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Biomedical subjects

M Platten

Publications and source records attributed to M Platten.

At least 19 recordsLinked to original sources
PubMed2002

Primary cerebral non-Langerhans cell histiocytosis: MRI and differential diagnosis.

We report a young woman with primary cerebral non-Langerhans cell histiocytosis of the juvenile xanthogranuloma family. The clinical course was complicated by extensive infiltration of cranial nerves and meninges and epi- and intramedullary spinal dissemination. Whereas the cutaneous form of juvenile xanthogranuloma is usually benign and self-limited, central nervous system involvement is associated with high morbidity and mortality and might therefore be considered a separate clinical entity.

Adult↗
PubMed2001

N-[3,4-dimethoxycinnamoyl]-anthranilic acid (tranilast) inhibits transforming growth factor-beta relesase and reduces migration and invasiveness of human malignant glioma cells.

Extensive infiltration of normal brain tissue and suppression of anti-tumor immune surveillance mediated by molecules such as transforming growth factor-beta (TGF-beta) are key biological features that contribute to the malignant phenotype of human gliomas. Tranilast (N-[3,4-dimethoxycinnamoyl]-anthranilic acid) is an anti-allergic compound used clinically to control atopic and fibrotic disorders. These effects are attributed to the suppression of TGF-beta1 synthesis and interference with growth factor-mediated proliferation and migration of fibroblasts and vascular smooth muscle cells. Here, we show that tranilast inhibits DNA synthesis and proliferation of human malignant glioma cells and promotes p21 accumulation in the absence of cytotoxicity. Further, tranilast reduces the release of TGF-beta1 and TGF-beta2 by glioma cells and inhibits migration, chemotactic responses and invasiveness. These effects are not associated with a reduction of alpha(v)beta(3) integrin expression at the cell surface but appear to involve inhibition of matrix metalloproteinase-2 expression and activity. Neither the tranilast-mediated inhibition of proliferation nor the inhibition of migration was counteracted by supplementation with exogenous TGF-beta. Finally, tranilast administered orally inhibited the growth of experimental 9L rat gliomas and reduced expression of TGF-beta2 in vivo. We conclude that tranilast might be a useful therapeutic agent for the treatment of human malignant glioma because of a TGF-beta-independent abrogation of the malignant phenotype of proliferation, migration and invasiveness and because of the antagonism of TGF-beta-associated immunosuppression.

3T3 Cells↗
PubMed2001

Processing of immunosuppressive pro-TGF-beta 1,2 by human glioblastoma cells involves cytoplasmic and secreted furin-like proteases.

TGF-beta is a putative mediator of immunosuppression associated with malignant glioma and other types of cancer. Subtilisin-like proprotein convertases such as furin are thought to mediate TGF-beta processing. Here we report that human malignant glioma cell lines express furin mRNA and protein, exhibit furin-like protease (FLP) activity, and release active furin into the cell culture supernatant. FLP activity is not modulated by exogenous TGF-beta or neutralizing TGF-beta Abs. Exposure of LN-18 and T98G glioma cell lines to the furin inhibitor, decanoyl-Arg-Val-Lys-Arg-chloromethylketone, inhibits processing of the TGF-beta1 and TGF-beta2 precursor molecules and, consequently, the release of mature bioactive TGF-beta molecules. Ectopic expression of PDX, a synthetic antitrypsin analog with antifurin activity, in the glioma cells inhibits FLP activity, TGF-beta processing, and TGF-beta release. Thus, subtilisin-like proprotein convertases may represent a novel target for the immunotherapy of malignant glioma and other cancers or pathological conditions characterized by enhanced TGF-beta bioactivity.

Cell Line, Transformed↗
PubMed2001

Ezrin-dependent promotion of glioma cell clonogenicity, motility, and invasion mediated by BCL-2 and transforming growth factor-beta2.

