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PubMed1994

Anti-(glioma surface antigen) monoclonal antibody G-22 recognizes overexpressed CD44 in glioma cells.

We raised an anti-glioma monoclonal antibody, named G-22, that specifically recognizes a human glioma-associated surface antigen. Proven to be useful for target imaging of malignant gliomas after radioisotope labeling and cerebrospinal fluid diagnosis by enzyme-linked immunospecific assay, G-22 was found to immunoprecipitate an 85-kDa glycoprotein of the human glioma U-251MG cell. We purified this antigen by G-22-coupled cyanogenbromide-activated Sepharose affinity chromatography, and sequence analysis demonstrated that the 54 amino acid residues were identical to positions 55-108 of human CD44. The results show that the smallest spliced form (85 kDa) of CD44 is strongly expressed in glioma cells.

Amino Acid Sequence↗
PubMed2002

Highly unsaturated fatty acid induced tumour regression in glioma pharmacodynamics and bioavailability of gamma linolenic acid in an implantation glioma model: effects on tumour biomass, apoptosis and neuronal tissue histology.

Highly unsaturated fatty acids (HUFAs) are naturally occurring anti-tumour agents. HUFAs act as intracellular signalling molecules in cell proliferation and death. In human glioma, HUFAs may stimulate tumour regression and apoptosis. An implantation glioma model, using the C6 glioma cell line, was used to investigate the bioactivity of locally infused n-6 HUFA gamma linolenic acid (GLA). Rat brains (15 normal and 37 C6 tumour bearing) were infused with vehicle or GLA 200 microM-2 mM. The most active local concentration of GLA for anti-tumour activity was 2 mM, infused at 1 microl/h over 7 days. Tumour regression, increased apoptosis and decreased proliferation were observed in tumours of rats infused with this concentration of GLA. Little effect on normal neuronal tissue was detected. The intraparenchymal route was an effective method of GLA administration in the treatment of glioma. These studies provide further insights into the potential role of HUFAs as anti-glioma agents.

Animals↗
PubMed1999

Immune rejection of intracerebral gliomas using lymphocytes from glioma-bearing rats.

Naturally occurring malignancies do not induce immune responses against cancer antigens. Is the lack of an immune response caused by an antigen presentation defect or by induced antigen-specific immune suppression? The current study was performed to determine whether a progressing intracerebral malignancy affects production of peripheral autologous glioma antigen-specific immune responses. Peripheral immunization of both glioma-bearing and non-glioma-bearing animals with cancer cells and adjuvant generated similar levels of glioma antigen-specific cytotoxic T lymphocyte activity. However, immune cell populations from glioma bearers were significantly less efficient than immune cell populations from non-cancer bearers in their ability to reject progressing intracerebral tumors. A variety of manipulations designed to reduce nonspecific immune suppression in vivo and in vitro had no effect on the in vivo efficacy of the activated T-lymphocyte populations. The presence of progressing tumors appeared to augment rather than suppress cancer antigen-specific responses, leading to the speculation that reduced efficacy was caused not by generalized immune suppression but rather by a reduction in the number of immune effector cells by either clonal anergy or clonal deletion. Most importantly, the data demonstrated that, despite decreased in vivo efficacy, immune effector cells capable of rejecting an intracerebral malignancy could be generated from cancerous hosts.

Animals↗
PubMed1985

Antigenic heterogeneity of human anaplastic gliomas and glioma-derived cell lines defined by monoclonal antibodies.

