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  • 1
    Abstract: This volume mainly contains information on the diagnosis, therapy, and prognosis of brain tumors. Insights on the understanding of molecular pathways involved in tumor biology are explained, which should lead to the development of effective drugs. Information on pathways (e.g., hedgehog) facilitates targeted therapies in cancer. Tumor models are also presented, which utilize expression data, pathway sensitivity, and genetic abnormalities, representing targets in cancer. For example, rat model of malignant brain tumors using implantation of doxorubicin with drug eluting beads for delivery is explained. The future of pathway-driven therapies for tumors is summarized. The importance of personalizing cancer care is emphasized. The need for supportive measures for survivors of brain cancer is pointed out, so is the quality of life monitoring. The need of rehabilitation therapy for patients with primary and metastatic brain tumors is also emphasized. Role of MicroRNA in distinguishing primary tumors from metastatic primary tumors is discussed. Advantages and limitations of chemotherapy (e.g., temozolomide and doxorubicin) are discussed. The complexity of tumor to tumor transfer is explained; examples discussed are: brain metastases from breast cancer and brain metastases fro non-small cell lung carcinoma. Identification and characterization of biomarkers, including those for metastatic brain tumors, are presented. Genomic analysis for identifying clinically relevant subtypes of glioblastoma is included. A large number of imaging modalities are detailed to study progression and invasion of gliomas
    Type of Publication: Book chapter
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  • 2
    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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  • 3
    Keywords: adhering junctions, AREA-COMPOSITA, ASTROCYTES, BLOOD-BRAIN-BARRIER, CELLS, DOMAINS, endothelial cel
    Abstract: The genes encoding transmembrane glycoproteins of the cadherin family, i.e., the Ca2+-dependent cell-cell adhesion molecules, are typically expressed in cell-type- or cell-lineage-specific patterns. One of them, vascular endothelial (VE)-cadherin, is widely considered to be specific for vascular endothelia in which it is either the sole or the predominant cadherin, often co-existing with N-cadherin. This specificity of VE-cadherin for vascular endothelial cells is important not only in blood and lymph vessel biology and medicine, but also for cell-type-based diagnoses, notably those of metastatic tumors. Surprisingly, however, we have recently noted the frequent synthesis, surface exposure, and junction assembly of VE-cadherin in certain other cells, in which this glycoprotein is clustered into adherens junctions (AJs), either alone or in combination with N-cadherin and/or cadherin-11. Such cells include mammalian astrocytes and glioma, probably mostly astrocytoma cells growing in culture, and a specific subtype of astrocytoma in situ. Moreover, VE-cadherin synthesis and AJ assembly, plus the regional clustering of such AJs in certain domains, are not clonally fixed but can appear again and again in cells of the progeny of cloned homogeneous-appearing individual cells, thus resulting in clonal cell colonies that are often heterogeneous in their cadherin junction patterns. We discuss the constitutive presence of VE-cadherin in some non-endothelial cells with respect to certain architectural features and possible physiological and pathogenic functions of the cells, and in comparison with recent reports of VE-cadherin-positive melanomas
    Type of Publication: Journal article published
    PubMed ID: 19002500
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  • 4
    Keywords: IONIZING-RADIATION ; KINASE ; PHOSPHORYLATION ; REPAIR ; IN-SITU HYBRIDIZATION ; MAMMALIAN-CELLS ; DOUBLE-STRAND BREAKS ; HISTONE H2AX ; PULSED-FIELD ELECTROPHORESIS ; LET RADIATION
    Abstract: Purpose: To investigate chromosomal instability and radiation response mechanisms in glioblastoma cells. Methods and materials: We undertook a comparative analysis of two patient-derived glioblastoma cell lines. Their resistance to low and high linear energy transfer (LET) radiation was assessed using clonogenic survival assay and their intrinsic chromosome instability status using fluorescence in situ hybridization. DNA damage was analyzed by pulsed-field gel electrophoresis and by gamma-H2AX foci quantification. Expression of DNA damage response proteins was assessed by immunoblot. Results: Increased radioresistance to X-rays as well as carbon ions was observed in glioblastoma cells exhibiting high levels of naturally occurring chromosomal instability and impaired Ataxia-telangiectasia mutated (ATM) signaling, as reflected by lack of phosphorylation of ATM, CHK2 and p53 after double-strand breaks induction Conclusion: Our results indicate the existence of highly radioresistant glioblastoma cells, characterized by dysfunctional ATM signaling and high levels of intrinsic chromosomal instability.
