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  • EXPRESSION  (34)
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  • 1
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; IONIZING-RADIATION ; proliferation ; CELL ; COMBINATION ; Germany ; IN-VIVO ; KINASE ; PATHWAY ; PATHWAYS ; THERAPY ; TYROSINE KINASE ; SUPPORT ; EXPOSURE ; TISSUE ; radiation ; TISSUES ; tumour ; CONTRAST ; cell culture ; culture ; TARGET ; immunohistochemistry ; RADIATION-THERAPY ; EFFICACY ; NETHERLANDS ; SQUAMOUS-CELL CARCINOMAS ; RECEPTORS ; GLIOMAS ; PERMEABILITY FACTOR ; BRAIN-TUMORS ; TUMOR-GROWTH ; GLIOMA ; anti-angiogenic therapy,glioblastoma multiforme,radiotherapy,VEGF receptor-coexpression ; FACTOR RECEPTOR-1 ; HUMAN GLIOMAS
    Abstract: In tumour-induced angiogenesis of gliomas, vascular endothelial growth factor (VEGF) and its receptors fms-like tyrosine kinase (Flt-1) and kinase-insert-domain-containing receptor (KDR) play a major role and are promising targets for tumour therapy. Nevertheless, preliminary results of such therapies could not prove clinical efficacy and thus make a profound knowledge of VEGF regulation essential. Based on earlier results, which demonstrated an inhibitory influence of VEGF on Flt-1-expressing glioblastoma cells [1], in the present study we focused on the extent of VEGF and VEGF receptor coexpression and possible therapeutical consequences.Protein expression of VEGF, Flt-1 and KDR was analysed by immunohistochemistry in native tumour tissues of 63 glioblastomas. VEGF could be detected in all glioblastomas. Additionally and independently to the expected Flt-1 and KDR expression in tumour endothelia, we found a coexpression of VEGF with Flt-1 in tumour cells of 46 and with KDR in 45 glioblastomas. After exposure of glioblastoma cells to X-ray radiation we observed a strong dose-dependent increase of VEGF secretion in two glioblastoma cell cultures by up to 46% and 96%, respectively that originated from an increased VEGF mRNA expression. In contrast, under the same conditions secretion of HGF/SF was only slightly elevated and bFGF despite being strongly increased remained at very low overall amounts compared to VEGF. Based on previous data on an autocrine function of VEGF in Flt-1-expressing glioblastoma cells we hypothesise that the X-ray radiation induced upregulation of VEGF might result in a downregulation of tumour cell proliferation and thus lead to a reduced sensitivity to radiation therapy. Therefore our results support the idea that a combination of anti-VEGF and radiation therapy might prove a promising new option in fighting against one of the most fatal tumour types
    Type of Publication: Journal article published
    PubMed ID: 15015778
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  • 2
    Keywords: brain ; CELLS ; EXPRESSION ; SURVIVAL ; tumor ; TUMOR-CELLS ; BLOOD ; CELL ; Germany ; THERAPY ; DISEASE ; LONG-TERM ; TUMORS ; TIME ; PATIENT ; INFECTION ; prognosis ; SKIN ; T cell ; T cells ; T-CELL ; T-CELLS ; cell culture ; culture ; MEMORY ; virus ; NERVOUS-SYSTEM ; NO ; immunohistochemistry ; ASSAY ; NUMBER ; VACCINE ; SAFETY ; CD8(+) ; immune response ; IMMUNE-RESPONSE ; IMMUNITY ; T-LYMPHOCYTES ; vaccination ; T lymphocyte ; side effects ; NEWCASTLE-DISEASE VIRUS ; ESTABLISHMENT ; TUMOR CELLS ; LONG-TERM SURVIVORS ; GLIOMAS ; T lymphocytes ; IMMUNIZATION ; ONCOLOGY ; AUTOLOGOUS TUMOR ; overall survival ; NEWCASTLE-DISEASE-VIRUS ; SURVIVORS
