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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  61. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC) im Rahmen der Neurowoche 2010; 20100921-20100925; Mannheim; DOCP1707 /20100916/
    Publication Date: 2010-09-17
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 2
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  59. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC), 3. Joint Meeting mit der Italienischen Gesellschaft für Neurochirurgie (SINch); 20080601-20080604; Würzburg; DOCDI.03.06 /20080530/
    Publication Date: 2008-05-30
    Keywords: Apoptosis ; Glioblastoma therapy ; Redox regulation ; Apoptose ; Glioblastom-Therapie ; Redox-Regulation ; ddc: 610
    Language: English
    Type: conferenceObject
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  • 3
    Keywords: ANGIOGENESIS ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; proliferation ; tumor ; carcinoma ; CELL ; CELL-PROLIFERATION ; COMBINATION ; Germany ; IN-VIVO ; MODEL ; VITRO ; VIVO ; DRUG ; MOLECULES ; NF-KAPPA-B ; MECHANISM ; treatment ; MOLECULE ; ANTITUMOR-ACTIVITY ; TARGET ; MOUSE ; INDUCED APOPTOSIS ; FIBROBLAST-GROWTH-FACTOR ; NECROSIS-FACTOR-ALPHA ; chemotherapy ; MIGRATION ; HEAD ; CARCINOMAS ; NECK ; squamous cell carcinoma ; MOUSE MODEL ; CISPLATIN ; CELL-MIGRATION ; MULTIPLE-MYELOMA ; PHASE-II ; CELL CARCINOMA ; ONCOLOGY ; tube formation ; fibroblast ; TUMOR-GROWTH ; endothelial cells ; interaction ; thalidomide ; antiangiogenic therapy ; cell proliferation ; TUMOR-CELL ; USA ; head and neck squamous cell carcinoma ; DRUGS ; vascular endothelial growth factor ; in vivo ; ENDOTHELIAL-CELL ; SQUAMOUS-CELL ; mechanism of action ; ENDOTHELIAL GROWTH ; head and neck squamous cell carcinomas ; ADVANCED MELANOMA ; DOCETAXEL TAXOTERE ; PLUS THALIDOMIDE
    Abstract: Thalidomide is an immunomodulatory, antiangiogenic drug. Although there is evidence that it might be more effective in combination with chemotherapy the exact mechanism of action is unclear. Therefore, we investigated its effect in combination with metronomically applied cisplatin in a xenotransplant mouse model characteristic for advanced head and neck squamous cell carcinomas, its possible synergistic action in vitro, and which tumor-derived factors might be targeted by thalidomide. Although thalidomide alone was ineffective, a combined treatment with low-dose cisplatin inhibited significant tumor growth, proliferation and angiogenesis in vivo as well as migration and tube formation of endothelial cells in vitro. Noteworthy, the latter effect was enhanced after coapplication of cisplatin in nontoxic doses. An inhibitory effect on tumor cell migration was also observed suggesting a direct antitumor effect. Although thalidomide alone did not influence cell proliferation, it augmented antiproliferative response after cisplatin application emphasizing the idea of a potentiated effect when both drugs are combined. Furthermore, we could show that antiangiogenic effects of thalidomide are related to tumor-cell derived factors including vascular endothelial growth factor, basic fibroblast growth factor, hepatocyte growth factor and I1-8 some known and with, granulocyte colony stimulating growth factor and granulocyte macrophage colony stimulating growth factor, some new target molecules of thalidomide. Altogether, our findings reveal new insights into thalidomide-mediated antitumor and antiangiogenic effects and its interaction with cytostatic drugs
    Type of Publication: Journal article published
    PubMed ID: 17557286
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  • 4
    Keywords: ANGIOGENESIS ; CANCER ; CELLS ; GROWTH ; IN-VITRO ; proliferation ; tumor ; TUMOR-CELLS ; CELL ; ENDOTHELIAL GROWTH-FACTOR ; Germany ; IN-VIVO ; MICROSCOPY ; MODEL ; THERAPY ; VITRO ; VIVO ; POPULATION ; GENE-EXPRESSION ; DIFFERENTIATION ; cytokines ; ACID ; TARGET ; DESIGN ; resistance ; EFFICACY ; STEM-CELLS ; PPAR-GAMMA ; RETINOIC ACID ; PHASE-II ; chemoresistance ; TRANS-RETINOIC ACID ; CYTOKINE ; ONCOLOGY ; secretion ; GLIOMA ; GLIOMA-CELLS ; MALIGNANT GLIOMAS ; TUMORIGENICITY ; MOTILITY ; GLIOBLASTOMA ; STEM ; TUMOR-INITIATING CELLS ; MARKER CD133
    Abstract: Purpose: Stem-like tumor cells comprise a highly tumorigenic and therapy-resistant tumor subpopulation, which is believed to substantially influence tumor initiation and therapy resistance in glioma. Currently, therapeutic, drug-induced differentiation is considered as a promising approach to eradicate this tumor-driving cell population; retinoic acid is well known as a potent modulator of differentiation and proliferation in normal stem cells. In glioma, knowledge about the efficacy of retinoic acid-induced differentiation to target the stem-like tumor cell pool could have therapeutic implications. Experimental Design: Stem-like glioma cells (SLGC) were differentiated with all-trans retinoic acid-containing medium to study the effect of differentiation on angiogenesis, invasive growth, as well as radioresistance and chemoresistance of SLGCs. In vivo effects were studied using live microscopy in a cranial window model. Results: Our data suggest that in vitro differentiation of SLGCs induces therapy-sensitizing effects, impairs the secretion of angiogenic cytokines, and disrupts SLGCs motility. Further, ex vivo differentiation reduces tumorigenicity of SLGCs. Finally, we show that all-trans retinoic acid treatment alone can induce antitumor effects in vivo. Conclusions: Altogether, these results highlight the potential of differentiation treatment to target the stem-like cell population in glioblastoma. Clin Cancer Res; 16(10); 2715-28. (C) 2010 AACR
