transforming-growth-factor-beta and Meningioma

Meningiomas account for 36% of primary brain tumors. The pathogenesis of these tumors is not completely established, hindering development of effective chemotherapy. Numerous studies have identified alterations in several growth factors and receptor kinases that regulate meningioma growth. These may be targets for new therapies. One of these, sometimes overlooked, is the transforming growth factor beta (TGF-β) family of proteins. Its receptors and signaling pathways play a critical role in development or progression of many forms of neoplasia.. Evidence suggesting a potential role for TGF-β, bone morphogenetic protein, and their mediators is reviewed.. TGF-β inhibition of growth in normal leptomeninges may be lost in neoplasia. Moreover, loss of TGF-β and bone morphogenetic protein signaling components and TGF-β type III receptor likely contribute to the development and/or progression of higher grade meningiomas.. Accumulating evidence suggests that derangement of TGF-β family signaling contributes to development and progression of meningiomas. The TGF-β family may represent new targets for chemotherapy and could include inhibitors of kinases activated by TGF-β.

Topics: Animals; Antineoplastic Agents; Evidence-Based Medicine; Gene Expression Regulation, Neoplastic; Humans; Meningeal Neoplasms; Meningioma; Molecular Targeted Therapy; Neoplasm Proteins; Transforming Growth Factor beta; Treatment Outcome

Tumor-associated macrophages (TAMs) have been shown to be an essential component of the tumor microenvironment and facilitate the proliferation and invasion of a variety of malignancies. However, the contribution of TAMs to meningioma progression has not been characterized in detail. In this study, we aimed to discover a novel regulatory pathway by which exosome-mediated M2-polarized macrophages participate in meningioma tumorigenesis and progression.

Topics: Carcinogenesis; Cell Line, Tumor; Exosomes; Humans; Macrophages; Meningeal Neoplasms; Meningioma; Signal Transduction; Transforming Growth Factor beta; Tumor Microenvironment

E-Cadherin has been suggested to be involved in meningioma progression but is also known as a key player of epithelial to mesenchymal transition (EMT). We wondered whether the adherens junction protein E-Cadherin, the tight junction protein Zo-1, and transcription factors suppressing E-Cadherin expression (Slug, Snail, Twist, Zeb-1) are differentially expressed between histopathological subtypes of meningioma, and if the expression of these factors is related to biological features of meningiomas. Analyzing 85 meningiomas of various histopathological subtypes and grades of malignancy by immunohistochemistry and 50 of them in addition by real-Time-PCR, we observed significantly reduced expression of Zeb-1, Twist and Slug, together with slightly increased expression levels for E-Cadherin and Zo- 1 in fibroblastic WHO-grade I tumors compared to meningothelial WHO grade I tumors, contradicting the hypothesis of EMT in the fibroblastic meningiomas characterized by mesenchymal appearance. However, comparing aggressive WHO grade II or III meningiomas with WHO-grade I tumors, we observed altered expression levels (loss of E-Cadherin and Zo-1, increased expression of Zeb-1 and Slug) indicating molecular features of EMT in aggressive meningiomas. This was supported by reduced E-Cadherin and increased Slug levels in recurrent compared to non-recurrent meningiomas. The expression levels of E-cadherin and Zo-1 were positively correlated with expression of NF2 mRNA. In primary meningioma cultures and IOMM-Lee meningioma cells, EMT induction by TGF-ß resulted in altered morphology and increased expression of EMT associated transcription factors. Meningioma cells with allelic losses of NF2 showed generally higher levels of various EMT relevant proteins, but were unresponsive to TGF-ß treatment. Our data indicate that aggressive meningiomas of WHO grade II/III are characterized by molecular alterations indicating partial EMT. This might contribute to the aggressive biology of these tumors.

Topics: Adult; Aged; Aged, 80 and over; Antigens, CD; Cadherins; Cells, Cultured; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Genes, Neurofibromatosis 2; Humans; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Neoplasm Grading; RNA, Messenger; Transcription Factors; Transforming Growth Factor beta; Young Adult; Zonula Occludens-1 Protein

In meningiomas, neovascularization through angiogenesis is essential for tumor expansion. As the vascular endothelial growth factor-A (VEGF-A) plays an outstanding role in this process, we have studied basal VEGF-A release and some aspects of its regulation in 46 meningiomas and in Ben-Men-1 cells in vitro. Among two putative VEGF-A stimulating growth factors tested, TGF-1β was more potent than TGF-α in enhancing VEGF-A secretion. Hypoxia-mimicking conditions induced by CoCl2 treatment also strongly increased VEGF-A secretion. The synthetic glucocorticoid dexamethasone (DEX) potently suppressed both basal and growth factor or CoCl2-induced VEGF-A release. All these effects were also seen in the Ben-Men-1 cell line in which studies on the role of HIF-1 in the regulation of VEGF-A showed that not only hypoxia but also the growth factors induced HIF-1α and DEX suppressed HIF-1α induction. Therefore, in Ben-Men-1 cells with HIF-1α knock-down the effects of hypoxia, growth factors and DEX on VEGF-A production were strongly impaired. This clearly indicates that HIF-1 not only regulates hypoxia-induced VEGF-A production but also mediates at least in part the effects of growth factors and DEX on VEGF-A synthesis and release. Our findings show the complexity of VEGF-A regulation in meningiomas and point to new options for the pharmacological treatment of these tumors.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Cell Hypoxia; Cell Line, Tumor; Cells, Cultured; Cobalt; Dexamethasone; Dose-Response Relationship, Drug; Female; Gene Knockdown Techniques; Humans; Hypoxia-Inducible Factor 1; Male; Meningioma; Middle Aged; Transforming Growth Factor alpha; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