Ezrin belongs to the ezrin-radixin-moesin family proteins, which cross-link actin cytoskeleton and plasma membrane. Malignant glioma cells are paradigmatic for their strong migratory and invasive properties. Here, we report that the expression of dominant-negative ezrins inhibits clonogenicity, migration, and invasiveness of human malignant glioma cells. Furthermore, dominant-negative ezrins block hepatocyte growth factor (HGF)-mediated stimulation of clonogenicity and migration, without altering HGF-induced protein kinase B/Akt and focal adhesion kinase phosphorylation. Glioma cells expressing dominant-negative ezrins exhibit a shift of the BCL-2/BAX rheostat toward apoptosis, reduced alpha(V)beta(3) integrin expression and reduced matrix metalloproteinase (MMP) expression and activity. These changes are associated with a dramatic loss of transforming growth factor beta(2) (TGF-beta(2)) release. Exogenous supplementation of TGF-beta(2) overcomes the inhibitory effects of dominant-negative ezrins on migration and clonogenicity. A neutralizing TGF-beta(2) antibody mimics the effects of dominant-negative ezrins on clonogenicity and migration. Exogenous HGF markedly induces TGF-beta(2) protein levels, and a neutralizing TGF-beta(2) antibody abolishes the HGF-mediated increase in glioma cell motility. Finally, TGF-beta(2) does not modulate BCL-2 or BAX expression, but BCL-2 gene transfer increases the levels of latent and active TGF-beta(2). Intracranial xenografts of U87MG glioma cells transfected with the dominant-negative ezrins in athymic mice grow to significantly smaller volumes, and the median survival of these mice is 50 d compared with 28 d in the control group. These data define a novel pathway for HGF-induced glioma cell migration and invasion, which requires ezrin, changes in the BCL-2/BAX rheostat, and the induction of TGF-beta(2) expression in vitro, and underscore the important role of HGF signaling in vivo.

Animals↗
PubMed2001

Soluble decoy receptor 3 is expressed by malignant gliomas and suppresses CD95 ligand-induced apoptosis and chemotaxis.

Decoy receptor 3 (DcR3) is a newly identified soluble protein that binds to CD95 ligand (CD95L) and inhibits its proapoptotic activity. Here we report that DcR3 is expressed by the majority of long-term and ex vivo malignant glioma cell lines as well as in human glioblastoma in vivo. Expression of DcR3 correlates with the grade of malignancy: 15 of 18 (83%) glioblastomas (WHO grade IV) but none of 11 diffuse astrocytomas (WHO grade II) exhibited DcR3 immunoreactivity. We also demonstrate that human malignant glioma cells engineered to release high amounts of DcR3 into the cell culture supernatant are protected from CD95L-induced apoptotic cell death. In contrast, DcR3 does not confer protection from the death ligand Apo2 ligand (TRAIL). Importantly, ectopic expression of DcR3 resulted in substantial differences in immune cell infiltration in the 9L rat gliosarcoma model. Thus, the infiltration of CD4+ and CD8+ T cells as well as microglia/macrophages into glioma was substantially decreased in DcR3-producing tumors compared with control tumors. Chemotaxis assays revealed that DcR3 counteracts the chemotactic activity of CD95L against microglial cells in vitro. These findings suggest that DcR3 may be involved in the progression and immune evasion of malignant gliomas.

Animals↗
PubMed2001

Malignant glioma biology: role for TGF-beta in growth, motility, angiogenesis, and immune escape.

Characteristics of human malignant glioma are excessive proliferation, infiltrative growth, angiogenesis and suppression of anti-tumor immune surveillance. Transforming growth factor-beta (TGF-beta), a versatile cytokine, is intimately involved in the regulation of these processes. Here, we discuss the interactions of TGF-beta with growth factors, such as basic fibroblast growth factor (bFGF), epidermal growth factor (EGF) and platelet derived growth factor (PDGF), metalloproteinases (MMP-2, MMP-9) and their inhibitor, plasmin activator inhibitor-1 (PAI-1), and immune cells, like natural killer cells, T-cells and microglia. The differential effects of TGF-beta in glioma biology are outlined with emphasis on the induction of a survival advantage for glioma cells by enforced cell growth, migration, invasion, angiogenesis and immune paralysis. By virtue of its growth regulatory and immunomodulatory properties, TGF-beta promises to become a novel target for the experimental therapy of human malignant glioma.