    Type of Publication: Journal article published
    PubMed ID: 20442299
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  • 5
    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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  • 6
    Keywords: GENE-EXPRESSION ; DIFFERENTIATION ; MARKER ; CENTRAL-NERVOUS-SYSTEM ; GLIOMA-CELLS ; PROFILES ; SELF-RENEWAL ; MAINTENANCE ; TUMOR-INITIATING CELLS ; CD133
    Abstract: Glioblastomas are highly aggressive brain tumours and are characterised by substantial cellular heterogeneity within a single tumour. A sub-population of glioblastoma stem-like cells (GSCs) that shares properties with neural precursor cells has been described, exhibiting resistance to therapy and therefore being considered responsible for the high recurrence rate in glioblastoma. To elucidate the underlying cellular processes we investigated the role of phosphatases in the GSC phenotype, using an in vitro phosphatome-wide RNA interference screen. We identified a set of genes, the knockdown of which induces a significant decrease in the glioma stem cell marker CD133, indicating a role in the glioblastoma stem-like phenotype. Among these genes, the ecto-nucleotidase ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) was found to be highly expressed in GSCs compared with normal brain and neural stem cells. Knockdown of ENPP1 in cultured GSCs resulted in an overall downregulation of stem cell-associated genes, induction of differentiation into astrocytic cell lineage, impairment of sphere formation, in addition to increased cell death, accumulation of cells in G1/G0 cell cycle phase and sensitisation to chemotherapeutic treatment. Genome-wide gene expression analysis and nucleoside and nucleotide profiling revealed that knockdown of ENPP1 affects purine and pyrimidine metabolism, suggesting a link between ENPP1 expression and a balanced nucleoside-nucleotide pool in GSCs. The phenotypic changes in E-NPP1-deficient GSCs are assumed to be a consequence of decreased transcriptional function of E2F1. Together, these results reveal that E-NPP1, by acting upstream of E2F1, is indispensable for the maintenance of GSCs in vitro and hence required to keep GSCs in an undifferentiated, proliferative state.
    Type of Publication: Journal article published
    PubMed ID: 24531536
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  • 7
    Keywords: GENE-EXPRESSION ; BREAST-CANCER ; CRYSTAL-STRUCTURE ; BRAIN-TUMORS ; MOLECULAR-MECHANISMS ; COORDINATION-COMPLEXES ; HUMAN GLUTATHIONE-REDUCTASE ; THIOREDOXIN REDUCTASE INHIBITION ; PHOSPHINE GOLD(I) COMPLEXES ; ANTICANCER THERAPEUTICS
    Abstract: Glioblastoma, an aggressive brain tumor, has a poor prognosis and a high risk of recurrence. An improved chemotherapeutic approach is required to complement radiation therapy. Gold(I) complexes bearing phosphole ligands are promising agents in the treatment of cancer and disturb the redox balance and proliferation of cancer cells by inhibiting disulfide reductases. Here, we report on the antitumor properties of the gold(I) complex 1-phenyl-bis(2-pyridyl)phosphole gold chloride thio-beta-d-glucose tetraacetate (GoPI-sugar), which exhibits antiproliferative effects on human (NCH82, NCH89) and rat (C6) glioma cell lines. Compared to carmustine (BCNU), an established nitrosourea compound for the treatment of glioblastomas that inhibits the proliferation of these glioma cell lines with an IC50 of 430muM, GoPI-sugar is more effective by two orders of magnitude. Moreover, GoPI-sugar inhibits malignant glioma growth in vivo in a C6 glioma rat model and significantly reduces tumor volume while being well tolerated. Both the gold(I) chloro- and thiosugar-substituted phospholes interact with DNA albeit more weakly for the latter. Furthermore, GoPI-sugar irreversibly and potently inhibits thioredoxin reductase (IC50 4.3nM) and human glutathione reductase (IC50 88.5nM). However, treatment with GoPI-sugar did not significantly alter redox parameters in the brain tissue of treated animals. This might be due to compensatory upregulation of redox-related enzymes but might also indicate that the antiproliferative effects of GoPI-sugar in vivo are rather based on DNA interaction and inhibition of topoisomerase I than on the disturbance of redox equilibrium. Since GoPI-sugar is highly effective against glioblastomas and well tolerated, it represents a most promising lead for drug development. This article is part of a Special Issue entitled: Thiol-Based Redox Processes.