The roles of bone morphogenetic proteins (BMPs) and their receptors (BMPRs) in meningioma biology are not known. In this study, frozen tissues from 26 World Health Organization Grades I to III meningiomas were analyzed by Western blot for BMP-2/4, BMPR IA, and BMPR II, and activation of downstream p-Smad1, p38 mitogen-activated protein kinase (MAPK), and p44/42 MAPK signaling molecules. Sections from 20 normal leptomeninges, 2 arachnoid cysts, and 51 meningiomas were analyzed for BMP-4 and p44/42 MAPK by immunohistochemistry. Primary meningioma cultures from 11 meningiomas were treated with BMP-4 and evaluated for cell proliferation and signaling pathway activation. Conditioned media from 7 cultures were analyzed for BMP-4 by ELISA. Bone morphogenetic protein 4 was variably detected in adult leptomeninges but was detected in 89% or 84% of Grade I meningiomas and in 60% of Grade II meningiomas by Western blot and immunohistochemistry, respectively. Bone morphogenetic protein receptors IA and II were detected in leptomeninges and in all meningiomas studied, and activated Smad1 was detected in all meningiomas studied. Bone morphogenetic protein 4 stimulated meningioma cell proliferation and phosphorylation/activation of Smad1 but not p38 MAPK or p44/42 MAPK in vitro, and it was detected in conditioned media from 4 of 7 cultures. These findings suggest that BMP-4 and BMPRs may play autocrine/paracrine roles and interact with other transforming growth factor-beta superfamily members in regulating meningioma growth and differentiation.

Topics: Adult; Aged; Aged, 80 and over; Bone Morphogenetic Protein 4; Bone Morphogenetic Protein Receptors, Type II; Cell Differentiation; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Tumor Cells, Cultured

The role of transforming growth factor-beta (TGF-beta) in regulation of meningioma growth and intracellular events transducing its signals are not established. In this study, we evaluated the effects of TGF-beta1 on basal meningioma cell proliferation in 10 primary human meningioma cell cultures and whether TGF-beta's signals are transduced by the Smad 2/3, MAPK/Erk kinase-1 (MEK-1)-mitogen-activated protein kinase (MAPK), Akt-p70(S6K) or p38-JUNK pathways in 5. We also tested whether neutralizing antibodies to TGF-beta alter CSF stimulation of meningioma cell proliferation. On average, TGF-beta reduced meningioma cell [3H]-thymidine incorporation to 58% of controls at 24% and to 61% of controls at 36 h. TGF-beta inhibition of meningioma cell proliferation was associated with a suggestion increased phosphorylation of Smad 2/3 in 2 cases and high basal phosphorylation in 3 but no change in activation of the MEK-1-MAPK, Akt-p70(S6K) or p38-JUNK pathways. As shown previously, CSF stimulated meningioma cell proliferation in the 3 cultures tested. Neutralizing antibody against TGF-beta augmented this stimulation in 2 of 3 cultures. These findings suggest that TGF-beta exerts a largely inhibitory effect on basal meningioma proliferation, perhaps in part through Smad 2/3.

Topics: Aged; Antibodies; Cell Division; Cerebrospinal Fluid; DNA-Binding Proteins; Female; Humans; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Phosphorylation; Signal Transduction; Smad2 Protein; Smad3 Protein; Thymidine; Trans-Activators; Transforming Growth Factor beta; Transforming Growth Factor beta1; 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