    Type of Publication: Journal article published
    PubMed ID: 24991884
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  • 5
    Keywords: METABOLISM ; RELEASE ; RECEPTORS ; CNS ; BRAIN-TUMORS ; MALIGNANT GLIOMAS ; TRANSPORTERS ; CYSTINE/GLUTAMATE ANTIPORTER ; ACTIVATED MICROGLIA ; AMPA-TYPE
    Abstract: Glioblastoma cells produce and release high amounts of glutamate into the extracellular milieu and subsequently can trigger seizure in patients. Tumor-associated microglia/macrophages (TAMs), consisting of both parenchymal microglia and monocytes-derived macrophages (MDMs) recruited from the blood, are known to populate up to 1/3 of the glioblastoma tumor environment and exhibit an alternative, tumor-promoting and supporting phenotype. However, it is unknown how TAMs respond to the excess extracellular glutamate in the glioblastoma microenvironment. We investigated the expressions of genes related to glutamate transport and metabolism in human TAMs freshly isolated from glioblastoma resections. Quantitative real-time PCR analysis showed (i) significant increases in the expressions of GRIA2 (GluA2 or AMPA receptor 2), SLC1A2 (EAAT2), SLC1A3 (EAAT1), (ii) a near-significant decrease in the expression of SLC7A11 (cystine-glutamate antiporter xCT) and (iii) a remarkable increase in GLUL expression (glutamine synthetase) in these cells compared to adult primary human microglia. TAMs co-cultured with glioblastoma cells also exhibited a similar glutamatergic profile as freshly isolated TAMs except for a slight increase in SLC7A11 expression. We next analyzed these genes expressions in cultured human MDMs derived from peripheral blood monocytes for comparison. In contrast, MDMs co-cultured with glioblastoma cells compared to MDMs co-cultured with normal astrocytes exhibited decreased expressions in the tested genes except for GLUL. This is the first study to demonstrate transcriptional changes in glutamatergic signaling of TAMs in a glioblastoma microenvironment, and the findings here suggest that TAMs and MDMs might potentially elicit different cellular responses in the presence of excess extracellular glutamate.
    Type of Publication: Journal article published
    PubMed ID: 26047211
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  • 6
    Keywords: brain ; RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; CELL ; Germany ; DEATH ; POPULATION ; TISSUE ; MACROPHAGES ; MARKER ; RECOGNITION ; MOUSE ; prevention ; PHAGOCYTOSIS ; MARKERS ; DAMAGE ; NETHERLANDS ; CLEARANCE ; CENTRAL-NERVOUS-SYSTEM ; RECEPTORS ; microglia ; MULTIPLE-SCLEROSIS ; mannose receptor ; SUBPOPULATION ; RE ; BRAIN-TUMORS ; GLIOMA ; GLIOMA-CELLS ; FUNCTIONAL-CHARACTERIZATION ; cell death ; APOPTOTIC CELLS ; immunology ; STRAIN
    Abstract: Microglia phagocytic activity for apoptotic glioma cells is hardly analysed inspite of its relevance to tissue damage prevention. We provide evidence for a phosphatidyl serine-independent clearance of mouse glioma cells at an advanced stage of death, suggesting microglia recognition of late apoptotic markers. Dying cells were immediately cleared or stayed for hours in that stage before engulfment occurred. This phagocytic activity was restricted to a microglia subset representing 30 to 70% of the population according to the used strain. Expression of receptors involved in late apoptotic markers recognition therefore seems confined to a subpopulation of microglia and to be strain-dependent. (C) 2008 Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 18495256
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  • 7
    Keywords: CANCER ; INDUCTION ; SIGNALING PATHWAYS ; OXIDATIVE STRESS ; GLUTATHIONE-PEROXIDASE ; unfolded protein response ; MALIGNANT GLIOMA-CELLS ; SERINE PALMITOYLTRANSFERASE ; ER STRESS ; SPHINGOSINE-1-PHOSPHATE
