epidermal-growth-factor and Meningioma

Epidermal growth factor can activate several signaling pathways, leading to proliferation, differentiation, and tumorigenesis of epithelial tissues by binding with its receptor. The EGF protein is involved in nervous system development, and polymorphisms in the EGF gene on chromosome band 4q25 are associated with brain cancers. The purpose of this study was to investigate the association between the single-nucleotide polymorphism of EGF+61G/A and extraaxial brain tumors in a population of the southeast of Brazil. We analyzed the genotype distribution of this polymorphism in 90 patients and 100 healthy subjects, using the polymerase chain reaction-restriction fragment length polymorphism technique. Comparison of genotype distribution revealed a significant difference between patients and control subjects (P < 0.001). The variant genotypes of A/G and G/G were associated with a significant increase of the risk of tumor development, compared with the homozygote A/A (P < 0.0001). When the analyses were stratified, we observed that the genotype G/G was more frequent in female patients (P=0.021). The same genotype was observed more frequently in patients with low-grade tumors (P=0.001). Overall survival rates did not show statistically significant differences. Our data suggest that the EGF A61G polymorphism can be associated with susceptibility to development of these tumors.

Topics: Brain Neoplasms; Case-Control Studies; Epidermal Growth Factor; Female; Genetic Predisposition to Disease; Humans; Male; Meningioma; Middle Aged; Nervous System Neoplasms; Neurilemmoma; Polymorphism, Single Nucleotide

ErbB family receptors mediate major cellular functions implied in tumorigenesis, though their role in meningiomas was not thoroughly studied. Meningiomas represent 30% of primary cranial tumors, are mostly benign, and prevail in the second half of life. Tumor therapy requires information about molecular alterations, thus we studied expression of ErbB receptor and ligand genes by real-time RT-PCR in different meningioma grades. Receptors were overexpressed (ErbB1, ErbB2) or underexpressed (ErbB3, ErbB4). Ligands EGF, TGFA, AREG, DTR, BTD were underexpressed and the neuregulins were overexpressed or underexpressed. A strong ErbB1-ErbB2 correlation was found. These data might be useful for gene therapy.

Topics: Adult; Aged; Aged, 80 and over; Amphiregulin; Betacellulin; EGF Family of Proteins; Epidermal Growth Factor; Epigen; ErbB Receptors; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes, erbB; Glycoproteins; Heparin-binding EGF-like Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Ligands; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Neoplasm Staging; Neuregulins; Polymerase Chain Reaction; Receptor, ErbB-2; Receptor, ErbB-4; RNA, Messenger; Transforming Growth Factor alpha

To investigate the clinical significance of urinary epidermal growth factor (EGF) in patients with brain tumors.. The levels of EGF in urine samples collected from 20 patients (9 low grade astrocytomas, 6 anaplastic astrocytomas, and 5 meningiomas) and 5 healthy individuals were determined. EGF levels were measured by radioimmunoassay technique. A preoperative and one postoperative determination were performed.. Preoperative urinary EGF levels of astrocytoma patients were statistically higher than those of meningioma patients and the controls (P < 0.01). Preoperative urinary EGF levels showed a positive correlation with the degree of malignance in the astrocytoma patients (P < 0.05). A significant decrease of the postoperative levels of EGF was observed in the astrocytoma patients who underwent gross total resection (P < 0.01). The pre/postoperative urinary EGF levels of the meningioma patients showed no significant fluctuations and showed no significant difference with those of healthy individuals (P > 0.05).. The urinary EGF levels of astrocytoma patients correlate with the WHO grade of malignance and significantly decrease after gross total removal. Urinary EGF may be of practical value in diagnosing and evaluating the surgical efficacy of astrocytomas.

Topics: Adolescent; Adult; Aged; Astrocytoma; Biomarkers, Tumor; Brain Neoplasms; Epidermal Growth Factor; Female; Humans; Male; Meningioma; Middle Aged

The biological factors responsible for the increased aggressiveness in atypical meningiomas are not well known. The aim of this study is to evaluate the discriminatory value of a number of biological markers (S100 proteins and galectin-3 and its ligand profile) with respect to benign and atypical meningiomas. Using 63 meningiomas (39 benign and 24 atypical), we performed a semi-quantitative histochemical analysis of both the expression of galectin-3 and its ligand profile and the Ca2+-binding proteins S100A5, S100A6 and S100B. Three features were considered for each marker, namely the labeling index (LI), the staining intensity (SI) and the global score (LI + SI). A low S100A6 labeling index was observed in 51% of the benign and 25% of the atypical meningiomas (P=0.035). Furthermore, high S100B scores were observed in 46% of the benign and in only 8% of the atypical meningiomas (P=0.001). Seventy-one percent of the atypical meningiomas exhibited a low level of staining intensity for the galectin-3-binding sites as compared to only 36% of the benign meningiomas (P=0.007). The combination of these three markers (by means of a decision tree) enabled an improved discriminatory criterion to be established between the benign and the atypical meningiomas. Our results thus suggest that the galectin-3-binding sites and S100B (and S100A6 to a lesser extent) could play a role in the aggressiveness characterizing atypical meningiomas.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Autoantigens; Biomarkers; Cell Cycle Proteins; Decision Trees; Epidermal Growth Factor; Female; Galectin 3; Humans; Immunohistochemistry; Ligands; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Neoplasm Staging; Nerve Growth Factors; Prognosis; S100 Calcium Binding Protein A6; S100 Calcium Binding Protein beta Subunit; S100 Proteins

Somatostatin receptors are highly expressed in almost all meningiomas but in this setting their functional role is not clear. A 59-yr-old woman had been treated with octreotide after an unsuccessful operation for a GH-secreting pituitary adenoma. After 8 yr of treatment, a nuclear magnetic resonance (NMR) scan disclosed a 3 cm meningioma of the tentorium. Mean GH was 2.2 ng/ml and IGF-I 325 ng/ml. Meningioma was resected and tissue was digested to obtain tumor cell suspension. Aim of the study was to measure epidermal growth factor (EGF)-induced proliferation of cultured meningioma cells in the presence of either somatostatin or octreotide. Cells were grown to semiconfluency in Dolbecco's modified eagle medium (D-MEM) supplemented with 10% fetal calf serum (FCS). After 48 h in D-MEM without serum, the medium was replaced by fresh medium plus recombinant EGF (10 ng/ml) and somatostatin or octreotide were added in the final concentrations of 1, 10 and 100 nM. 20 h later 1 microcgCi of 3H-thymidine was added to each well. After 4 h, incorporated radioactivity was measured. While octreotide did not influence significantly cell growth at the three dose tested, somatostatin increased thymidine incorporation dose-dependently (peak 100 nM: 150% +/- 27% vs medium plus EGF, p<0.05). Octreotide effectively suppressed GH secretion in our acromegalic patient but is unlikely that its long-term use could have stimulated the growth of meningioma since it did not significantly influence the in vitro proliferation of the meningioma cells. These results suggest that somatostatin-mediated proliferative effect on meningioma cells is not mediated by the subtype 2 of the somatostatin receptor.