The expression of cytokine transcripts has been investigated in a series of cultured human meningiomas using reverse transcriptase linked polymerase chain reaction (RT-PCR), which allowed simultaneous analysis of a range of cytokines. The main histological subgroups of meningioma were investigated; these included transitional, fibroblastic, and syncytial as well as atypical meningiomas. Meningiomas from each of the different histological subgroups were subjected to a standard tissue culture regime. Total RNA was extracted from representative cultures and reverse-transcribed to yield cDNA. PCR was performed using oligonucleotide primers designed to detect interleukin (IL)-1 alpha/beta to IL-8, transforming growth factor (TGF)beta 1-3, tumour necrosis factor (TNF)alpha/beta, and interferon (IFN)gamma. Transcripts for IL-3, IL-6, IL-8, and TGF beta 3 were detected in all cultures. Transcripts for the three isomers of TGF beta were expressed in the transitional and fibroblastic meningioma cells. TGF beta 2 and TGF beta 3 transcripts were expressed in the syncytial and TGF beta 1 and TGF beta 3 in the atypical meningioma cells. IL-1 beta transcripts were expressed in fibroblastic and atypical cultures and TNF beta transcripts were expressed in syncytial and transitional cultures only. Transcripts for IL-1 alpha, IL-2, IL-4, IL-5, IL-7, TNF alpha, or IFN gamma were not detected in any of the meningioma cultures. This investigation using cells cultured from a small number of tumours from each of the classic histological subtypes suggests that there is a distinct pattern of cytokine mRNA expression linked with histological classification.

Topics: Cytokines; Humans; Interleukins; Meningioma; Polymerase Chain Reaction; RNA, Messenger; RNA, Neoplasm; Transcription, Genetic; Transforming Growth Factor beta; Tumor Cells, Cultured

To examine which growth factors correlate with neovascularization in human brain tumors, the mRNA levels of transforming growth factor alpha, transforming growth factor beta, basic fibroblast growth factor, and vascular endothelial growth factor (VEGF) genes were determined by a Northern blot analysis in surgically obtained human gliomas and meningiomas. The vascular development was determined by counting the number of microvessels which were immunostained with von Willebrand factor. We normalized the growth factor mRNA levels versus the glyceraldehyde phosphate dehydrogenase mRNA level. In the 17 gliomas and 16 meningiomas examined, the mRNA of transforming growth factors alpha and beta, basic fibroblast growth factor, and VEGF were expressed at various levels. Among those 4 growth factors, the mRNA levels of VEGF, but not those of transforming growth factors alpha and beta and basic fibroblast growth factor, correlated significantly with vascularity in both gliomas (correlation coefficient r = 0.499; P < 0.05) and meningiomas (correlation coefficient r = 0.779; P < 0.001). These findings thus suggest that VEGF may be a positive factor in tumor angiogenesis in both human gliomas and meningiomas.

Topics: Brain Neoplasms; Endothelial Growth Factors; Fibroblast Growth Factor 2; Glioma; Humans; Lymphokines; Meningioma; Neovascularization, Pathologic; RNA, Messenger; Transforming Growth Factor alpha; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

The transforming growth factor-beta (TGF beta) family in mammals includes three closely related peptides that influence proliferation and numerous physiologic processes in most mesenchymal cells. In this study, Northern blots, immunohistochemistry, TGF beta radioreceptor assays, TGF beta receptor affinity labeling and [3H] thymidine incorporation were used to evaluate whether primary cell cultures of human meningiomas synthesize the three TGF beta isoforms, bear TGF beta receptors, and respond to TGF beta. Transcripts for TGF beta 1 and 2 were detected in the three cases analyzed. Transforming growth factor-beta 1 immunoreactivity was detected in three of six cases, and TGF beta 2 and 3 immunoreactivity were detected in each case analyzed. Media conditioned by cells cultured from six meningiomas also contained latent TGF beta-like activity. Transforming growth factor-beta receptor cross-linking studies identified TGF beta binding sites corresponding to the type 1, type 2, and type 3 receptors on meningioma cells. Treatment with active TGF beta 1 produced a statistically significant reduction in [3H] thymidine incorporation after stimulation with 10% fetal calf serum and epidermal growth factor in all six cases studied.

Topics: Blotting, Northern; Cross-Linking Reagents; Humans; Immunohistochemistry; Meningeal Neoplasms; Meningioma; Radioligand Assay; Receptors, Cell Surface; Thymidine; Transforming Growth Factor beta; Tumor Cells, Cultured

Polypeptides, characterized by their ability to confer a transformed phenotype on an untransformed indicator cell have been isolated directly from surgical specimens of intracranial meningioma by using an acid/ethanol extraction procedure. Transforming activity in meningeal cells was based on the ability to induce NRK 49F rat kidney fibroblasts to form colonies in soft agar. This polypeptide was separated by gel filtration into two fragments of 15 and 40 kilodalton (kDa) molecular weight. Among other cases of brain neoplasms, one case of glioblastoma multiforme had moderate TGF-beta activity, but medulloblastoma and neurinoma had no activity. Purified TGF-beta also stimulated DNA synthesis in primary cultured meningioma cells, but no effect was seen in U 251MG human glioma cells. While the physiological function of TGF-beta is still ill-defined and the molecular character of its receptor has not been analyzed, intracranial meningiomas are noted to have TGF-beta-like activity. TGF-beta also induces the DNA synthesis of cultured meningioma cells. From these results, TGF-beta would be considered one of the growth promoting factors in meningioma.

Topics: Animals; Cell Division; Cell Line; Chromatography, Gel; DNA Replication; Female; Humans; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Rats; Transforming Growth Factor beta; Tumor Cells, Cultured