The antigenic heterogeneity of human neuroectodermal tumors defined by both murine and human monoclonal antibodies (MAs) is reported; no patterns of reactivity defining degree of anaplasia, in vitro morphology, or immunogen used were apparent. We investigated the reactivity of 20 distinct murine MAs defining markers of glioma-associated or predominantly lymphoid distribution for 13 human glioma-derived (HGL) cell lines and frozen sections of 19 human glioblastoma multiforme (GBM) and six astrocytomas (AST). Methods included radioimmunoassay, immunofluorescence, immunohistochemistry, and absorption analysis. Two markers, HLA-A,B and human Thy-1, exhibited no deviation; all HGL cell lines tested bound high levels of specific MA. Individual HGL cell line reactivity with the MA panel ranged from 30 to 70%. HGL cell lines (7/13) which reacted with greater than or equal to 50% of the antiglioma MAs had the highest (30-70%) positive reactivity rates with the anti-lymphoid marker MA panel; complex antigenicity in one system correlated with multiple antigens in the other. Within the anti-lymphoid marker MA panel, subpopulations of 4/13 HGL cell lines were clearly positive for the HLA-DR (Ia) antigens; another 3/13 HGL cell lines were strongly positive for common acute lymphocytic leukemia antigen (CALLA). With the exception of Thymocyte 1 antigen (Thy-1), reactivity for early and mature T-cell markers was infrequent and sporadic. Lymphoid marker expression by HGL cell lines is highly heterogeneous, ranging from few (Thy-1 and HLA-A,B) to complex expression of Ia, T-cell, and lymphoid tumor markers. GBM and AST tissues were antigenically less complex; for each of 6/8 anti-glioma MA, 70-100% of GBM and 66-100% of AST were positive. Two MAs were highly reactive (7/10, 8/9) with GBM sections and minimally so (1/6) with AST. Antigenic expression in gliomas is complex and heterogeneous; however, clear differences in lymphoid marker expression, the identification of widely and rarely expressed glioma-associated antigens, and the potential of immunologic differentiation between GBM and AST by large panels of MAs will serve to reduce the complexity and may be of potential diagnostic or prognostic significance.

Animals↗
PubMed2006

Optic-nerve gliomas, chiasmal gliomas and neurofibromatosis type 1.

PURPOSE OF REVIEW: To review the most recent literature describing the natural history and disease progression patterns of optic-pathway gliomas in neurofibromatosis type 1 (NF1) patients. To aid in clarifying the current treatment patterns and follow-up recommendations. RECENT FINDINGS: Contrary to prior documentation, current literature reveals that optic-pathway gliomas in NF1 can be diagnosed after the age of 6, and may progress until the age of 12. The disease progression occurs most frequently in the first two years following diagnosis. SUMMARY: Optic-pathway gliomas in NF1 can display a variety of manifestations and exhibit an unpredictable disease course. No specific characteristics have been found thus far to predict an aggressive compared with indolent disease course. Recently primary diagnoses of optic-pathway gliomas have been made in children aged six or older, and have been shown to progress until the age of 12. Although large-scale studies are required to change current follow-up recommendations, the data suggest that NF1 patients should be vigilantly evaluated for optic-pathway gliomas past the age of 12.

Humans↗
PubMed1995

Long-term culture of organotypic multicellular glioma spheroids: a good culture model for studying gliomas.

Gliomas, as well as other solid tumours, contain tumour stroma composed of connective tissue, macrophages, capillaries and other non-cellular constituents. Therefore, a homogeneous culture of tumour cells alone, as is often used as a culture model for gliomas, is not ideal to study all aspects of gliomas. In the present study we describe an alternative culture model, i.e. organotypic multicellular spheroids (OMS), that histologically closely resembles the tumour in vivo. Glioma explants, obtained at surgery from five patients, were cultured on agarose to form OMS, which were cultured for up to 16 weeks. At regular intervals, OMS were fixed and histological and immunocytochemical analyses were carried out. The histology as well as the immunocytochemical characteristics of the OMS proved to be almost unchanged after a culture period of 16 weeks. In contrast to monolayer cultures, glial fibrillary acidic protein (GFAP) expression in the OMS is preserved after 16 weeks of culture. However, in OMS from three out of five patients, small GFAP-negative cells appeared in the outer cell layers between 1 and 2 weeks of culture. Furthermore, after about 6 weeks of culture, the capillaries disappeared from the OMS. After prolonged culture, tumour cell heterogeneity, the cellular composition, and the histology of the OMS still closely resembled the tumour in vivo. It is suggested that OMS provide a good long-term culture model for the study of gliomas.

