular immunodeficiency state detected in the patients.
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PMID:T cell suppressor factor from human glioblastoma cells is a 12.5-kd protein closely related to transforming growth factor-beta. 349 30

The secretion of transforming growth factor-beta (TGF-beta), a growth inhibitory factor with immunosuppressive properties, was investigated in one glioblastoma cell line and seven surgically resected malignant glioma cells. Cultured cells from surgically resected tumors were examined immunohistochemically for glial fibrillary acidic protein (GFAP) and S-100 protein. The levels of TGF-beta 1 and TGF-beta 2 in culture supernatants from malignant glioma cells were determined by a specific bioassay using anti-TGF-beta 1 and anti-TGF-beta 2 antibodies. Two glioblastoma cell lines were cultured in the presence of TGF-beta 1 or TGF-beta 2 to assess the effect of TGF-beta on the growth of glioblastoma cells. Cultured cells from surgically resected tumors were positive for both GFAP and S-100 protein. Both active and latent forms of TGF-beta 1 and TGF-beta 2 were detected in the culture supernatants from malignant gliomas, except in one patient with anaplastic astrocytoma which secreted only latent forms of TGF-beta 1 and TGF-beta 2. There was no statistical difference in the levels of TGF-beta 1 and TGF-beta 2 in glioblastomas and anaplastic astrocytomas. Neither TGF-beta 1 nor TGF-beta 2 affected the growth of glioblastoma cells. These findings suggest that most malignant glioma cells secrete both TGF-beta 1 and TGF-beta 2, can convert TGF-beta from a latent to active form, and may suppress cytokine secretion by activated lymphocytes in vivo as well as in vitro.
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PMID:Secretion of transforming growth factor-beta 1 and -beta 2 by malignant glioma cells. 747 84


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