    Abstract: Glioblastomas (GBMs) are very aggressive tumors with low chemosensitivity. The DNA-alkylating agent temozolomide (TMZ) is currently the most efficient chemotoxic drug for GBM therapy; however, many patients develop resistance to TMZ. Combining TMZ with another agent could present an improved treatment option if it could overcome TMZ resistance and avoid side effects. Sphingosine kinase inhibitors (SKIs) have emerged as anticancer agents. Sphingosine kinases are often overexpressed in tumors where their activity of phosphorylating sphingosine (Sph) contributes to tumor growth and migration. They control the levels of the pro-apoptotic ceramide (Cer) and Sph and of the pro-survival sphingosine-1 phosphate. In the present work, TMZ was combined with a specific SKI, and the cytotoxic effect of each drug alone or in combination was tested on GBM cell lines. The combination of sublethal doses of both agents resulted in the cell death potentiation of GBM cell lines without affecting astrocyte viability. It triggered a caspase-3-dependent cell death that was preceded by accumulation of dihydrosphingosine (dhSph) and dihydroceramide (dhCer), oxidative stress, endoplasmic reticulum stress, and autophagy. Autophagy was identified as the crucial switch that facilitated induction of this cell death potentiation. The sublethal dose of the inhibitor induced these stress events, whereas that of TMZ induced the destructive autophagy switch. Remarkably, neither Cer nor Sph, but rather the Cer intermediates, dhSph and dhCer, was involved in the cytotoxicity from the combination. Cell lines sensitive to the combination expressed low levels of the antioxidant enzyme glutathione peroxidase-1, indicating this enzyme as a potential marker of sensitivity to such treatment. This work shows for the first time a strong interaction between a SKI and TMZ, leading to a tumor cell-specific death induction. It further demonstrates the biological relevance of dihydrosphingolipids in cell death mechanisms and emphasizes the potential of drugs that affect sphingolipid metabolism for cancer therapy.
    Type of Publication: Journal article published
    PubMed ID: 25255218
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  • 8
    Abstract: Glioblastoma multiforme (GBM) exhibits high resistance to the standard treatment of temozolomide (TMZ) combined with radiotherapy, due to its remarkable cell heterogeneity. Accordingly, there is a need to target alternative molecules enhancing specific GBM autocrine or paracrine mechanisms and amplifying the effect of standard treatment. Sphingosine 1-phosphate (S1P) is such a lipid target molecule with an important role in cell invasion and proliferation. Sphingosine kinase inhibitors (SKI) prevent S1P formation and induce increased production of reactive oxygen species (ROS), which may potentiate radiation cytotoxicity. We analyzed the effect of SKI singular versus combined treatments with TMZ and radiation on 2 human GBM cell lines characterized by a lack of MGMT expression and low or high expression of the anti-oxidant enzyme, glutathione peroxidase 1 (GPx1). Effects were drug concentration-, cell line-dependent and partly ROS-mediated. Clonogenic survival assay demonstrates that SKI was more effective than TMZ in increasing the sensitivity of U87 cells, which express low GPx1 amount, to a 2 Gy X-ray dose. Addition of both SKI and TMZ drastically decreased U87 cells survival compared with the combination temozolomide/radiation. SKI less effectively than TMZ sensitized LN229 cells to the 2 Gy X-ray dose. Its combination to TMZ in absence of irradiation was as efficient as TMZ combination with X-ray. We provide first evidence for SKI as an alternative or complementary treatment to TMZ, and for efficient combinations of low doses of drugs and X-ray. These may help as novel bi-modal and tri-modal therapies to contend with GBM heterogeneity.