Brain Neoplasms↗
PubMed2001

Glioma cell invasion: regulation of metalloproteinase activity by TGF-beta.

Matrix metalloproteinases (MMPs) are a family of extracellular endopeptidases that selectively degrade components of the extracellular matrix. MMPs are implicated in tumor cell invasion because they mediate the breakdown of the basal membrane. In addition, they seem to be important for the creation and maintenance of a microenvironment that facilitates tumor cell survival. Among the essential characteristics of human malignant gliomas are infiltrative growth, angiogenesis and suppression of antitumor immune surveillance. Transforming growth factor-beta (TGF-beta) is intimately involved in the regulation of these processes. We have previously demonstrated that TGF-beta promotes the migration of LN- 18 and LN-229 glioma cells via a process that may involve the upregulation of alphaVbeta3 integrin expression. Furthermore, we have defined a novel pathway for hepatocyte growth factor (HGF)-induced glioma cell migration and invasion which requires the induction of TGF-beta2 expression. Here, we demonstrate that TGF-beta2 induces MMP-2 expression and suppresses tissue inhibitor of metalloproteinases (TIMP)-2 expression and that concentration-dependently promotes the invasion of U87MG and LN-229 glioma cells in a matrigel invasion assay. Similarly, ectopic expression of the anti-apoptotic BCL-x, protein leads to enhanced matrigel invasion by LN-18 and LN-229 glioma cells. We outline the possible interrelations of TGF-beta, proteins of the BCL-2 family, integrins and metalloprotease activity. By virtue of its promotion of glioma invasion and its growth regulatory and immunomodulatory properties. TGF-beta continues to be one of the most promising targets for the experimental therapy of human malignant glioma.

3T3 Cells↗
PubMed2001

N-[3,4-dimethoxycinnamoyl]-anthranilic acid (tranilast) suppresses microglial inducible nitric oxide synthase (iNOS) expression and activity induced by interferon-gamma (IFN-gamma).

1. Microglial cells up-regulate inducible nitric oxide synthase (iNOS) expression in response to various pro-inflammatory stimuli including interferon-gamma (IFN-gamma), allowing for the release of nitric oxide (NO). Tranilast (N-[3,4-dimethoxycinnamoyl]-anthranilic acid) is an antiallergic compound with suppressive effects on the activation of monocytes. 2. Here, we show that N9 murine microglial cells express iNOS mRNA and protein and release nitric oxide into the culture medium in response to IFN-gamma (200 u x ml(-1)) as measured by Northern and Western blot analyses and Griess assay. 3. Exposure to non-toxic doses of tranilast (30-300 microM) leads to a concentration-dependent inhibition of IFN-gamma-induced (200 u x ml(-1)) iNOS mRNA and protein expression. This is paralleled by a suppression of NO-release into the cell culture medium. 4. Inhibition of IFN-gamma-induced iNOS mRNA expression by tranilast is paralleled by an inhibition of nuclear factor-kappaB (NF-kappaB) activation and phosphorylation of inhibitory kappaB (IkappaB) as determined by Western blot analyses and NF-kappaB reporter gene assay. 5. These results suggest that tranilast-mediated suppression of microglial iNOS activity induced by IFN-gamma involves the inhibition of NF-kappaB-dependent iNOS mRNA expression.

Animals↗
PubMed2001

Extraskeletal myxoid chondrosarcoma: a light microscopic, immunohistochemical, ultrastructural and immuno-ultrastructural study indicating neuroendocrine differentiation.