Topics: Acromegaly; Cell Division; Epidermal Growth Factor; Female; Humans; Magnetic Resonance Imaging; Meningeal Neoplasms; Meningioma; Middle Aged; Octreotide; Receptors, Somatostatin; Somatostatin; Tumor Cells, Cultured

Matrix metalloproteinases (MMPs) are a growing family of zinc-dependent endopeptidases that are capable of degrading various components of the extracellular matrix. These enzymes have been implicated in a variety of physiological and pathological conditions including embryogenesis and tumour invasion. The synthesis of many MMPs is thought to be regulated by growth factors, cytokines and hormones. In this study, we investigated the effects of five exogenous growth factors known to be expressed by gliomas [epidermal growth factor (EGF), basic growth factor (bFGF), transforming growth factor beta (TGF-beta1,2) and vascular endothelial growth factor (VEGF)].on MMP-2 and MMP-9 expression in an ependymoma, two grade III astrocytomas, a grade III oligoastrocytoma and a benign meningioma. Zymogram analysis revealed that the effects of the growth factors depended upon the cell lines used in the study. Growth factors generally up-regulated MMP-2 and MMP-9 expression in the gliomas but were least effective in the meningioma; the effect being most prominent with TGF-beta1 and TGF-beta2 in all the cell lines. It is hypothesized that paracrine growth factor interplay may be crucial in the regulation of MMP expression by glioma invasion of the normal brain.

Topics: Brain Neoplasms; Endothelial Growth Factors; Epidermal Growth Factor; Fibroblast Growth Factor 2; Glioma; Growth Substances; Humans; Lymphokines; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Meningeal Neoplasms; Meningioma; Neoplasm Proteins; Transforming Growth Factor alpha; Transforming Growth Factor beta; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

We have previously demonstrated that calcium channel antagonists inhibit the growth of human meningiomas in culture after stimulation with growth factors. This study examined the effects of these drugs on signaling transduction pathways in an attempt to elucidate potential mechanisms by which this growth inhibition is mediated.. Primary cell cultures from patients with intracranial meningiomas were established. Cell growth studies were performed with inhibitors and stimulators of tyrosine kinase signal transduction. Intracellular calcium changes and inositol phosphate production were measured after growth factor exposure, with or without pretreatment by calcium channel antagonists.. The growth of meningiomas in culture can be inhibited by tyrosine kinase receptor inhibitors. Inhibitors and stimulators of phospholipase C can stimulate or inhibit the growth of in vitro meningiomas, respectively. Calcium channel antagonists inhibit intracellular calcium changes induced by serum and epidermal growth factor. Inositol phosphate production is increased after growth factor stimulation, and calcium channel antagonists potentiate this effect.. Calcium channel antagonists interfere with intracellular signaling pathways of cultured meningioma cells. This inhibition is unrelated to voltage-sensitive calcium channels. The findings of this project may aid in the understanding of the signal transduction mechanisms involved in growth factor-mediated meningioma proliferation and may lead to clinically relevant strategies for growth inhibition.

Topics: Adult; Aged; Blood Physiological Phenomena; Calcium; Calcium Channel Blockers; Culture Techniques; Enzyme Activation; Enzyme Inhibitors; Epidermal Growth Factor; Female; Growth Substances; Humans; Inositol Phosphates; Intracellular Membranes; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Quinazolines; Signal Transduction; Type C Phospholipases; Tyrphostins

We have previously documented that the vast majority of high-grade gliomas over-express binding sites for interleukin 13 (IL13) in situ. We now extend this analysis to evaluate the distribution of the binding of IL13 among other brain tumors. Tumor specimens from patients with low-grade gliomas, oligodendrogliomas, ependymomas, pilocytic astrocytomas, gliosarcomas, medulloblastomas, meningiomas, and metastases to the brain were analyzed and compared to a new series of glioblastoma multiforme (GBM) samples. Serial tumor tissue sections were incubated with 125I-labeled (i) IL13, (ii) antibody against transferrin (Tf) receptor, and (iii) epidermal growth factor (EGF). Most (17/18) GBMs stained specifically for IL13 binding sites while sections from 3/11 low-grade gliomas, 5/5 high-grade gliomas (grade III), 3/5 oligodendrogliomas (all three were anaplastic), and 1/2 gliosarcomas also showed specific binding for IL13. We did not detect IL13 binding sites in medulloblastomas (0/4) and found them only in 2/20 meningiomas. Metastases to the brain (4/12, i.e., lung adenocarcinomas and renal cell carcinoma) showed some binding of 125I-IL13. The presence of receptors for Tf was ubiquitous among all studied tumors while EGF receptor expression was much more variable. Since it appears that primarily the least differentiated forms of gliomas possess IL13 binding sites in abundance, it is plausible that IL 13 receptor expressed in low-grade gliomas might be a prognostically significant marker associated with their progression to high-grade gliomas. Finally, we demonstrate that the glioma-associated IL13 receptor is truly more restrictive in nature also due to its selective representation among brain tumors of glial origin.

Topics: Adenocarcinoma; Biomarkers, Tumor; Brain Neoplasms; Carcinoma; Cell Transformation, Neoplastic; Disease Progression; Ependymoma; Epidermal Growth Factor; ErbB Receptors; Gene Expression Regulation, Neoplastic; Glioma; Gliosarcoma; Humans; Interleukin-13; Interleukin-13 Receptor alpha1 Subunit; Interleukin-4; Medulloblastoma; Meningeal Neoplasms; Meningioma; Neoplasm Proteins; Oligodendroglioma; Receptors, Interleukin; Receptors, Interleukin-13; Receptors, Transferrin; Recombinant Proteins; Substrate Specificity

The purpose of this study was to compare the differential susceptibility to photodynamic therapy (PDT) mediated damage in human U-105MG glioma cells and CH-157MN meningioma cells in vitro using 5-amino-levulinic acid (ALA) as photosensitizer, and to determine if growth factors would enhance PDT-mediated damage of these cells.. U-105MG or CH-157MN cells were irradiated with polychromatic light in the presence of ALA. A Xenon lamp (150 W) was used as the light source. For the study on the effect of growth factor on ALA-PDT, cells were cultured in serum free medium for 24 hours. Epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), or platelet derived growth factor BB (PDGF-BB) was added to achieve a final concentration of 50 ng/ml. 30 minutes later, cells were incubated with ALA (100 microg/ml) for 24 hours, washed, and irradiated with light (11 J/cm2). MTT tetrazolium assays were performed 24 hours after light irradiation.. The inhibition of metabolic cellular function in U-105MG cells by ALA depended on both light energy density and ALA concentration. The susceptibility to ALA-PDT was profoundly lower for CH-157MN meningioma cells than U-105MG glioma cells. When incubated with ALA (100 microg/ml), U-105MG cells exhibited an LD50 around 8 J/cm2 of light irradiation, whereas that of CH-157MN cells was more than 25 J/cm2. EGF, bFGF, or PDGF-BB did not have any effects on the susceptibility of these two cell lines to ALA-PDT.. ALA-PDT was more effective in killing U-105MG glioma cells than CH-157MN meningioma cells. The differential susceptibility was likely due to differential accumulation of PpIX in these cells. EGF, bFGF, or PDGF-BB did not have stimulatory or inhibitory effect on the efficiency of ALA-PDT.