    Abstract: Purpose Prognosis of patients with glioblastoma is poor. Therefore, in glioblastoma patients, we analyzed whether antitumor vaccination with a virus-modified autologous tumor cell vaccine is feasible and safe. Also, we determined the influence on progression-free survival and overall survival and on vaccination-induced antitumor reactivity. Patients and Methods In a nonrandomized study, 23 patients were vaccinated and compared with nonvaccinated controls (n = 87). Vaccine was prepared from patient's tumor cell cultures by infection of the cells with Newcastle Disease Virus, followed by gamma-irradiation, and applied up to eight times. Antitumor immune reactivity was determined in skin, blood, and relapsed tumor by delayed-type hypersensitivity skin reaction, ELISPOT assay, and immunohistochemistry, respectively. Results Establishment of tumor cell cultures was successful in approximately 90% of patients. After vaccination, we observed no severe side effects. The median progression-free survival of vaccinated patients was 40 weeks (v 26 weeks in controls; log-rank test, P =.024), and the median overall survival of vaccinated patients was 100 weeks (v 49 weeks in controls; log-rank test, P 〈.001). Forty-five percent of the controls survived 1 year, 11% survived 2 years, and there were no long-term survivors (greater than or equal to3 years). Ninety-one percent of vaccinated 39% survived 2 years, and 4% were long-term survivors. In the patients survived I year, vaccinated group, immune monitoring revealed significant increases of delayed-type hypersensitivity reactivity, numbers of tumor-reactive memory T cells, and numbers of CD8(+) tumor-infiltrating T-lymphocytes in secondary tumors. Conclusion Postoperative vaccination with virus-modified autologous tumor cells seems to be feasible and safe and to improve the prognosis of patients with gliobiastomas. This could be substantiated by the observed antitumor immune response. (C) 2004 by American Society of Clinical Oncology
    Type of Publication: Journal article published
    PubMed ID: 15452186
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  • 3
    Keywords: brain ; APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; CELL ; Germany ; human ; IN-VIVO ; INHIBITION ; KINASE ; PATHWAY ; VITRO ; PROTEIN ; RNA ; TUMORS ; BIOLOGY ; MOLECULAR-BIOLOGY ; PHOSPHORYLATION ; resistance ; genetics ; CANCER-CELLS ; ONCOGENE ; GLUCOSE ; OVEREXPRESSION ; heredity ; MAP KINASES ; INTEGRIN ACTIVATION ; signaling ; molecular biology ; molecular ; ONCOLOGY ; RE ; BRAIN-TUMORS ; GLIOMA ; GLIOMA-CELLS ; TRANSPORTER ; brain tumors ; LEVEL ; analysis ; PHOSPHOPROTEIN ; ENGLAND ; GLIOBLASTOMA ; ASTROCYTES ; CYTOPLASMIC SEQUESTRATION ; DEATH EFFECTOR DOMAIN ; ERK1/2 ; PEA-15/PED ; PED/PEA-15
    Abstract: PEA-15 ( phosphoprotein enriched in astrocytes 15 kDa) is a death effector domain-containing protein, which is involved in the regulation of apoptotic cell death. Since PEA-15 is highly expressed in cells of glia l origin, we studied the role of PEA-15 in human malignant brain tumors. Immunohistochemical analysis of PEA-15 expression shows strong immunoreactivity in astrocytomas and glioblastomas. Phosphorylation of PEA-15 at Ser(116) is found in vivo in perinecrotic areas in glioblastomas and in vitro after glucose deprivation of glioblastoma cells. Overexpression of PEA-15 induces a marked resistance against glucose deprivation-induced apoptosis, whereas small interfering RNA (siRNA)-mediated downregulation of endogenous PEA-15 results in the sensitization to glucose withdrawal-mediated cell death. This antiapoptotic activity of PEA-15 under low glucose conditions depends on its phosphorylation at Ser116. Moreover, siRNA-mediated knockdown of PEA-15 abolishes the tumorigenicity of U87MG glioblastoma cells in vivo. PEA-15 regulates the level of phosphorylated extracellular-regulated kinase ( ERK) 1/ 2 in glioblastoma cells and the PEA-15-dependent protection from glucose deprivation-induced cell death requires ERK1/2 signaling. PEA-15 transcriptionally upregulates the Glucose Transporter 3, which is abrogated by the inhibition of ERK1/2 phosphorylation. Taken together, our findings suggest that Ser(116)-phosphorylated PEA-15 renders glioma cells resistant to glucose deprivation-mediated cell death as encountered in poor microenvironments, for example in perinecrotic areas of glioblastomas