AIMS: Extraskeletal myxoid chondrosarcoma is a rare low-grade soft-tissue sarcoma with locally aggressive and metastasizing potential. Extraskeletal myxoid chondrosarcoma has distinctive clinical, light microscopic, immunophenotypic, cytogenetic and ultrastructural features. Evidence that extraskeletal myxoid chondrosarcoma often shows neuroendocrine features was first provided by Chhieng et al. on the basis of an immunohistochemical and ultrastructural study of seven cases. Our study aims to further confirm by immunohistochemistry and ultrastructural studies, including immunoelectron microscopy, that extraskeletal myxoid chondrosarcoma indeed may show neuroendocrine differentiation. METHODS AND RESULTS: Fifteen cases of extraskeletal myxoid chondrosarcoma and seven control cases of skeletal chondrosarcomas were studied. Extensive immunohistochemical analysis was performed in all cases and ultrastructural studies were done in 11 extraskeletal myxoid chondrosarcomas and three skeletal chondrosarcomas. Immunoelectron microscopy was performed on one case each of extraskeletal myxoid chondrosarcoma and skeletal chondrosarcoma. Extraskeletal myxoid chondrosarcomas expressed neuron-specific enolase (100%), synaptophysin (87%), S100 (50%), PGP 9.5 (40%), and epithelial membrane antigen (25%). Co-expression of synaptophysin and PGP 9.5 was observed in six tumours. Skeletal chondrosarcomas showed expression of S100 protein, vimentin and neuron-specific enolase in all cases. Synaptophysin, chromogranin and PGP 9.5 were not expressed in any skeletal chondrosarcoma case. Ultrastructurally, extraskeletal myxoid chondrosarcoma was characterized by distinct cords of cells immersed in a glycosaminoglycan-rich matrix. The cells were rich in mitochondria, had well-developed Golgi apparatus and there were numerous smooth vesicles. In three cases there were easily found 140-180 nm diameter membrane-bound dense-core granules in cell bodies and in processes, unrelated to the Golgi, compatible with neurosecretory granules. Fewer such granules were present in the remaining extraskeletal myxoid chondrosarcoma cases, three of which also contained intracisternal tubules typical of extraskeletal myxoid chondrosarcoma. The skeletal chondrosarcomas had scalloped cell surfaces, prominent rough endoplasmic reticulum focally distended with secretory product, and lacked neurosecretory granules. Intermediate filaments were prominent in both extraskeletal myxoid chondrosarcoma and skeletal chondrosarcomas. Immunoelectron microscopy showed synaptophysin expression in the extraskeletal myxoid chondrosarcoma but not in the skeletal chondrosarcoma case. CONCLUSIONS: This study confirms that a substantial proportion of extraskeletal myxoid chondrosarcomas show immunophenotypic and/or ultrastructural evidence of neuroendocrine differentiation, and are unlikely to be related to conventional skeletal chondrosarcomas.

Adult↗
PubMed2000

Secreted Frizzled-related proteins inhibit motility and promote growth of human malignant glioma cells.

Cellular resistance to multiple proapoptotic stimuli and invasion of surrounding brain tissue by migrating tumor cells are main obstacles to an effective therapy for human malignant glioma. Here, we report that the Wnt family of embryonic differentiation genes modulate growth of malignant glioma cells in vitro and in vivo and inhibit cellular migration in vitro. sFRPs (soluble Frizzled-related proteins) are soluble proteins that bind to Wnt and interfere with Wnt signaling. We find that sFRP-1 and sFRP-2 are produced by the majority of longterm and ex vivo malignant glioma cell lines. Glioma cells that ectopically express sFRPs exhibit increased clonogenicity and enhanced resistance to serum starvation. In contrast, sFRPs do not modulate glioma cell susceptibility to apoptosis induced by the cytotoxic cytokines, CD95 (Fas/APO-1) ligand (CD95L) or Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL), or various cytotoxic drugs. sFRP-2 strongly promotes the growth of intracranial glioma xenografts in nude mice. In contrast, enhanced expression of sFRPs inhibits the motility of glioma cells in vitro. sFRP-mediated effects on glioma cells are accompanied by decreased expression and activity of matrix metalloproteinase-2 (MMP-2) and decreased tyrosine phosphorylation of beta-catenin. Thus, sFRPs promote survival under non-supportive conditions and inhibit the migration of glioma cells. We suggest that the regulation of these cellular processes involves expression of MMP-2 and tyrosine phosphorylation of beta-catenin. These data support a function for Wnt signaling and its modulation by sFRPs in the biology of human gliomas. Oncogene (2000) 19, 4210 - 4220