Topics: Aminolevulinic Acid; Analysis of Variance; Dose-Response Relationship, Radiation; Epidermal Growth Factor; Glioma; Humans; Meningeal Neoplasms; Meningioma; Photochemotherapy; Photosensitizing Agents; Tumor Cells, Cultured

The objective of this study was to examine the expression of transforming growth factor alpha (TGFalpha), a mitogen for many cell types, and its receptor in basic subtypes of meningiomas as well as in meningiomas of varying grade. Formalin-fixed tissues from 26 meningiomas including 15 benign (5 meningothelial, 5 transitional, and 5 fibrous variants), 6 atypical, and 5 malignant examples were immunohistochemically examined for both TGFalpha protein and EGF/TGFalpha receptor protein. In addition, in situ hybridization (ISH) was used to detect TGFalpha mRNA expression. Immunostaining for TGFalpha was strongest in fibrous and atypical meningiomas, followed closely by transitional and malignant tumors. Only weak reactivity was observed in the meningothelial variant. In all but 4 tumors (2 fibrous, 2 atypical), ISH showed TGFalpha mRNA to be present, the signal being stronger in malignant than in conventional or atypical tumors. Lastly, immunostaining for EGF/TGFalpha receptor was positive in all tumors studied. Strong TGFalpha protein expression in meningiomas is commonly associated with fibrous morphology. Although the frequent detection of both TGFalpha protein and its mRNA, as well as of EGF/TGFalpha receptor within tumors of all type and grades, suggests that TGFalpha serves to promote tumor growth, its possible role in tumorigenesis or malignant progression is uncertain. In summary, demonstration of these substances is of no utility in the classification or grading of this common tumor because the differences in their expression among the various meningioma subtypes were not statistically significant.

Topics: Adult; Arachnoid; Cell Division; Cytokines; Epidermal Growth Factor; Growth Substances; Humans; Meningeal Neoplasms; Meningioma; Neurons; Pia Mater; Platelet-Derived Growth Factor; Reference Values; Transforming Growth Factor alpha; Tumor Cells, Cultured

The authors report the case of a young man suffering from neurofibromatosis type 2 (NF2) who harbored bilateral acoustic schwannomas and a parasellar meningioma. Neuroimaging studies performed during a 4-year follow-up period showed that the bilateral schwannomas had grown very little and at similar rates. However, after the meningioma had infiltrated the tentorium and approached the ipsilateral schwannoma at the incisura, both Schwann cell tumors started to grow rapidly, particularly the one adjacent to the meningioma, of which the percentage of annual growth rate increased by approximately a factor of 10(2). At the same time, magnetic resonance imaging showed that this tumor also changed its features. During surgery, the acoustic schwannoma was firmly adherent to both meningioma and tentorium. Histological examination revealed meningotheliomatous cells in the schwannoma adjacent to the meningioma. Antiphosphotyrosine immunoblotting of PC12 cells was compatible with the presence of an epidermal growth factor (EGF)-like molecule in the cerebrospinal fluid (CSF) of the patient. This factor was not detected in the CSF of five other NF2 patients, two of whom bore associated bilateral acoustic schwannomas and meningioma in remote locations. It is hypothesized that the meningotheliomatous cells infiltrating the schwannoma triggered an autocrine/paracrine growth-stimulatory mechanism that involved an EGF-like factor.

Topics: Adolescent; Autocrine Communication; Cerebellar Neoplasms; Cerebellopontine Angle; Epidermal Growth Factor; Follow-Up Studies; Humans; Immunoblotting; Magnetic Resonance Imaging; Male; Meningeal Neoplasms; Meningioma; Neurofibromatosis 2; Neuroma, Acoustic; Paracrine Communication; Phosphotyrosine; Sella Turcica

The hormone sensitivity of a tumor is traditionally based on the presence of steroid receptors. Other factors should be taken into consideration. Here, we studied the influence of 10 nM epidermal growth factor (EGF) or gastrin on the proliferation of human ex vivo tumor cultures by means of [3H]thymidine autoradiography. The immunohistochemical EGF-receptor expression was also quantified by means of computer-assisted microscopy. The results demonstrated that the proliferation of 6/11 astrocytic tumors and 3/16 meningiomas was sensitive to at least one factor tested, i.e. EGF or gastrin (P < 0.01), and 5 of these 9 'hormone-sensitive' tumors were sensitive to both factors. The immunohistochemical labeling index for the EGF receptor was higher than 80% in 15/16 meningiomas, but only in 6/11 gliomas (P < 0.01). These results suggest that EGF and gastrin are important for astrocytic tumor proliferation and significantly (P < 0.01) less important for meningiomas. Thus, astrocytic tumors may be steroid insensitive in term of cell growth, but are certainly not hormone insensitive.

Topics: Astrocytoma; Cell Division; Epidermal Growth Factor; ErbB Receptors; Gastrins; Humans; Immunohistochemistry; Meningioma; Tumor Cells, Cultured

Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is an endothelial cell-specific mitogen that is structurally related to platelet-derived growth factor (PDGF). Vascular endothelial growth factor/vascular permeability factor induces angiogenesis in vivo and may play a critical role in tumor angiogenesis. Using immunohistochemical analysis, the authors demonstrated the presence of VEGF/VPF protein in surgical specimens of glioblastoma multiforme and cultured glioma cells. By means of an enzyme-linked immunosorbent assay (ELISA) of cell supernatants, the authors showed that VEGF/VPF is variably secreted by all nine cultured human malignant glioma cell lines (CH-235MG, D-37MG, D-54MG, D-65MG, U-87MG, U-105MG, U-138MG, U-251MG, U-373MG) and by a single meningioma cell line (CH-157MN). An immunocytochemical survey of these cell lines revealed a cytoplasmic and cell-surface distribution of VEGF/VPF. In the U-105MG glioma cell line, VEGF/VPF secretion was induced with physiological concentrations of epidermal growth factor, PDGF-BB, or basic fibroblast growth factor, but not with PDGF-AA. Moreover, it was observed that activation of convergent growth factor signaling pathways led to increased glioma VEGF secretion. Similar results were obtained using these growth factor combinations in the D-54MG glioma cell line. The data obtained suggest a potential role for VEGF/VPF in tumor hypervascularity and peritumoral edema. These observations may lead to development of new therapeutic strategies.

Topics: Adult; Blotting, Western; Brain Neoplasms; Capillary Permeability; Electrophoresis, Polyacrylamide Gel; Endothelial Growth Factors; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Female; Fibroblast Growth Factor 2; Glioblastoma; Humans; Lymphokines; Meningioma; Middle Aged; Platelet-Derived Growth Factor; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Studies have shown that a majority of meningiomas contain receptors for platelet-derived growth factor and epidermal growth factor and that these growth factors promote the proliferation of meningioma cells in culture. Although the mechanism of action has not been elucidated, intracellular calcium appears to be part of the signal transduction mechanism. Because alterations in intracellular calcium could interrupt this pathway and decrease cellular proliferation, we investigated the effects of calcium channel-blocking agents on the growth of meningioma cells in vitro. Primary meningioma cell cultures were established, and the cells were characterized by light and electron microscopy and by immunohistochemical studies. Then, the cultures were given growth factors and/or various calcium channel antagonists, and growth rates were measured. A dose-response decrease in cell growth was seen when verapamil, nifedipine, or diltiazem (voltage-dependent calcium channel-blocking agents) was added to serum-containing media. Also, these drugs blocked the growth stimulation of epidermal growth factor and platelet-derived growth factor in a similar fashion. Dantrolene, which inhibits the release of sequestered intracellular calcium, was also an effective blocker of the mitogenic stimulation of these growth factors.