    Type of Publication: Journal article published
    PubMed ID: 24440405
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  • 8
  • 9
    Keywords: brain ; CELLS ; EXPRESSION ; IN-VITRO ; IN-VIVO ; VITRO ; PROTEIN ; PATIENT ; TISSUES ; ANTIGEN ; T-CELLS ; IDENTIFICATION ; PROGRESSION ; PEPTIDES ; IMMUNOTHERAPY ; MALIGNANT GLIOMA ; HUMAN BRAIN-TUMORS ; GLIOBLASTOMA ; CHONDROITIN SULFATE PROTEOGLYCAN ; LYMPHOCYTE ; AVIDITY ; peptidome ; TENASCIN-C ; tumour antigen ; tumour-infiltrating lymphocytes ; V-BETA REPERTOIRE
    Abstract: Peptides presented at the cell surface reflect the protein content of the cell; those on HLA class I molecules comprise the critical peptidome elements interacting with CD8 T lymphocytes. We hypothesize that peptidomes from ex vivo tumour samples encompass immunogenic tumour antigens. Here, we uncover 〉6000 HLA-bound peptides from HLA-A*02(+) glioblastoma, of which over 3000 were restricted by HLA-A*02. We prioritized in-depth investigation of 10 glioblastoma-associated antigens based on high expression in tumours, very low or absent expression in healthy tissues, implication in gliomagenesis and immunogenicity. Patients with glioblastoma showed no T cell tolerance to these peptides. Moreover, we demonstrated specific lysis of tumour cells by patients' CD8(+) T cells in vitro. In vivo, glioblastoma-specific CD8(+) T cells were present at the tumour site. Overall, our data show the physiological relevance of the peptidome approach and provide a critical advance for designing a rational glioblastoma immunotherapy. The peptides identified in our study are currently being tested as a multipeptide vaccine (IMA950) in patients with glioblastoma.
    Type of Publication: Journal article published
    PubMed ID: 22418738
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  • 10
    Keywords: RECEPTOR ; GROWTH ; IN-VITRO ; INVASION ; DISEASE ; LINES ; ACTIVATED MACROPHAGES ; BIOLOGY ; HEALTH ; ASSAY ; CANCER-CELLS ; IMMUNOTHERAPY ; inflammation ; GLIOMA ; GLIOMA-CELLS ; GLIOBLASTOMA ; INNATE IMMUNE-RESPONSES ; ASTROCYTES ; antitumor response ; human microglia ; poly (I:C)
    Abstract: The role of microglia, the brain-resident macrophages, in glioma biology is still a matter of debate. Clinical observations and in vitro studies in the mouse model indicate that microglia and macrophages that infiltrate the brain tumor tissue in high numbers play a tumor-supportive role. Here, we provide evidence that human microglia isolated from brain tumors indeed support tumor cell growth, migration, and invasion. However, after stimulation with the Toll-like receptor 3 agonist poly (I:C), microglia secrete factors that exerted toxic and suppressive effects on different glioblastoma cell lines, as assessed in cytotoxicity, migration, and tumor cell spheroid invasion assays. Remarkably, these effects were tumor-specific because the microglial factors impaired neither growth nor viability of astrocytes and neurons. Culture supernatants of tumor cells inhibited the poly (I:C) induction of this microglial M1-like, oncotoxic profile. Microglia stimulation before coculture with tumor cells circumvented the tumor-mediated suppression, as demonstrated by the ability to kill and phagocytose glioma cells. Our results show, for the first time to our knowledge, that human microglia exert tumor-supporting functions that are overridden by tumor-suppressing activities gained after poly (I:C) stimulation.
    Type of Publication: Journal article published
    PubMed ID: 22015597
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