    Type of Publication: Journal article published
    PubMed ID: 17700518
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  • 4
    Keywords: brain ; CANCER ; CELLS ; EXPRESSION ; INVASION ; tumor ; TUMOR-CELLS ; CELL ; Germany ; IN-VIVO ; KINASE ; MODEL ; PATHWAY ; THERAPY ; TISSUE ; NF-KAPPA-B ; LIGAND ; MECHANISM ; FAMILY ; ACTIVATED PROTEIN-KINASE ; BINDING ; CD95 ligand ; NUMBER ; COMPLEX DISC ; ONCOLOGY ; RE ; FAMILIES ; THERAPIES ; MATRIX METALLOPROTEINASES ; GLIOMA ; MEDIATED APOPTOSIS ; SRC FAMILY KINASES ; MOLECULAR-MECHANISMS ; TECHNOLOGY ; USA ; GLIOBLASTOMA ; matrix metalloproteinase ; FAS-INDUCED APOPTOSIS ; MATRIX-METALLOPROTEINASE ; HUMAN GLIOMA-CELLS ; TRIMERIZATION DOMAIN
    Abstract: Invasion of surrounding brain tissue by isolated tumor cells represents one of the main obstacles to a curative therapy of glioblastoma multiforme. Here we unravel a mechanism regulating glioma infiltration. Tumor interaction with the surrounding brain tissue induces CD95 Ligand expression. Binding of CD95 Ligand to CD95 on glioblastoma cells recruits the Src family member Yes and the p85 subunit of phosphatidylinositol 3-kinase to CD95, which signal invasion via the glycogen synthase kinase 3-beta pathway and subsequent expression of matrix metalloproteinases. In a murine syngeneic model of intracranial GBM, neutralization of CD95 activity dramatically reduced the number of invading cells. Our results uncover CD95 as an activator of P13K and, most importantly, as a crucial trigger of basal invasion of glioblastoma in vivo
    Type of Publication: Journal article published
    PubMed ID: 18328427
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  • 5
    Keywords: brain ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; LUNG-CANCER ; SYSTEM ; DISEASE ; PROTEIN ; TISSUE ; MICE ; PATIENT ; ANTIGEN ; T-CELL ; T-CELLS ; BONE-MARROW ; MEMORY ; RECOGNITION ; MOUSE ; IDENTIFICATION ; LYMPHOMA ; EFFICACY ; MELANOMA ; MASS-SPECTROMETRY ; HEAD ; NECK ; EPITOPE ; IMMUNOTHERAPY ; IMMUNOGENICITY ; CANCER PATIENTS ; CALCIUM-BINDING PROTEINS ; TUMOR-ASSOCIATED ANTIGENS ; NECK-CANCER ; brain tumor ; head and neck cancer ; endothelial cells ; proteome ; EGFR ; SEPARATION ; EXPRESSION PROFILES ; Type ; HEAD-AND-NECK
    Abstract: Identifying the antigens that have the potential to trigger endogenous antitumor responses in an individual cancer patient is likely to enhance the efficacy of cancer immunotherapy, but current methodologies do not efficiently identify such antigens. This study describes what we believe to be a new method of comprehensively identifying candidate tissue antigens that spontaneously cause T cell responses in disease situations. We used the newly developed automated, two-dimensional chromatography system PF2D to fractionate the proteome of human tumor tissues and tested protein fractions for recognition by preexisting tumor-specific CD4(+) Th cells and CTLs. Applying this method using mice transgenic for a TCR that recognizes an OVA peptide presented by MHC class I, we demonstrated efficient separation, processing, and cross-presentation to CD8(+) T cells by DCs of OVA expressed by the OVA-transfected mouse lymphoma RMA-OVA. Applying this method to human tumor tissues, we identified MUC1 and EGFR as tumor-associated antigens selectively recognized by T cells in patients with head and neck cancer. Finally, in an exemplary patient with a malignant brain tumor, we detected CD4(+) and CD8(+) T cell responses against two novel antigens, transthyretin and calgranulin B/S100A9, which were expressed in tumor and endothelial cells. The immunogenicity of these antigens was confirmed in 4 of 10 other brain tumor patients. This fast and inexpensive method therefore appears suitable for identifying candidate T cell antigens in various disease situations, such as autoimmune and malignant diseases, without being restricted to expression by a certain cell type or HLA allele