Animals↗
PubMed2000

Transforming growth factors beta(1) (TGF-beta(1)) and TGF-beta(2) promote glioma cell migration via Up-regulation of alpha(V)beta(3) integrin expression.

The migratory behaviour of malignant gliomas relies on the interaction of integrins with extracellular matrix (ECM) components. Transforming growth factor-beta(1) (TGF-beta(1)) potently stimulates glioma cell motility whereas TGF-beta(2) is known for its immunosuppressive properties. Here, we show that both TGF-beta(1) and TGF-beta(2) promote migration of glioma cells. In parallel, TGF-beta(1) and TGF-beta(2) induce alpha(V) and beta(3) intergrin mRNA expression and enhance cell surface expression of alpha(V)beta(3) integrin. TGF-beta-mediated promotion of migration is abrogated by echistatin, a Arg-Gly-Asp (RGD) peptide antagonist of alpha(V)beta(3) integrin, and by a neutralizing anti-alpha(V)beta(3) integrin antibody. Taken together, we report a novel mechanism by which TGF-beta modulates cell ECM interactions and promotes glioma cell motility.

Cell Movement↗
PubMed2000

Comprehensive allelotype and genetic anaysis of 466 human nervous system tumors.

Brain tumors pose a particular challenge to molecular oncology. Many different tumor entities develop in the nervous system and some of them appear to follow distinct pathogenic routes. Molecular genetic alterations have increasingly been reported in nervous system neoplasms. However, a considerable number of affected genes remain to be identified. We present here a comprehensive allelotype analysis of 466 nervous system tumors based on loss of heterozygosity (LOH) studies with 129 microsatellite markers that span the genome. Specific alterations of the EGFR, CDK4, CDKN2A, TP53, DMBT1, NF2, and PTEN genes were analyzed in addition. Our data point to several novel genetic loci associated with brain tumor development, demonstrate relationships between molecular changes and histopathological features, and further expand the concept of molecular tumor variants in neuro-oncology. This catalogue may provide a valuable framework for future studies to delineate molecular pathways in many types of human central nervous system tumors.

Alleles↗
PubMed1998

Chorea as a paraneoplastic complication of Hodgkin's disease.

Neurologic complications of Hodgkin's disease (HD) include both metastatic and non-metastatic involvement of the nervous system. There are at least five paraneoplastic syndromes associated with HD but chorea has not been described. We report the first choreiform disorder as a paraneoplastic complication of HD and only the second case of paraneoplastic chorea in the literature.

Aged↗
PubMed1998

Immunoadsorption therapy for paraneoplastic syndromes.