Topics: Adult; Aged; Blood Physiological Phenomena; Calcium Channel Blockers; Cell Division; Epidermal Growth Factor; Female; Humans; Immunohistochemistry; Male; Meningeal Neoplasms; Meningioma; Microscopy, Electron; Middle Aged; Platelet-Derived Growth Factor; Tumor Cells, Cultured

The growth of human cerebral meningiomas depends on various growth factors, including epidermal growth factor (EGF), transforming growth factor (TGF)-alpha and TGF-beta, platelet-derived growth factor (PDGF)-BB, insulin-like growth factor (IGF)-I and IGF-II, and acidic and basic fibroblast growth factors. The latter three have been shown to form autocrine loops that are thought to be a major component of uncontrolled growth in meningioma tissue. Suramin is known to prevent binding of a variety of growth factors to their receptors in mammalian tissue, thus abolishing para- and/or autocrine-mediated cell growth. The authors therefore tested the effect of suramin on the proliferation of cultured human meningioma cells. Suramin (10(-5) to 10(-4) M) significantly inhibited the growth of meningioma cells in culture. The maximum effect observed was with the higher dose (10(-4) M), which resulted in a 40% to 70% reduction in cellular proliferation. This effect was observed in all 15 tumor samples studied and was confirmed by [3H]thymidine uptake. In studies using DNA flow cytometry, suramin inhibited meningioma cell proliferation in five tumor samples by arresting cells in the S and G2/M phases of the cell cycle. Growth factor (EGF, IGF-I, and PDGF-BB)-induced cell proliferation was completely abolished in five tumor samples when 10(-4) M suramin was applied to meningioma cells. Western blot analysis of three tumor samples showed that the intracellular PDGF-BB content of meningioma cells was significantly reduced after treating the cells with 10(-4) M suramin. Binding of iodinated growth factors (that is, [125I]EGF, [125I]IGF-I, and [125I]PDGF-BB) to their receptor sites was prevented by suramin in a dose-dependent manner in 10 meningioma membrane fractions. Lowering of the intracellular PDGF content and prevention of extracellular growth factor receptor binding demonstrates that suramin disrupts autocrine loops and paracrine growth stimulation in meningioma tissue. These data provide evidence that growth of cerebral meningiomas in culture is strongly inhibited by suramin at a concentration of 10(-4) M. Suramin acts as a scavenger neutralizing exogenous growth factors; thus it can interrupt autocrine loops and paracrine stimulation of human meningioma cell growth. The evidence favors suramin as a therapeutic option for controlling meningioma proliferation in patients with inoperable and recurrent high-grade meningiomas.

Topics: Blotting, Western; Brain Neoplasms; Cell Cycle; Cell Division; DNA; Dose-Response Relationship, Drug; Epidermal Growth Factor; Flow Cytometry; Growth Substances; Humans; Insulin-Like Growth Factor I; Meningioma; Platelet-Derived Growth Factor; Receptors, Growth Factor; Suramin; Thymidine; Tumor Cells, Cultured

We have previously reported that calcium channel antagonists can block both the growth of meningiomas in culture and the potent growth stimulation of meningioma cells by epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). This study further defines the nature of this growth inhibition. Primary meningioma cultures were established, and cells were characterized. Fibroblast growth factor or insulin-like growth factor-I growth stimulation in the presence of calcium channel antagonists was examined. In addition, the effects of ethylene glycol-bis-(aminoethylether) N,N,N',N"-tetraacetic acid and Bay K 8644, a calcium channel agonist, on the growth factors were analyzed. Growth factor receptor immunohistochemistry was performed on the original tumors and the in vitro meningioma cells. Twelve of 17 (71%) meningiomas in this study were positive for the EGF receptor, and 14 of 17 (82%) were positive for the PDGF receptor. Five of six (83%) of the culture cells were positive for the EGF receptor, and four of five (80%) were positive for the PDGF receptor. Intracellular calcium changes were quantified using the intracellular calcium-chelating, fluorescent dye, Fura-2. The growth stimulation of fibroblast growth factor and insulin-like growth factor-I on meningioma cells in culture was decreased in a dose-dependent manner by calcium channel antagonists. The growth stimulation of fibroblast growth factor and insulin-like growth factor-I was not affected by a reduction of extracellular calcium, whereas the growth stimulation of EGF and PDGF was. Interestingly, intracellular calcium was not increased after exposure to growth factors but was increased after serum stimulation. This increase could be blocked by preincubation with verapamil. Calcium channel antagonists can inhibit proliferation of meningioma cells in culture after stimulation with a number of growth factors. These drugs might disrupt intracellular calcium homeostasis or interfere with key elements of the growth factor signal transduction pathways. These mechanisms as well as the potential clinical relevance of these findings are discussed.

Topics: Adult; Aged; Calcium; Calcium Channel Blockers; Cell Division; Epidermal Growth Factor; Female; Fibroblast Growth Factors; Growth Substances; Homeostasis; Humans; Insulin-Like Growth Factor I; Intracellular Fluid; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Platelet-Derived Growth Factor; Receptors, Growth Factor; Signal Transduction; Tumor Cells, Cultured

In 75 gliomas and 31 meningiomas, mutations at the epidermal growth factor receptor (EGFR) gene locus were restricted to gliomas. The ligands of this receptor, epidermal growth factor and transforming growth factor alpha, lacked quantitative changes at their loci in gliomas and meningiomas. EGFR gene amplification occurred in astrocytomas, oligodendrogliomas, ependymomas and glioblastomas. The frequency of this mutation significantly increased with the malignancy grade and the patient's age. Especially in glioblastomas of individuals aged over 64 years, EGFR gene mutations were observed without chromosome-10-specific allele losses. This finding contradicts the hypothesis that deletion of one entire chromosome 10 regularly precedes EGFR gene amplification in primary glioblastomas of patients aged over 50 years. It was found that most individuals whose gliomas carry an EGFR gene mutation have a poor prognosis, comparable to that of glioblastoma patients even when the tumour is graded as benign.

Topics: Adolescent; Adult; Aged; Brain Neoplasms; Child; Child, Preschool; Chromosome Mapping; Epidermal Growth Factor; ErbB Receptors; Female; Gene Amplification; Glioblastoma; Glioma; Humans; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Mutation; Prognosis; Remission Induction; Survival Rate; Transforming Growth Factor alpha

Meningiomas are common brain tumours which are generally benign, well circumscribed and slow growing. In a minority of patients complete surgical removal of the tumour is not possible, and re-growth of tumour tissue is a major clinical problem. The presence of receptors for progesterone in a large proportion of human meningioma tissues is well established. The occurrence of increased rates of growth of meningiomas during pregnancy suggests the existence of a relationship between high progesterone concentrations and the growth of meningiomas. These observations suggest that the use of antiprogestins may be of value in the treatment of meningiomas. However, experiments with cultured meningioma tissue (cells or explants) have shown only minimal effects of progesterone. It has been shown recently that many meningiomas have receptors for epidermal growth factor. We have investigated the response of cultured human meningioma cells to epidermal growth factor and the modulation of this response by progesterone and the progesterone-receptor blocking agent mifepristone (RU486). The results suggest that the presence of progesterone in the culture medium increases the sensitivity of meningioma cells to specific mitogenic stimuli without having direct mitogenic effects, whereas mifepristone can counteract the stimulating effects of progesterone.