    Type of Publication: Journal article published
    PubMed ID: 20458140
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  • 6
    Keywords: brain ; APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; INHIBITOR ; proliferation ; tumor ; CELL ; CELL-PROLIFERATION ; Germany ; INHIBITION ; MODEL ; PATHWAY ; PATHWAYS ; THERAPY ; VITRO ; EXPOSURE ; GENE ; microarray ; PROTEIN ; RNA ; DIFFERENTIATION ; MECHANISM ; INDUCTION ; mechanisms ; BIOLOGY ; ACID ; TARGET ; PROGRESSION ; AMPLIFICATION ; ASSAY ; PROMOTER ; genetics ; ONCOGENE ; STEM-CELLS ; PROGENITOR CELLS ; CANCER-THERAPY ; GLIOMAS ; RETINOIC ACID ; TRANS-RETINOIC ACID ; INHIBITORS ; signaling ; ONCOLOGY ; GLIOMA ; GLIOMA-CELLS ; MOLECULAR-MECHANISMS ; LOCUS ; GLIOBLASTOMA ; MicroRNAs ; MICRORNA ; CELL BIOLOGY ; TUMOR-INITIATING CELLS ; Genetic ; tumor grade ; Molecular mechanisms ; CTGF ; miR-17-92 ; NEURAL PRECURSORS ; spheroid culture
    Abstract: All-trans retinoic acid is a potent promoter of cellular differentiation processes, which is used in cancer therapy. Glioblastoma spheroid cultures are enriched in tumor-initiating cells, and provide a model to test new treatment options in vitro. We investigated the molecular mechanisms of response to exposure to differentiation-promoting conditions in such cultures. Microarray analyses of five independent cultures showed that after induction of differentiation, inhibitors of transforming growth factor beta/bone morphogenetic protein, Wnt/beta-catenin and IGF signaling were upregulated, whereas expression of several microRNAs decreased, particularly that of the miR-17-92 cluster. In primary astrocytic gliomas (n = 82), expression of several members of miR-17-92 was significantly higher relative to those of normal brain (n = 8) and significantly increased with tumor grade progression (P 〈 0.05). A high-level amplification of the miR-17-92 locus was detected in one glioblastoma specimen. Transfection of inhibitors of miR-17-92 induced increased apoptosis and decreased cell proliferation in glioblastoma spheroids. Mir-17-92 inhibition was also associated with increased messenger RNA (mRNA) and/or protein expression of CDKN1A, E2F1, PTEN and CTGF. The CTGF gene was shown to be a target of miR-17-92 in glioblastoma spheroids by luciferase reporter assays. Our results suggest that miR-17-92 and its target CTGF mediate effects of differentiation-promoting treatment on glioblastoma cells through multiple regulatory pathways. Oncogene (2010) 29, 3411-3422; doi:10.1038/onc.2010.83; published online 22 March 2010
    Type of Publication: Journal article published
    PubMed ID: 20305691
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  • 7
    Keywords: CANCER ; EXPRESSION ; INHIBITOR ; THERAPY ; SYSTEM ; GENE ; meningioma ; TUMORS ; COMPONENT ; MUTATIONS ; DUPLICATION ; GLIOMAS ; BRAF ; brain tumor ; PATHWAY ACTIVATION ; MAPK PATHWAY ; ATYPICAL TERATOID/RHABDOID TUMOR ; B-RAF GENE ; Ganglioglioma ; Pleomorphic xanthoastrocytoma ; V600E mutation