    Type of Publication: Journal article published
    PubMed ID: 28494176
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  • 9
    Keywords: brain ; CELLS ; EXPRESSION ; IN-VITRO ; SURVIVAL ; AGENTS ; Germany ; MODEL ; THERAPY ; GENE ; PROTEIN ; PROTEINS ; gene therapy ; MICE ; TUMOR-NECROSIS-FACTOR ; IFN-GAMMA ; INFECTION ; ALPHA ; culture ; MOUSE ; VECTOR ; NECROSIS-FACTOR-ALPHA ; CELL-LINE ; LINE ; MINUTE VIRUS ; REPLICATION ; MOUSE MODEL ; INTERFERON ; sensitivity ; autonomous parvovirus ; mannose receptor ; CYTOTOXICITY ; FACTOR-ALPHA ; BRAIN-TUMORS ; CAPACITY ; GLIOMA ; parvovirus ; VIRIONS ; FUNCTIONAL-CHARACTERIZATION ; astrocytoma ; uptake ; CANDIDATE ; glial cells ; IMMUNE FUNCTION ; lipopolysaccharide ; MICROGLIAL CELLS
    Abstract: The sensitivity of brain tumour cells to wild-type or recombinant parvoviruses H1-PV and MVMp makes these agents promising candidates for gene therapy of astrocytoma. This application raises the question of whether parvoviruses exert deleterious or bystander effects on normal glial cells surrounding tumours. We addressed this question in the mouse model by using cell cultures derived from BALB/c, C57BL/6 and VM/Dk strains. Astrocytes and a large proportion of microglia cultures were competent for MVMp uptake. Infection was, however, abortive as replication-associated viral proteins synthesis took place in less than 10% of astrocytes and no progeny virions were produced. This restriction was even more pronounced for microglia in which no viral protein expression could be detected, save for a minute fraction of VM/Dk-derived cells. Infection with MVMp had no significant effect on glial cell survival and did not interfere with their immune potential. Indeed, neither the lipopolysaccharide (LPS)/interferon (IFN-gamma)-induced cytotoxicity of VM/Dk-derived microglia towards the mouse glioma (MT539MG) cell line, nor the glial cells capacity for tumour necrosis factor alpha production upon LPS stimulation or LPS/IFN-gamma stimulation were affected by infection with MVMp. Moreover, stimulation with LPS and/or IFN-gamma resulted in a decreased expression of the viral replicative and cytotoxic protein NS1. Together, our data indicate that, in the natural host, a majority of normal glial cells are not competent for MVMp replication and that the abortive infection taking place in a minor fraction of these cells fails to impede their survival and immunocompetence, giving credit to the consideration of autonomous parvoviruses for glioma therapy
    Type of Publication: Journal article published
    PubMed ID: 16699801
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  • 10
    Keywords: RECEPTOR ; CELLS ; ENDOTHELIAL-CELLS ; IN-VITRO ; CELL ; INHIBITION ; SYSTEM ; PROTEIN ; LIGAND ; IFN-GAMMA ; MACROPHAGES ; murine ; ANTIGEN ; DENDRITIC CELLS ; antibody ; GLYCOPROTEIN ; MOUSE-BRAIN ; NERVOUS-SYSTEM ; innate immunity ; FLOW-CYTOMETRY ; INTERFERON-GAMMA ; rodent ; SERUM ; PERIPHERAL-NERVE ; FUNCTIONAL-CHARACTERIZATION ; CLASS-II ; MOLECULAR-MECHANISMS ; USA ; macrophage ; PATTERN-RECOGNITION RECEPTOR ; NERVE INJURY ; STATE ; CULTURES ; SCHWANN-CELLS ; ENDOCYTIC ACTIVITY ; glia ; mannosylated protein ; NONLYMPHOID ORGANS ; pattern recognition receptor
    Abstract: The mannose receptor (MR) is a transmembrane glycoprotein, postulated to be a link between innate and adaptive immunity. MR is expressed in several cell types but no information is available on that for Schwann cells (SC). We show that rodent SC in primary cultures take up the MR ligand mannosyl/bovine serum albumin-fluorescein isothiocyanate (man/BSA-FITC) in a highly specific manner and bind an antibody against the C-terminus of the murine macrophage MR (anti-cMR). After incubation with man/BSA-FITC, flow cytometry demonstrates 90% positive SC, a dose-dependent increase in tagged cellular components and near total inhibition of the neoglycoprotein uptake by d-mannose or by the mannosylated protein horseradish peroxidase (HRP). Western blot for MR shows that SC share a unique protein of about 180 kDa with peritoneal resident macrophages. Treatment of cultured SC with interferon-gamma (IFN-gamma) or dexamethasone (DM) followed by the addition of man/BSA-FITC and analysis by flow cytometry shows down- or upregulation, respectively, of man/BSA-FITC uptake. Our results show that SC express the MR in a prospectively functional state and suggest an antigen-presenting function of SC, compatible with a role in infectious/inflammatory states of the peripheral nervous system
    Type of Publication: Journal article published
    PubMed ID: 19691530
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