Topics: Adult; Aged; Cell Division; DNA Replication; Epidermal Growth Factor; ErbB Receptors; Female; Humans; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Mifepristone; Neoplasms, Hormone-Dependent; Progesterone; Receptors, Progesterone; Tumor Cells, Cultured

In order to elucidate some of the signal transduction processes in human meningioma cells, the authors studied the effect of epidermal growth factor (EGF) and bromocriptine on inositol phospholipid hydrolysis, using low-passage human meningioma cells in culture. Epidermal growth factor is a well-studied mitogenic factor for meningioma cells, whereas bromocriptine is known to have an inhibitory effect on meningioma cell proliferation. The addition of EGF to meningioma cells caused stimulation of inositol phosphate accumulation in a dose-dependent manner at 60 minutes posttreatment, with the maximum effect (120% to 167% of control) achieved at a concentration of 10 ng/ml. Extraction of separate inositol phosphates accumulation in a dose-dependent manner at 60 minutes posttreatment, with the maximum effect (120% to 167% of control) achieved at a concentration of 10 ng/ml. Extraction of separate inositol phosphates revealed that inositol monophosphate (IP1) and inositol bisphosphate (IP2), but not inositol trisphosphate (IP3), accounted for the increase at 60 minutes. Kinetic analysis of EGF-stimulated inositol phospholipid hydrolysis showed that a sharp and transient increase in IP3 from 5 to 12 minutes post-EGF and a transient but more gradual increase in IP2 from 2 to 12 minutes post-EGF were followed by a gradual and steady increase in IP1, which was significantly greater than control after 5 minutes. On the other hand, long-term studies showed a down-regulation of inositol phosphate accumulation (a 64% decrease vs. control) after 7 days of treatment with EGF (10 ng/ml). Bromocriptine (5 microM) exhibited no significant effect on inositol phosphate accumulation at 60 minutes in four of five meningiomas studied. However, of two meningiomas studied with bromocriptine in combination with EGF, both showed a significant additive increase in inositol phosphate accumulation compared to those treated with EGF alone. The results suggest a close involvement of inositol phospholipid turnover in human meningioma cells in response to mitogenic stimulation by EGF.

Topics: Bromocriptine; Cell Division; Epidermal Growth Factor; Humans; Inositol Phosphates; Meningioma; Signal Transduction; Tumor Cells, Cultured

1. We studied the effects of suramin, a nonspecific growth factor antagonist, on epidermal growth factor (EGF) binding to cell surface receptors in surgically excised human meningiomas, using quantitative receptor autoradiographic methods with radioluminography. 2. High concentrations (10(-4) - 10(-2) M) of suramin inhibited 125I-EGF binding to meningioma sections with IC50's of 3.2 +/- 0.4 x 10(-4) M, whereas lower concentrations (10(-5) - 10(-4) M) of the drug significantly enhanced EGF binding to the tumor. Scatchard analysis of EGF binding profile revealed significant increases in binding affinity following incubation in the presence of 5 x 10(-5) M suramin, without significant alterations in maximal binding capacity. 3. The addition of 10(-3) M suramin to the incubation buffer rapidly dissociated 125I-EGF previously bound to meningioma tissues as a function of time (dissociation half-life, T1/2 = 12.4 min). 4. Preincubation in the presence of 5 x 10(-5) M suramin resulted in significant increases in the subsequent binding of 125I-EGF to meningiomas, compared to findings in the control. 5. Our data indicate that (a) suramin exerts biphasic effects on EGF binding to the tissue sections of meningiomas in vitro, depending on the concentration of the drug; and (b) low concentrations of suramin enhance the affinity of the EGF receptor in the tumor sections, probably by interacting with the EGF receptor molecule rather than with the EGF peptide. 6. The functional role of increased EGF receptor affinity in meningioma sections in the presence of lower concentrations of suramin remains to be determined.

Topics: Aged; Autoradiography; Epidermal Growth Factor; ErbB Receptors; Female; Humans; Iodine Radioisotopes; Kinetics; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Suramin; Time Factors

Epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha) are potent mitogens for normal cells of ectodermal and mesodermal origin. Evidence is accumulating that suggests that EGF, TGF alpha and their common receptor (EGF/TGF alpha-R) influence development and functioning of tissues of the central nervous system (CNS). To further investigate the possible roles of EGF, TGF alpha and their receptor in autocrine/paracrine regulation of tumor growth in the CNS, a series of tumors of the CNS were analyzed for the presence of specific, high affinity EGF/TGF alpha receptors and for the presence of immunoreactive TGF alpha protein. Binding of 125I-EGF to crude membranes from a pool of meningiomas was competed for equally well by low concentrations of unlabeled EGF or TGF alpha, but not by high concentrations of other protein hormones, demonstrating the high degree of specificity of the EGF/TGF alpha receptor. Specific binding of 125I-EGF was dependent upon time and temperature, with maximum specific binding achieved after two hours at 22 degrees C. Scatchard analysis of six tumors of the CNS large enough to permit titration analysis generated linear plots with an average kilodalton of 1.1 +/- 0.1 nanometer (+/- standard error of the mean), suggesting the presence of a single class of EGF/TGF alpha-R with high affinity. EGF also stimulated phosphorylation of a 170 kilodalton protein in membrane fraction of a meningioma, demonstrating that the EGF/TGF alpha-R in this tumor retained EGF-stimulated kinase autophosphorylating activity. Membranes for 17 additional smaller tumors of the CNS were analyzed for specific binding of 125I-EGF by single, high concentration method, and all 17 tumors were found to contain specific binding of 125I-EGF. The average level of 125I-EGF for all 23 tumors of the CNS was 46 +/- 27 femtomoles per milligram protein with a range of 1 femtomoles per milligram for both a pituitary adenoma and meningioma to 638 femtomoles per milligram for a glioblastoma. A series of 13 tumors of the CNS were analyzed for EGF alpha with use of a specific radioimmunoassay. TGF alpha immunoreactive protein was detected in all four malignant tumors of the CNS assayed at an average level of 2.6 +/- 1.1 nanograms per milligram soluble protein, whereas TGF alpha immunoreactive protein was detected in only two of nine benign tumors of the CNS. These results add support to the hypothesis that TGF alpha and its receptor may act by autocrine/paracr

Topics: Central Nervous System Neoplasms; Epidermal Growth Factor; ErbB Receptors; Humans; Meningeal Neoplasms; Meningioma; Radioligand Assay; Receptors, Transforming Growth Factor beta; Transforming Growth Factor alpha