    Abstract: Missense mutations of the V600E type constitute the vast majority of tumor-associated somatic alterations in the v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) gene. Initially described in melanoma, colon and papillary thyroid carcinoma, these alterations have also been observed in primary nervous system tumors albeit at a low frequency. We analyzed exon 15 of BRAF spanning the V600 locus by direct sequencing in 1,320 adult and pediatric tumors of the nervous system including various types of glial, embryonal, neuronal and glioneuronal, meningeal, adenohypophyseal/sellar, and peripheral nervous system tumors. A total of 96 BRAF mutations were detected; 93 of the V600E type and 3 cases with a three base pair insertion between codons 599 and 600. The highest frequencies of BRAF (V600E) mutations were found in WHO grade II pleomorphic xanthoastrocytomas (42/64; 66%) and pleomorphic xanthoastrocytomas with anaplasia (15/23; 65%), as well as WHO grade I gangliogliomas (14/77; 18%), WHO grade III anaplastic gangliogliomas (3/6) and pilocytic astrocytomas (9/97; 9%). In pilocytic astrocytomas BRAF (V600E) mutation was strongly associated with extra-cerebellar location (p = 0.009) and was most frequent in diencephalic tumors (4/12; 33%). Glioblastomas and other gliomas were characterized by a low frequency or absence of mutations. No mutations were detected in non-glial tumors, including embryonal tumors, meningiomas, nerve sheath tumors and pituitary adenomas. The high mutation frequencies in pleomorphic xanthoastrocytomas, gangliogliomas and extra-cerebellar pilocytic astrocytomas implicate BRAF (V600E) mutation as a valuable diagnostic marker for these rare tumor entities. Future clinical trials should address whether BRAF (V600E) mutant brain tumor patients will benefit from BRAF (V600E)-directed targeted therapies
    Type of Publication: Journal article published
    PubMed ID: 21274720
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  • 8
    Keywords: ANGIOGENESIS ; EXPRESSION ; GROWTH-FACTOR ; INVASION ; IN-VIVO ; IMMUNE-RESPONSES ; MALIGNANT GLIOMA ; PROGNOSTIC-FACTOR ; BLOOD-BRAIN-BARRIER ; LYMPHOCYTE
    Abstract: Purpose: In glioma-in contrast to various other cancers-the impact of T-lymphocytes on clinical outcome is not clear. We investigated the clinical relevance and regulation of T-cell infiltration in glioma. Experimental Design: T-cell subpopulations from entire sections of 93 WHO degrees II-IV gliomas were computationally identified using markers CD3, CD8, and Foxp3; survival analysis was then done on primary glioblastomas (pGBM). Endothelial cells expressing cellular adhesion molecules (CAM) were similarly computationally quantified from the same glioma tissues. Influence of prominent cytokines (as measured by ELISA from 53 WHO degrees II-IV glioma lysates) on CAM-expression in GBM-isolated endothelial cells was determined using flow cytometry. The functional relevance of the cytokine-mediated CAM regulation was tested in a transmigration assay using GBM-derived endothelial cells and autologous T-cells. Results: Infiltration of all T-cell subsets increased in high-grade tumors. Most strikingly, within pGBM, elevated numbers of intratumoral effector T cells (T(eff), cytotoxic and helper) significantly correlated with a better survival; regulatory T cells were infrequently present and not associated with GBM patient outcome. Interestingly, increased infiltration of T(eff) cells was related to the expression of ICAM-1 on the vessel surface. Transmigration of autologous T cells in vitro was markedly reduced in the presence of CAM-blocking antibodies. We found that TGF-beta molecules impeded transmigration and downregulated CAM-expression on GBM-isolated endothelial cells; blocking TGF-beta receptor signaling increased transmigration. Conclusions: This study provides comprehensive and novel insights into occurrence and regulation of T-cell infiltration in glioma. Specifically, targeting TGF-beta 1 and TGF-beta 2 might improve intratumoral T-cell infiltration and thus enhance effectiveness of immunotherapeutic approaches.