Adult↗
PubMed2003

P-glycoprotein and multidrug resistance-associated protein mediate specific patterns of multidrug resistance in malignant glioma cell lines, but not in primary glioma cells.

Understanding and overcoming multidrug resistance (MDR) may be a promising strategy to develop more effective pharmacotherapies for malignant gliomas. In the present study, human malignant glioma cell lines (n=12) exhibited heterogeneous mRNA and protein expression and functional activity of the mdr gene-encoded P-glycoprotein (PGP) and MDR-associated protein (MRP). Correlation between mRNA expression, protein levels and functional activity was strong. Inhibition of PGP activity by verapamil or PSC 833 enhanced the cytotoxic effects of vincristine, doxorubicin, teniposide and taxol. Inhibition of MRP activity by indomethacin or probenecid enhanced the cytotoxic effects of vincristine, doxorubicin and teniposide. The human cerebral endothelial cell line, SV-HCEC, exhibited the strongest PGP activity of all cell lines. Five primary human glioblastomas and one anaplastic astrocytoma displayed heterogenous protein levels of PGP and MRP-1 in tumor cells and of PGP in biopsy specimens in vivo, but no functional activity of these proteins upon ex vivo culturing. These data suggest that the glioma cell line-associated MDR-type drug resistance is a result of long-term culturing and that cerebral endothelial, but not glioma cells, may contribute to MDR-type drug resistance of gliomas in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1988

Comparison of in vitro glioma cell cytotoxicity of LAK cells from glioma patients and healthy subjects.

Peripheral blood mononuclear cells from 11 glioma patients and 11 healthy control subjects were cultured in medium containing recombinant interleukin-2 for a period of 5 days. The cytotoxicity of these lymphokine-activated killer (LAK) cells was tested on chromium-51-labeled freshly prepared allogeneic glioblastoma cells, and on the cell lines K562 (natural killer cell (NK)-sensitive) and Daudi (NK-resistant). Peripheral blood mononuclear cells from all subjects showed high levels of cytotoxicity against these targets. There was no significant difference between the patients and the control group when LAK cytotoxicity was compared. Thus, although glioma patients are known to have depressed immunological reactivity, the cytotoxic capacity of LAK cells derived from glioma patients is similar to that of LAK cells from healthy control subjects. However, the glioma patients had significantly reduced numbers of mononuclear cells in their peripheral blood, possibly due to steroid treatment. Therefore, the volume of blood required to generate the same number of LAK cells was approximately three times larger from the glioma patients than from control subjects.

Adult↗
PubMed2005

Malignant glioma-induced neuronal cell death in an organotypic glioma invasion model. Technical note.

Rapid growth and diffuse brain infiltration are hallmarks of malignant gliomas. The underlying molecular pathomechanisms of these tumors, however, remain to be determined. The authors present a novel glioma invasion model that allows researchers to monitor consecutively tumor cell proliferation and migration in an organotypic brain environment. Enhanced green fluorescent protein-labeled F98 rat glioma cells were implanted into slice cultures obtained from a rat hippocampus, and tumor growth was microscopically documented up to 20 days in vitro. Invasion along radially oriented migratory streams could be observed 5 days after implantation of rat F98, human U87MG, and mouse GL261 glioma cells, whereas human Be(2)c neuroblastoma cells and mouse HT22 hippocampal neurons failed to invade the brain parenchyma. Following implantation of F98 glioma cells into the entorhinal cortex, cell death was observed within the infiltrated brain parenchyma as well as in the neuroanatomically connected dentate gyrus. Application of the N-methyl-D-aspartate receptor antagonist MK801 to the culture medium significantly reduced neuronal degeneration in the dentate gyrus, whereas the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antagonist GYKI 52466 inhibited peritumoral cytotoxicity. This new model allows researchers to address in a systematic manner the molecular pathways of brain invasion as well as specific tumor-host interactions such as necrosis.