In a previous study, the authors demonstrated that meningioma cells secrete platelet-derived growth factor (PDGF)-like molecules that stimulate their own growth in an autocrine manner. Based on that finding, a study was undertaken to examine the effect of trapidil, a drug known to have an antagonistic action against PDGF, on cell proliferation of human meningiomas in culture. Trapidil showed a dose-dependent inhibition of meningioma cell proliferation in the absence of any exogenous mitogenic stimulation. The maximum effect was observed at a concentration of 100 micrograms/ml, with the decrease in cell growth ranging from 16% to 54% compared to control samples. Trapidil similarly inhibited the basal deoxyribonucleic acid (DNA) synthesis assessed by [3H]-thymidine incorporation in three of seven meningiomas. While the conditioned medium generated from meningioma cells remarkably stimulated the proliferation of meningioma cells (166% to 277% of control), this effect was strikingly inhibited by the addition of trapidil. Trapidil also inhibited conditioned medium-stimulated DNA synthesis, even when there was no effect on basal DNA synthesis. Furthermore, trapidil significantly inhibited the epidermal growth factor (EGF)-stimulated proliferation of meningioma cells. This inhibitory effect on EGF-stimulated cell proliferation was also observed in nontumorous fibroblasts, demonstrating that trapidil is not an antagonist specific to PDGF. The addition of trapidil (30 micrograms/ml) in combination with bromocriptine (1 microM) showed an additive inhibitory effect on the meningioma cell growth compared to trapidil or bromocriptine alone. The overall results suggest that trapidil exhibits an inhibitory effect on meningioma cell proliferation through blocking the mitogenic stimulation induced by autocrine or exogenous growth factors, and may be considered as a possible new approach to the medical treatment of meningiomas.

Topics: Cell Division; Epidermal Growth Factor; Humans; Meningeal Neoplasms; Meningioma; Platelet-Derived Growth Factor; Trapidil

It has been reported previously that most human meningiomas have receptors for somatostatin. Here we report the results of investigations of the effect of somatostatin and the somatostatin analog octreotide on the growth in vitro of human meningioma cells. Neither somatostatin nor its analog showed a direct growth inhibitory action on cultured human meningioma cells. Rather, there was a slight but significant stimulation of growth in the presence of somatostatin. The somatostatin receptors in meningioma tissue were shown to be functional since somatostatin inhibited forskolin-stimulated formation of cAMP by meningioma membranes. In addition, cAMP inhibited the growth of cultured meningioma cells. We conclude that the stimulation by somatostatin of the growth of human meningioma cells in vitro is caused by its inhibitory effect on cAMP formation. These results suggest that therapeutic trials of patients with (recurrent) inoperable meningiomas with somatostatin analogs have to be carried out with great caution.

Topics: Adenylyl Cyclase Inhibitors; Bucladesine; Cell Division; Colforsin; Cyclic AMP; DNA Replication; Dose-Response Relationship, Drug; Epidermal Growth Factor; Humans; Imidazoles; Insulin; Kinetics; Meningeal Neoplasms; Meningioma; Octreotide; Receptors, Neurotransmitter; Receptors, Somatostatin; Somatostatin; Thymidine; Tumor Cells, Cultured

The aim of this study was to examine meningeal tissue under normal, reactive, and neoplastic conditions for expression of epidermal growth factor receptor (EGFR) using an improved histochemical method, namely biotinylated epidermal growth factor. EGFR was found in all the examined meningiomas (12 benign and three anaplastic) and in neonatal rat meninges, whereas normal and injured adult human and rat meninges did not exhibit detectable EGFR. These observations indicate that EGFR is involved in the development of meningeal tissue. Further, EGFR is abnormally expressed in meningeal tumours, indicating a role of EGFR in the neoplastic process of these tumours. The regular expression of EGFR in human meningiomas suggests EGFR as a tumour marker for this tumour type.

Topics: Adult; Aged; Epidermal Growth Factor; ErbB Receptors; Female; Humans; Male; Meningeal Neoplasms; Meninges; Meningioma; Middle Aged

The expression of epidermal growth factor receptor (EGF-R) was examined in 27 primary human brain tumors (7 glioblastomas, 10 astrocytomas, 5 oligodendrogliomas, 1 schwannoma, 1 ganglioneuroma, 1 medulloblastoma, 1 ependymoma, 1 histiocytic lymphoma), in 6 brain metastases from lung carcinomas and in 20 meningiomas. Peritumoral tissues histologically normal excised surgically along with a large tumor were used as control. All plasma membranes from brain tissues tested showed specific EGF binding. The EGF receptor is expressed at low levels in the control human brain and at very high levels in 60% of the total intracranial tumors studied. When the various histological types of tumors were analyzed, the higher percentage of positive tumors was found with the meningiomas (85%) and the glioblastomas (71%), while the lower percentage of positivity was found with the oligodendrogliomas (40%) and the astrocytomas (30%). A good correlation between binding and total amount of EGF-R protein detected by Western Blot was also observed.

Topics: Adult; Aged; Astrocytoma; Blotting, Western; Brain Neoplasms; Cell Membrane; Epidermal Growth Factor; ErbB Receptors; Female; Glioma; Humans; Iodine Radioisotopes; Male; Meningioma; Middle Aged; Neurilemmoma; Oligodendroglioma; Radioligand Assay

In this paper the results of investigations on the effect of interferon-alpha (IFN-alpha) on the growth of meningioma cells in culture is reported. A consecutive series of six meningiomas and one meningioma/neurofibroma derived from a patient with neurofibromatosis type 2 was investigated and it was found that the growth of all seven tumours in response to mitotic stimuli (fetal bovine serum or epidermal growth factor) is strongly inhibited by IFN-alpha. Maximal response varied between 100% and 70% inhibition of the incorporation of tritiated thymidine. In some cases an inhibitory response was obtained already at very low doses (less than or equal to 10 U of IFN-alpha per ml). These results indicate that further clinical investigation of the application of IFN-alpha to the treatment of meningioma is warranted.

Topics: Adult; Aged; Blood Physiological Phenomena; Cell Division; Chromosome Deletion; Chromosomes, Human, Pair 22; Epidermal Growth Factor; Female; Humans; Interferon Type I; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Neuroma, Acoustic; Recombinant Proteins; Tumor Cells, Cultured

The presence of receptors for progesterone in a large proportion of human meningioma tissues is well established. The occurrence of increased rates of growth of meningiomas in situ during pregnancy suggests the existence of a relationship between high progesterone levels and the growth of meningiomas. However, experiments with cultured meningioma tissue (cells or explants) have shown only minimal effects of progesterone. It has been shown recently that many meningiomas have receptors for epidermal growth factor. In this paper we have investigated the response of cultured human meningioma cells to epidermal growth factor and other growth factors and the modulation of this response by progesterone and the progesterone-receptor blocking agent mifepristone (RU 38486). The results suggest that the presence of progesterone in the culture medium increases the sensitivity of meningioma cells to mitogenic stimuli, whereas mifepristone can counteract the stimulating effects of progesterone.