Paraneoplastic neurologic syndromes associated with systemic cancer are being increasingly recognized. Although these syndromes are thought to be immunologically mediated treatment with steroids, immunoglobulin and plasmapharesis has been disappointing. Based on our preliminary experience with the treatment of 6 cases of paraneoplastic neurologic syndromes with protein A immunoadsorption, an institutional, open-arm treatment protocol was established. Since our original report we have treated an additional 7 patients with this method. The 13 cases were accrued over a 2 year period and included 10 women and 3 men with an average age of 63. The paraneoplastic syndromes included 6 cases of cerebellar degeneration, 3 cases of opsoclonus/myoclonus, 3 cases of encephalomyelitis and 1 case of Lambert Eaton myasthenic syndrome. Primary cancers included 4 cases of small cell lung cancer, 2 cases of breast cancer, 2 cases of lymphoma and 1 each of acinic cell cancer, cholangiocarcinoma, Merkel cell cancer, pancreatic adenocarcinoma and rectal cancer. Anti-neuronal antibody status, cerebrospinal fluid and neuroimaging studies as well as cancer staging and treatment protocols were reviewed. Neurologic syndromes were clinically separated into component symptoms and signs for assessment of treatment effect. The treatment goal was a total of 6 sessions of protein A immunoadsorption given twice weekly. Twelve of 13 patients completed therapy and one patient developed cutaneous vasculitis during the second session with termination of treatment. Of the remaining patients 3/12 had a complete response of the primary clinical symptom/sign while 6/12 had a partial response for a total response rate of 9/12 (75%). Toxicity was limited to cutaneous vasculitis in 1 patient and an episode of hemisensory changes in another patient. Current treatment of paraneoplastic neurologic syndromes remains unsatisfactory. Despite the small number of patients in this report, protein A immunoadsorption is a promising therapy which deserves further study in a larger population of patients with paraneoplastic syndromes.

Adsorption↗
PubMed1997

A novel splice site associated polymorphism in the tuberous sclerosis 2 (TSC2) gene may predispose to the development of sporadic gangliogliomas.

The tuberous sclerosis 2 (TSC2) gene is thought to function as a growth suppressor in sporadic and TSC-associated hamartomas and tumors. Clusters of dysplastic glial cells are a common feature of cortical tubers and subependymal nodules in tuberous sclerosis patients. In an effort to identify TSC2 gene alterations in sporadic gliomas, we detected a novel polymorphism adjacent to the 3'splice site of intron 4. We evaluated the distribution of this variant allele in a series of 244 patients with glial tumors, including 55 gangliogliomas, 31 pilocytic astrocytomas (WHO grade I), 50 astrocytomas (WHO grades II and III), and 108 glioblastomas (WHO grade IV). The allelic distribution in the general population was estimated by examining 381 healthy blood donors. This rare allele appeared in the control population and in the patients with astrocytic gliomas with a virtually identical frequency (8.14%, and 8.20%, respectively). The frequency of the rare allele in gangliogliomas, however, was significantly higher (15.5%; p = 0.024). The fact that both gangliogliomas and cortical tubers in tuberous sclerosis contain neuronal and astrocytic elements and may resemble each other histologically suggests that the TSC2 gene may be involved in the development of these tumors. The rare allele of the TSC2 gene emerges as a candidate for a predisposing factor for the formation of sporadic gangliogliomas.

Adult↗
PubMed1996

Up-regulation of specific NF 1 gene transcripts in sporadic pilocytic astrocytomas.

Pilocytic astrocytomas of the optic nerve (optic nerve gliomas) are closely associated with neurofibromatosis 1 (NF1), and allelic losses of the NF1 gene region on chromosome 17q occur in sporadic pilocytic astrocytomas. We therefore hypothesized that the NF1 gene acts as a tumor suppressor gene in pilocytic astrocytomas, and that NF1 gene expression would be reduced or absent in these tumors. To evaluate this possibility, we examined quantitative and qualitative aspects of NF1 gene expression in six sporadic pilocytic astrocytomas. Surprisingly, the NF1 gene was overexpressed up to fourfold in these tumors when compared with normal brain. This up-regulation was accompanied by immunohistochemical positivity using a carboxyl-terminal antibody and by the absence of mutations in one kilobase of the NF1 coding sequence, consistent with the expressed transcript and protein being full length and probably wild type. Pilocytic astrocytomas showed a marked predominance of transcripts containing exon 23a and lacking exon 9br, the same isoforms that are expressed by normal and reactive astrocytes and malignant astrocytomas. These data illustrate that pilocytic astrocytomas overexpress specific NF1 gene transcripts, perhaps as a regulatory response to growth stimuli. The role of the NF1 gene as a tumor suppressor in pilocytic astrocytomas, however, remains to be proven.

Adolescent↗