Animals↗
PubMed1999

Characterization of Tu-2449, a glioma cell line derived from a spontaneous tumor in GFAP-v-src-transgenic mice: comparison with established murine glioma cell lines.

Glial fibrillary acidic protein (GFAP)-v-src transgenic mice develop spontaneous gliomas with a high incidence of malignant progression. We characterize the first glial cell line derived from v-src transgenic mice, Tu-2449 in comparison with a virally induced murine glioma, SRB-10, and a spontaneous murine glioma, P497. Doubling times were lowest, as clonogenicity in soft agar was highest for Tu-2449, and to a lesser degree, Tu-2449 cells formed spheroids and showed migratory behaviour and invaded fetal rat brain aggregates. BCL-2 and BAX expression were lower in Tu-2449 and P497 than in SRB-10 cells. Only Tu-2449 cells accumulated p53 protein in response to genotoxic stress. Tu-2449 and SRB-10 cells that showed low CD95 expression were resistant to CD95 ligand (CD95L)-induced apoptosis unless coexposed to CD95L and inhibitors of RNA or protein synthesis. A chemosensitivity profile revealed Tu-2449 to be rather chemoresistant. Tu-2449 thus displays growth characteristics and patterns of resistance to apoptosis similar to those of other mouse and human glioma cell lines and may therefore become a valuable tool to evaluate new therapies for malignant gliomas in vitro and in vivo.

Animals↗
PubMed2002

Cloning and characterization of glioma BK, a novel BK channel isoform highly expressed in human glioma cells.

Voltage-dependent large-conductance Ca2+-activated K+ channels (BK channels) are widely expressed in excitable and nonexcitable cells. BK channels exhibit diverse electrophysiological properties, which are attributable in part to alternative splicing of their alpha-subunits. BK currents have been implicated in the growth control of glial cells, and BK channels with novel biophysical properties have recently been characterized in human glioma cells. Here we report the isolation, cloning, and functional characterization of glioma BK (gBK), a novel splice isoform of hSlo, the gene that encodes the alpha-subunits of human BK channels. The primary sequence of gBK is 97% identical to its closest homolog hbr5, but it contains an additional 34-amino-acid exon at splice site 2 in the C-terminal tail of BK channels. hSlo transcripts containing this novel exon are expressed ubiquitously in various normal tissues as well as in neoplasmic samples, suggesting that the novel exon may modulate important physiological functions of BK channels. Expression of gBK in Xenopus oocytes gives rise to iberiotoxin-sensitive (IbTX) currents, with an IC(50) for IbTX of 5.7 nm and a Hill coefficient of 0.76. Single gBK channels have a unitary conductance of similar250 pS, and the currents show significantly slower activation and higher Ca2+ sensitivity than hbr5. Ca2+ sensitivity was enhanced specifically at physiologically relevant [Ca2+]i (100-500 nm). Examination of biopsies from patients with malignant gliomas has revealed specific overexpression of BK channels in gliomas compared with nonmalignant human cortical tissues. Importantly, tumor malignancy grades have correlated positively with BK channel expression, suggesting an important role for the gBK channel in glioma biology.

Alternative Splicing↗
PubMed1989

[Regrowth patterns of glioma--cases of glioma regrew away from the original tumor].

There have been conflicting opinions regarding the correct volume to be used in radiotherapy fields for malignant glioma. Whereas many clinicians recommend limited fields designed to cover the tumor volume with a margin according to the facts about 90% of recurrent malignant glioma regrew within 2 cm of the original tumor and regrowth away from the original tumor was seen in about 5%. Two cases of malignant glioma regrew away for the original tumor and one case of malignant glioma regrew into the resected site were presented. And the biological characteristics of glioma cells concerning with the invasiveness were discussed.

Adult↗
PubMed1994

Modulation of tumor immunogenicity of rat glioma cells by s-Myc expression: eradication of rat gliomas in vivo.