Topics: Adult; Aged; Epidermal Growth Factor; ErbB Receptors; Female; Humans; Insulin; Insulin-Like Growth Factor I; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Mifepristone; Progesterone; Receptors, Progesterone; Tumor Cells, Cultured

Cell culture and biochemical techniques have been employed to examine the effects of steroids, bromocriptine, and epidermal growth factor (EGF) on the growth and proliferative potential of meningiomas. In cell culture, the growth of meningiomas was not altered by progestogens, antiprogestogens, or 17beta-estradiol. The progestogen, norethisterone, had no effect on the uptake by meningiomas cell cultures of 3H-thymidine. Furthermore, cytosolic deoxyribonucleic acid (DNA) polymerase activity of meningiomas did not correlate with the progesterone receptor status of the same tumors. In contrast, the androgen antagonists, cyproterone acetate and 11-alpha-hydroxyprogesterone, and the dopamine agonist, bromocriptine, all inhibited the in vitro growth of meningioma cells. The growth of meningioma cell cultures was stimulated by EGF, and there was a positive correlation between the EGF content and DNA polymerase activity in meningioma cytosols. These results demonstrate that female sex steroids do not influence growth of meningiomas in vitro, whereas antiandrogens and bromocriptine have an antiproliferative effect. Consequently, bromocriptine and antiandrogens may have a role in the medical treatment of meningiomas. In addition, these results suggest that EGF may be involved in the genesis and/or progression of meningiomas.

Topics: Bromocriptine; Cell Division; DNA-Directed DNA Polymerase; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Estradiol; Humans; Meningeal Neoplasms; Meningioma; Neoplasms, Hormone-Dependent; Progestins; Radioimmunoassay; Steroids; Tumor Cells, Cultured

Receptors for insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF) were localized and characterized in eight samples of human meningioma (four fibrous, two meningothelial, and two angioblastic types), using quantitative autoradiographic techniques. Effects of both growth factors on deoxyribonucleic acid (DNA) synthesis in the cultured meningioma cells were examined. High numbers of specific binding sites for both IGF-I and EGF were homogeneously present in tissue sections derived from fibrous and meningothelial types of meningiomas, whereas binding sites for these growth factors were not detectable in adjacent leptomeninges. While relatively large numbers of IGF-I binding sites were located in the wall of the intratumoral vasculature, the number of binding sites in the stromal component was lower in angioblastic-type meningiomas, including a low number of EGF binding sites detected only in the stromal portion. Scatchard analysis revealed the presence of a single class of high-affinity binding sites for both IGF-I and EGF in the meningiomas examined (dissociation constant (Kd) = 0.6 to 2.9 nM, and the maximum number of binding sites (Bmax) = 16 to 80 fmol/mg for IGF-I; and Kd = 0.6 to 4.0 nM, Bmax = 3 to 39 fmol/mg for EGF). Both growth factors increased the synthesis of DNA, in a dose-dependent manner, as measured by 3H-thymidine incorporation. The combination of IGF-I and EGF synergistically stimulated the synthesis of DNA, and the effects seen with 10% fetal bovine serum could be reproduced at a concentration of 10(-10) M. These observations can be interpreted to mean that both IGF-I and EGF may be involved in the growth modulation of meningiomas, possibly through paracrine or autocrine mechanisms.

Topics: Adult; Aged; Autoradiography; Binding, Competitive; DNA Replication; Epidermal Growth Factor; ErbB Receptors; Female; Humans; Insulin-Like Growth Factor I; Iodine Radioisotopes; Kinetics; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Receptors, Cell Surface; Receptors, Somatomedin; Recombinant Proteins; Somatomedins

The expression of IGF-I and EGF receptors in the primary non-glial brain tumors (8 meningiomas, 2 neurinomas, 1 hemangioblastoma, 2 primary malignant lymphomas) was analyzed by using in vitro quantitative autoradiographic techniques. Specific binding sites for IGF-I were co-localized with those for EGF in the meningiomas and the hemangioblastoma examined. However, in the neurinomas and the malignant lymphomas, only IGF-I binding sites were present. In addition, IGF-I and EGF synergistically increased 3H-thymidine incorporation into DNA synthesis by the primary cultured meningioma cells, in dose-dependent manner. These observations can be interpreted to mean that both IGF-I and EGF may exist as autocrine or paracrine peptides involved in the growth not only of glioma but also of non-glial brain tumors.

Topics: Adult; Aged; Binding Sites; Brain Neoplasms; DNA, Neoplasm; Epidermal Growth Factor; ErbB Receptors; Female; Humans; Male; Meningioma; Middle Aged; Receptors, Cell Surface; Receptors, Somatomedin; Somatomedins; Tumor Cells, Cultured

The aim of the present work was to improve quantitative assessment of angiogenesis by chick chorioallantoic membrane (CAM) assay based on measurement of DNA synthesis. Following incubation of [3H]thymidine (3H-T) with CAM in vivo, incorporation of 3H-T to DNA fraction was expressed as percent of total 3H-T present in the initial homogenate of CAM, regardless of CAM weight and full recovery of applied radioactivity. The assay required simple, partial isolation of DNA to remove traces of free or unspecifically bound 3H-T. These modifications gave a reproducible assay with adequate precision (10-20%). DNA content of CAM did not change between 10-15 days of embryo development and growth of CAM was completed on day 11. 10 to 12-day old CAMs were used for evaluation of the assay. Using a qualitative approach (visual scoring), tissues of several tumors were implanted on CAM. Extracts of tumors that produced the highest score stimulated DNA synthesis in CAM. A similar effect was induced by EGF while cytostatics inhibited DNA synthesis in CAM. Since stimulation of angiogenesis is not a cell type-specific phenomenon, the assay in the present modification should aid the studies on angiogenic factors. With the help of this assay the angiogenic activity of adenocarcinoma of human endometrium was described.

Topics: Allantois; Animals; Chick Embryo; Chorion; DNA; Epidermal Growth Factor; Extraembryonic Membranes; Female; Meningioma; Neovascularization, Pathologic; Thymidine; Tissue Extracts; Uterine Neoplasms

A variety of tumors with different histologic types are included in a group of brain tumors. Although each histologic type of tumor has its own range of malignancy, the prognosis seems to be affected by several clinical, histologic and cell-biological factors. For example, relative survival rate of patients with glioblastoma is lower if the patient is older than 50 or 60 years. The leptomeningeal dissemination of glioma cells is a sign of poor prognosis. The presence of necrotic foci in the astrocytic tumors suggests shorter astrocytic tumors suggests shorter survival. Using a monoclonal antibody to bromodeoxyuridine (BrdU), the growth activity of the tumor can be estimated by BrdU labeling index (BrdU-LI, %). Higher BrdU-LI is correlated with more malignant histologic features in astrocytic tumors. In meningiomas, higher BrdU-LI is correlated with a more frequent or rapid recurrence of the tumor. The significance of growth factor receptors and oncogene of growth factor receptors and oncogene products as a cell-biologic marker of malignancy was investigated with an immunohistochemical method. Transferrin receptor was demonstrated in all tumors, and epidermal growth factor in about 40% of astrocytic tumors. The immunoreaction to c-myc oncogene product was detected in most astrocytic tumors; with higher intensity in anaplastic astrocytomas and glioblastomas than in low-grade astrocytomas. The role of these markers in the prognosis of brain tumors is, however, still unclear. Total or subtotal resection of glioblastoma results in longer resection of glioblastoma results in longer survival. Both postoperative radiotherapy and chemotherapy are effective. However, maintenance of chemotherapy longer than longer than 2 years does not significantly improve the prognosis.

