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  • 1
    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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  • 2
    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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  • 3
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; proliferation ; SURVIVAL ; tumor ; CELL ; CELL LUNG-CANCER ; Germany ; IN-VIVO ; INHIBITION ; MODEL ; VITRO ; VIVO ; DEATH ; PROTEIN ; PROTEINS ; DRUG ; LIGAND ; FAMILY ; INDUCTION ; BINDING ; BIOLOGY ; DOWN-REGULATION ; MOLECULAR-BIOLOGY ; MOLECULE ; PROGRESSION ; resistance ; CELL-DEATH ; TUMOR PROGRESSION ; genetics ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; EFFICIENT ; BAX ; ONCOGENE ; STEM-CELLS ; OVEREXPRESSION ; heredity ; TRAIL ; GLIOMAS ; Bcl-2 ; CYTOTOXICITY ; SUBPOPULATION ; signaling ; molecular biology ; molecular ; ONCOLOGY ; RE ; FAMILIES ; GLIOMA ; GLIOMA-CELLS ; MALIGNANT GLIOMA ; MALIGNANT GLIOMAS ; DEFECTS ; brain tumors ; stem cells ; LEVEL ; cell death ; CHEMOTHERAPEUTIC DRUGS ; IMMUNOHISTOCHEMICAL ANALYSIS ; DRUGS ; ENGLAND ; GLIOBLASTOMA ; GROWTH-FACTOR-RECEPTOR ; STEM ; MCL-1 ; Bcl-2 family proteins ; xenograft ; NOV ; BCL-2 FAMILY ; response ; CELL BIOLOGY ; PARTNER ; SMALL-MOLECULE ; CRUCIAL ROLE ; CHEMOTHERAPEUTIC-AGENTS ; ABT-737 ; Bcl-2 inhibitor ; BH3 MIMETIC ABT-737 ; HUMAN-MALIGNANT GLIOMA
    Abstract: Defects in the apoptotic signaling cascades contribute to the poor therapeutic response of malignant gliomas. As glioblastomas are characterized by high expression levels of anti-apoptotic Bcl-2 family proteins, we studied the effects of the novel Bcl-2 inhibitor, ABT-737, on malignant glioma cells. ABT-737 treatment released the pro-apoptotic Bax protein from its binding partner Bcl-2 and potently induced apoptotic cell death in glioblastoma cells in vitro and in vivo. The local administration of ABT-737 prolonged the survival in an intracranial glioma xenograft model. Downregulation of Mcl-1 and overexpression of Bcl-2 sensitized the cells to ABT-737mediated apoptosis. Moreover, ABT-737 potentiated the cytotoxicity of the chemotherapeutic drugs vincristine and etoposide, and of the death ligand TRAIL. As glioma stem cells may play a crucial role for the tumor progression and the resistance to treatment in glioblastomas, we investigated the effects of ABT-737 on the subpopulation of glioma cells exhibiting stem cell characteristics. Inhibition of proliferation and induction of apoptosis by ABT-737 were less efficient in glioma stem cells than in non-stem cell-like glioma cells. As the resistance of glioma stem cells was associated with high Mcl-1 expression levels, ABT-737 treatment combined with downregulation of Mcl-1 could represent a promising novel approach in glioblastoma treatment
    Type of Publication: Journal article published
    PubMed ID: 18663354
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  • 4
    Keywords: brain ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; SURVIVAL ; tumor ; CELL ; Germany ; SUPPORT ; LONG-TERM ; RISK ; PROTEIN ; TISSUE ; TUMORS ; TIME ; PATIENT ; MARKER ; primary ; prognosis ; TISSUES ; ANTIGEN ; NERVOUS-SYSTEM ; IDENTIFICATION ; PROGRESSION ; immunohistochemistry ; DESIGN ; AGE ; PROGNOSTIC-FACTORS ; RESECTION ; CANCER-CELLS ; MULTIVARIATE ; PROGNOSTIC FACTORS ; SERIES ; ORGANIZATION ; PROGNOSTIC FACTOR ; CLUSTERS ; GLIOMAS ; CLUSTER ; SUBPOPULATION ; ONCOLOGY ; RE ; TUMOR-GROWTH ; PATIENT SURVIVAL ; GLIOMA ; overall survival ; GRADE ; MALIGNANT PROGRESSION ; PROGNOSTIC-FACTOR ; TUMOR TISSUE ; analysis ; survival analysis ; HISTOLOGY ; USA ; correlation ; cancer research ; RISK-FACTOR ; EXTENT ; GLIOBLASTOMA ; STEM ; correlates ; PROGRESSION-FREE SURVIVAL ; AC133 ; PROMININ
    Abstract: Purpose: The CD133 antigen has been identified as a putative stem cell marker in normal and malignant brain tissues. In gliomas, it is used to enrich a subpopulation of highly tumorigenic cancer cells. According to the cancer stem cell hypothesis, CD133-positive cells determine long-term tumor growth and, therefore, are suspected to influence clinical outcome. To date, a correlation between CD133 expression in primary tumor tissues and patients' prognosis has not been reported. Experimental Design: To address this question, we analyzed the expression of the CD133 stem cell antigen in a series of 95 gliomas of various grade and histology by immunohistochemistry on cryostat sections. Staining data were correlated with patient outcome. Results: By multivariate survival analysis, we found that both the proportion of CD133-positive cells and their topological organization in clusters were significant (P 〈 0.001) prognostic factors for adverse progression-free survival and overall survival independent of tumor grade, extent of resection, or patient age. Furthermore, proportion of CD133-positive cells was an independent risk factor for tumor regrowth and time to malignant progression in WHO grade 2 and 3 tumors. Conclusions: These findings constitute the first conclusive evidence that CD133 stem cell antigen expression correlates with patient survival in gliomas, lending support to the current cancer stem cell hypothesis
    Type of Publication: Journal article published
    PubMed ID: 18172261
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