    Type of Publication: Journal article published
    PubMed ID: 21478334
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  • 9
    Keywords: EXPRESSION ; GROWTH ; proliferation ; CELL-PROLIFERATION ; INHIBITION ; ACTIVATION ; SIGNALING PATHWAY ; OVEREXPRESSION ; GLIOMA ; RNAi ; HUMAN ASTROCYTOMAS ; cancer research ; GLIOBLASTOMA ; Wnt signalling ; TRANSMEMBRANE PROTEIN ; CANCER STEM-CELLS ; Wnt secretion ; PLANAR CELL POLARITY
    Abstract: Malignant astrocytomas are highly aggressive brain tumours with poor prognosis. While a number of structural genomic changes and dysregulation of signalling pathways in gliomas have been described, the identification of biomarkers and druggable targets remains an important task for novel diagnostic and therapeutic approaches. Here, we show that the Wnt-specific secretory protein Evi (also known as GPR177/Wntless/Sprinter) is overexpressed in astrocytic gliomas. Evi/Wls is a core Wnt signalling component and a specific regulator of pan-Wnt protein secretion, affecting both canonical and non-canonical signalling. We demonstrate that its depletion in glioma and glioma-derived stem-like cells led to decreased cell proliferation and apoptosis. Furthermore, Evi/Wls silencing in glioma cells reduced cell migration and the capacity to form tumours in vivo. We further show that Evi/Wls overexpression is sufficient to promote downstream Wnt signalling. Taken together, our study identifies Evi/Wls as an essential regulator of glioma tumourigenesis, identifying a pathway-specific protein trafficking factor as an oncogene and offering novel therapeutic options to interfere with the aberrant regulation of growth factors at the site of production
    Type of Publication: Journal article published
    PubMed ID: 22147553
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  • 10
    Keywords: CANCER ; CELLS ; EXPRESSION ; TUMORS ; COMPLEX ; prognosis ; RETINOIC ACID RECEPTORS
    Abstract: Impairment of endogenous differentiation pathways like retinoic acid (RA) signaling seems to be a central pathogenetic event in astrocytic gliomas. Among others, expression of the differentiation-promoting RA chaperon protein cellular retinoic acid binding protein 2 (CRABP2) is extenuated in high-grade gliomas. Against this background, we aimed at identifying potential pathomechanisms underlying reduced CRABP2 expression in these tumors. Employing MassARRAY methylation analysis we detected extensive CpG methylation upstream of the CRABP2 gene locus in a study sample comprising 100 astrocytic gliomas of WHO grade II to IV. Compared to non-tumorous control samples tumors revealed increased CpG methylation and methylation levels were inversely correlated to CRABP2 mRNA expression. Substantiating our in situ findings, CRABP2 mRNA levels increased in glioma cell lines after exposure to the demethylating agent 5-aza-2'-deoxycytidine. Finally, a distinct CpG methylation signature distinguished between primary glioblastoma on the one hand and the group of astrocytoma WHO II-III and secondary glioblastoma on the other hand. Altogether, our observations suggest that epigenetic silencing of CRABP2 might contribute to an immature phenotype in glioma cells.
    Type of Publication: Journal article published
    PubMed ID: 22275178
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