Topics: Age Factors; Antibodies, Monoclonal; Astrocytoma; Biomarkers, Tumor; Brain Neoplasms; Bromodeoxyuridine; Cell Cycle; Epidermal Growth Factor; ErbB Receptors; Glioblastoma; Humans; Meningioma; Oligodendroglioma; Oncogenes; Prognosis

Urine specimens obtained from 19 patients with primary brain tumors were examined for the activity of transforming growth factors (TGF's). Urine was assayed for TGF's by soft agar colony formation and iodine-125 (125I)-epidermal growth factor (EGF)-binding competition. Two nontransformed cell lines, clonal NRK49F and BALB/3T3 A31-1-1 cells, were used as indicator cells for the soft agar colony assay, while EGF receptor-rich A431 cells were used for 125I-EGF-binding competition assay. Urine samples were dialyzed against acetic acid, then lyophilized, prepared with gel-permeation chromatography, and assayed. All 19 patients and a control group of healthy individuals showed high levels of alpha-type TGF's with low molecular weight (4 to 8 kD) in all urine samples. In addition, alpha-type TGF's of high molecular weight (20 to 50 kD) were detected at high levels in urine from all 10 patients with high-grade astrocytoma; at intermediate levels in urine from one of two patients with low-grade astrocytoma and from two of four patients with meningioma; and at low levels in urine from one of two patients with low-grade astrocytoma, from two of four patients with meningioma, from one patient with oligodendroglioma, from two patients with neurinoma, and from all healthy control individuals. The high level of alpha-type TGF's with high molecular weight detected in urine from patients with high-grade astrocytoma could be useful as a tumor marker.

Topics: Adult; Aged; Brain Neoplasms; Epidermal Growth Factor; Female; Glioma; Humans; Male; Meningioma; Middle Aged; Peptides; Transforming Growth Factors

Epidermal growth factor receptor (EGF-R) were assayed by 125I-EGF binding in 28 surgical samples of human meningiomas. High affinity EGF-R were found in 26/28 tumors (92 p. 100) at concentrations ranging from 20 to 410 femtomoles per mg of membrane protein (fmol/mg prot. mb.). In 18/26 cases (64 p. 100), the EGF-R concentration was between 95 and 230 fmol/mg prot. mb. No relationship was found between the EGF-R level and the site or histopathology of the tumor. The only noticeable observations were the low levels of EGF-R in the 3 anaplasic meningiomas as compared to the whole population and the undetectable level of EGF-R in the angiomatous tumors. In addition, no correlation was found between EGF-R levels and the hormonal status of the patients, nor between EGF-R levels and the intratumoral concentration of progesterone receptors assayed simultaneously. The biological relevance of EGF-R in meningioma is discussed in this context.

Topics: Adult; Aged; Epidermal Growth Factor; ErbB Receptors; Female; Humans; Iodine Radioisotopes; Male; Meningioma; Menopause; Middle Aged; Receptors, Estrogen; Receptors, Progesterone; Receptors, Steroid

Using the adhesive tumor cell culture system, we studied the effect of epidermal growth factor (EGF) on 16 primary and 7 metastatic fresh human tumors of the nervous system cultured in serum-free and serum-supplemented media at low cell density. In serum-free conditions, EGF significantly enhanced the growth of glial tumor cells. This positive effect was less pronounced for metastases to the brain. No significant enhancement was observed for the other tumor types (primitive neuroectodermal tumors and various tumors of neuroepithelial/mesenchymal origin). The addition of serum obscured this effect of EGF, even at the lowest cell densities. In 7 tumors, the simultaneous addition of platelet-derived growth factor did not enhance the EGF response. Subtypes of brain tumors respond to EGF in vitro under serum-free conditions.

Topics: Brain Neoplasms; Cell Division; Child; Child, Preschool; Epidermal Growth Factor; Glioma; Humans; Meningeal Neoplasms; Meningioma; Tumor Cells, Cultured

The binding capacity for epidermal growth factor (EGF) was determined in 34 intracranial neoplasms (14 glioblastoma, seven low-grade gliomas, six meningiomas, and seven others) and four specimens of normal brain by using [I125]EGF. EGF binding and binding affinity of the sites in the tumour and brain samples were compared to placenta and rat liver. All specimens of normal brain were negative. Ten of 14 glioblastoma specimens contained EGF binding (level range 10-39,660 fmol/mg protein), however, ligand binding affinity was high in only three tumours. Only one of nine low-grade gliomas contained EGF binding activity. Five of six meningiomas contained EGF binding sites (level range 49-776 fmol/mg protein) and binding affinity was high in two. When present EGF binding activity was found in all cellular fractions except the cytosol. There were no clinical or histopathological features within major tumour groups that were predictive of either high or specific EGF binding activity. These preliminary studies have confirmed that EGF receptor-like activity is present in the particulate fractions of intracranial neoplasms of both mesenchymal and neuroctodermal origin. In a large proportion of these tumours the EGF binding affinity is low, suggesting either a less specific or truncated EGF binding site.

Topics: Brain Neoplasms; Epidermal Growth Factor; ErbB Receptors; Female; Glioma; Humans; Male; Meningeal Neoplasms; Meningioma

We have characterized the epidermal growth factor (EGF) receptor in human meningioma (biopsy) microsomes, cellularly derived microsomes, and intact meningioma cells in culture. Scatchard analysis of competition studies reveals both high and low affinity EGF binding sites in the meningiomas tested [dissociation constant (Kd) = 0.9 nM, maximum number of binding sites (Bmax) = 280 fmol/mg protein; Kd = 5.0 nM, Bmax = 660 fmol/mg protein, respectively]. The binding of 125I-EGF is specific since it is abolished by excess unlabeled EGF but not by excess unlabeled platelet-derived growth factor or insulin. Meningioma cultures preincubated with platelet-derived growth factor (10 ng/ml) at 37 degrees C shifted the 125I-EGF competition curve to the right but did not affect receptor number (100,000 sites/cell) when compared to cultures preincubated at 4 degrees C. Cross-linking studies performed with ethyleneglycol bis(succinimidyl succinate) followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography reveal a major band of specifically bound EGF (Mr approximately 150,000), although the normal (Mr approximately 170,000) and another putative proteolytic form (Mr approximately 125,000) can also be seen. These results indicate that human meningiomas contain a mixed population of EGF binding sites and exhibit properties of previously described EGF receptors.

Topics: Epidermal Growth Factor; ErbB Receptors; Humans; Meningioma; Microsomes; Molecular Weight; Platelet-Derived Growth Factor

Equilibrium binding assays of EGF were performed on confluent cultures of 12 human meningiomas at early passage. In all meningiomas complete binding curves were obtained and the resulting ED 50 values ranged between 0.5 and 6.3 nM. In four cases (ED 50 values ranging from 1.5 nM to 3.0 nM) where saturation analysis was performed, the sites were saturable at similar levels (7 nM). In five cases additional experiments were undertaken to evaluate the biological response of cultured cells to EGF as assessed by 3H-thymidine incorporation. In all cases EGF was a potent stimulus and increased 3H-thymidine incorporation by 2.5 to 6-fold. Functionally intact EGF receptors appear to be a regular feature of meningiomas in cell culture and appear not to be related to histological classification.

Topics: Cells, Cultured; Epidermal Growth Factor; ErbB Receptors; Humans; Meningioma; Thymidine