The Myc family proteins represented by c-Myc are thought to play a crucial role in cellular proliferation, differentiation, transformation, and apoptosis. In this study, we demonstrated the novel role for a Myc family protein in elicitation of immunogenic phenotypes in tumor cells. Injection of rat 9L or C6 glioma cells, together with the s-myc gene linked to the cytomegalovirus promoter, completely prevented formation of both brain tumors and s.c. tumors derived from the parental glioma cells. However, introduction of the s-myc gene had no inhibitory effect on development of B104-derived neuroblastoma. In addition, unlike the s-myc gene, injection of the c-myc or wild type p53 (wt-p53) gene together with glioma cells did not modulate the tumor immunogenicity and resulted in formation of gliomas in the animals. These findings suggest that s-Myc expression may stimulate the presentation of a tumor antigen common to 9L and C6 cells to T lymphocytes and augment the activity of the host immune system, resulting in prevention of glioma formation in vivo. This success in tumor eradication indicates the possibility of application of the s-myc gene for gene therapy of human brain tumors.

Animals↗
PubMed2000

Antigen-presenting capability of glial cells under glioma-harboring conditions and the effect of glioma-derived factors on antigen presentation.

The antigen-presenting capability of syngeneic rat glial cells was investigated under glioma-harboring conditions. Microglia induced a significant proliferation of glioma-primed splenocytes, but astrocytes did not. Furthermore, astrocytes suppressed the accessory cell function of microglia. The presence of both indomethacin and anti-interleukin (IL)-10 neutralizing antibody during priming of microglia enhanced splenocyte proliferation. The glioma culture supernatants down-regulated the interferon-gamma-induced expression of major histocompatibility complex class II molecules on microglia. The down-regulation was blocked by indomethacin and anti-IL-10 antibody. The results suggest that microglia but not astrocytes may function as antigen-presenting cells in glioma, and that glioma may suppress the antigen-presenting abilities of microglia.

Animals↗
PubMed1999

Interleukin-6 transduction of a rat T9 glioma clone results in attenuated tumorigenicity and induces glioma immunity in Fischer F344 rats.

We transduced a highly tumorigenic T9 clone (T9.F), isolated from the rat T9 glioblastoma cell line, with a retroviral expression vector containing the human IL-6 cDNA and investigated the effects of IL-6 secretion on glioma formation in the syngeneic Fischer rat. Two subclones producing high and low levels (35 and 3.5 ng/10(6) cells/48 h) of IL-6 were identified and were termed T9.F/IL6/hi and T9.F/IL6/lo, respectively. Subcutaneous (SC) injection of 1 x 10(6) parental T9.F cells resulted in 100% tumor formation and progression. When 1 x 10(6) IL-6 secreting T9.F cells were injected SC, a small palpable tumor formed which sometimes regressed. In this regard, no tumors were detected after 30 days in 76% (13/17) of animals injected with T9.F/IL6/hi cells, whereas only 10% (1/10) of the rats injected with T9.F/IL6/lo cells completely rejected their tumors within this time frame. The addition of an IL-6 neutralizing antibody to the T9.F/IL6/hi SC inoculum followed by an intratumoral injection of the IL-6 neutralizing antibody, seven days later, abrogated the anti-tumor effects. Animals that rejected the IL-6 secreting tumors were 100% protected from subsequent intracranial (IC) challenges with the parental T9.F glioma as well as the original T9 glioblastoma; partially protected from an IC challenge with the unrelated, syngeneic RT-2 glioma; but were not protected from an IC challenge with the syngeneic MadB106 adenocarcinoma. When 1 x 10(4) cells were injected in the brain of naive animals, survival time was significantly increased for those rats implanted with T9.F/IL6/hi cells, but not T9.F/IL6/lo cells, as compared to animals implanted with T9.F parental cells (p = 0.003). This study demonstrates that IL-6 secretion attenuates SC and IC glioma growth and SC rejection of IL-6 secreting T9.F cells induces long-term glioma immunity which is effective in the brain.

Adenocarcinoma↗
PubMed2000

Biopsy versus resection for malignant glioma.

BACKGROUND: Patients with isolated supratentorial brain tumours, presumed to be primary on imaging, have two surgical management options - biopsy or resection. Surgical opinions appear to be equally divided when considering the relative risks and benefits of these two procedures. OBJECTIVES: To estimate the clinical effectiveness of radical surgical resection compared to simple biopsy in patients with malignant glioma. SEARCH STRATEGY: Electronic database searches of COCHRANE CONTROLLED TRIALS REGISTER (including the Cochrane Cancer Network Specialised Register of Trials), MEDLINE, CANCERLIT, EMBASE, BIOSIS and SCIENCE CITATION INDEX. Hand searching the references of all identified studies; hand searching the Journal of Neuro-Oncology over the previous 10 years, including all conference abstracts; personal communication. SELECTION CRITERIA: Randomised and clinical controlled trials were included if they compared biopsy to resection, or looked at effect of extent of resection on survival, time to progression or quality of life, for malignant glioma patients of all ages. DATA COLLECTION AND ANALYSIS: Studies were to be identified, critically appraised and data extracted by the author (SEM). For dichotomous data, Peto odds ratios (OR) with 95% confidence intervals (CI) were hoped to have been estimated. Normal continuous data were to have been summated using the weighted mean difference (WMD). MAIN RESULTS: The electronic database search yielded 2100 citations. Of these, two articles were identified for possible inclusion, however both were excluded. The hand search and personal communication were similarly unproductive. No studies were included in the review and no data was synthesised. REVIEWER'S CONCLUSIONS: Given that no qualifying studies were identified and because this is an important issue, both in terms of patient risk and benefit and health economics, the author feels it important to conduct a randomised controlled trial in this subject.

Biopsy↗
PubMed2004

Vaccination with tumor cell lysate-pulsed dendritic cells augments the effect of IFN-beta gene therapy for malignant glioma in an experimental mouse intracranial glioma.

Interferon-beta (IFN-beta) has been used as an antitumor drug against human glioma, melanoma and medulloblastoma since the 1980s. Recently, we developed a new gene therapy using the IFN-beta gene against malignant gliomas and then began clinical trials in 2000. Since stimulation of immune system was one mechanism of antitumor effect induced by IFN-beta gene therapy, we hypothesized that combination of IFN-beta gene therapy with immunotherapy might increase its effectiveness. In the present study, we tested whether combination therapy with IFN-beta gene therapy and immunotherapy using tumor cell lysate-pulsed dendritic cells (DCs) would increase the efficacy of IFN-beta gene therapy. In an experimental mouse intracranial glioma (GL261), which cannot be cured by either IFN-beta gene therapy or DC immunotherapy alone, IFN-beta gene therapy following DC immunotherapy resulted in a significant prolongation in survival of the mice. Moreover, when this combination was performed twice, 50% of treated mice survived longer than 100 days. Considering these results, this combination therapy may be one promising candidate for glioma therapy in the near future.

Animals↗
PubMed1980

Humoral immune response in glioma patients: A solubilized glioma-associated membrane antigen as a tool for detecting circulating antibodies.

Plasma membranes from normal and neoplastic human brain tissue were isolated and compared morphologically, biochemically and immunologically. There ultrastructure was identical, electrophoresis on polyacrylamide gel revealed at least 24 protein components, four of which were absent from membranes of normal tissue, whereas one was missing in the tumor pattern. The tumor-associated components could be solubilized by the non-ionic detergent Triton-X100 and were used as an antigen source for the immunological characterization of glioma membranes. By means of a rabbit antiserum immunologically identical components could be detected in the Triton extract of the membranes from all the 20 human gliomas tested so far, but not in normal or fetal brain, nor in liver, kidney or spleen tissue. These data indicate that the solubilized membrane components contain common glioma-associated membrane antigens which might be used in the detection of circulating antibodies in the sera of glioma patients. Of the 24 samples of sera tested so far, 19 (79%) contained precipitating antibodies against these membrane components as revealed by countercurrent electrophoresis.

Antibodies, Neoplasm↗