Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The myelodysplasia/myeloid leukemia factor 1-interacting protein MLF1IP is a novel gene which encodes for a putative transcriptional repressor. It is localized to human chromosome 4q35.1 and is expressed in both the nuclei and cytoplasm of cells. Northern and Western blot analyses have revealed MLF1IP to be present at very low amounts in normal brain tissues, whereas a number of human and rat glioblastoma (GBM) cell lines demonstrated a high level expression of the MLF1IP protein. Immunohistochemical analysis of rat F98 and C6 GBM tumor models showed that MLF1IP was highly expressed in the tumor core where it was co-localized with MLF1 and nestin. Moreover, MLF1IP expression was elevated in the contralateral brain where no tumor cells were detected. These observations, together with previous data demonstrating a role for MLF1IP in erythroleukemias, suggest a possible function for this protein in glioma pathogenesis and potentially in other types of malignancies.
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PMID:Regulation of myeloid leukemia factor-1 interacting protein (MLF1IP) expression in glioblastoma. 1589 39

D2-40 antibody is raised against an oncofetal antigen, the M2A antigen. It has been used as a marker for lymphatic endothelium as well as mesothelioma and cerebellar hemangioblastoma. We demonstrate here that positive D2-40 immunoreactivity was found in the developing cerebrum, particularly in the germinal matrix layer, immature ependyma, choroid plexus and meninges. In the developing cerebellum, positive D2-40 immunoreactivity was found in the external granular layer particularly of the outer portion and the Purkinje cell layer as well as meninges. Some brain tumors such as anaplastic ependymoma, some medulloblastomas, glioblastoma, pineal germinoma, craniopharyngioma, choroid plexus papilloma, choroid plexus carcinoma, and meningioma showed positive immunoreactivity with D2-40. Therefore, D2-40 antibody is considered a useful marker for research on developing brain and diagnosis of brain tumors, differentiation between choroid plexus carcinoma and metastatic carcinoma. In addition, on cultured human neural cells, D2-40 immunoreactivity was found in nestin-positive neural stem/progenitor cells and neuronal lineage cells. As D2-40 antibody recognizes cell surface antigen M2A, it might be a candidate cell surface marker for isolation of human neural stem cells/neuronal lineage cells in the fluorescence-activated cell sorting technique.
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PMID:D2-40 antibody immunoreactivity in developing human brain, brain tumors and cultured neural cells. 1664 67

We investigated in vitro the properties of selected populations of cancer stem-like cells defined as tumorospheres that were obtained from human glioblastoma. We also assessed their potential and capability of differentiating into mature cells of the central nervous system. In vivo, their tumorigenicity was confirmed after transplantation into the brain of non-obese diabetic/severe combined immunodeficient (NOD-SCID) mice. The angiogenic potential of tumorospheres and glioblastoma-derived cells grown as adherent cells was revealed by evaluating the release of angiogenic factors such as vascular endothelial growth factor and CXCL12 by ELISA, as well as by rat aortic ring assay. The proliferative response of tumorospheres in the presence of CXCL12 was observed for the first time. Multidrug resistance-associated proteins 1 and 3 as well as other molecules conferring multidrug resistance were higher when compared with primary adherent cells derived from the same tumor. Finally, we obtained cells from the tumor developing after grafting that clearly expressed the putative neural stem cell marker CD133 as shown by FACS analysis and also nestin and CXCR4. The cells' positivity for glial fibrillary acidic protein was very low. Moreover these cells preserved their angiogenic potential. We conclude that human glioblastoma could contain tumor cell subsets with angiogenic and chemoresistance properties and that this chemoresistance potential is highly preserved by immature cells whereas the angiogenic potential is, to a higher extent, a property of mature cells. A better understanding of the features of these cell subsets may favor the development of more specifically targeted therapies.
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PMID:Glioblastoma-derived tumorospheres identify a population of tumor stem-like cells with angiogenic potential and enhanced multidrug resistance phenotype. 1698 Nov 97

The notion that gliomas could originate from mutated glial precursor cells highlights the possibility of modulating the proliferative and migratory behaviour of glioma cells by acting on the molecular mechanisms operative during the development of the Central Nervous System (CNS), but absent in the normal adult brain. We show that the GL15 glioblastoma derived human cell line displays a high expression of nestin which, combined with the previously demonstrated high expression of vimentin, constitutes a characteristic of astrocyte restricted precursors. We also show that, in analogy with some leukaemia cells, GL15 cells display the constitutively phosphorylated form of Janus kinase 2 (JAK2), a tyrosine kinase expressed during CNS development but undetectable in the normal adult brain. The constitutive activation of JAK2 does not result from chromosomal aberrations involving the JAK2 gene, but most probably from abnormally activated transduction systems operative in glioblastoma cells. We then investigated the effects of tyrphostin AG490, an inhibitor of JAK2 autophosphorylation, on GL15 cell growth. In the absence of exogenous growth factors and cytokines, 10 microM tyrphostin AG490 induces an S phase arrest, combined with a partial impairment of the G2 phase of the cell cycle. The abnormally activated JAK2 could then potentially represent a target for a selective pharmacological approach in glioblastoma cells in which a combination of glial precursor characteristics and genetic alterations occurs.
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PMID:Constitutive phosphorylation of Janus kinase 2 in the GL15 glioblastoma derived human cell line. 1714 73

Phenotypic guidance of embryonic stem (ES) cell fate is paramount if these cells are to be used for tissue repair and regeneration. Our objective was to compare two different cell culture feeders and their effect on proliferation, apoptosis, and differentiation of human (h) ES cells. HSF-6 hES cells were grown in Knockout Dulbecco's modified Eagle medium (DMEM) on mouse embryonic fibro-blasts (MEFs) or U87 glioblastoma cells at densities of 50,000, 100,000, and 150,000 cells/well of a six-well plate for 7, 12, and 19 days. Immunocytochemistry was performed for bromodeoxyuridine (BrdU), TUNEL, and neural differentiation markers including class III beta-tubulin, NeuN, nestin, and doublecortin. Slides were examined by laser confocal microscopy with semiquantitative analyses of marker expression. BrdUand TUNEL-positive cells were primarily, but not exclusively, at edges and between established colonies. BrdU expression was higher on U87 feeders at low and intermediate densities at day 19. Both feeders demonstrated higher BrdU expression at day 7 compared to days 12 and 19. U87 produced more TUNEL-positive cells than MEFs with increasing numbers with increasing density and time in culture. Nuclear Oct-4 staining was seen only at day 7. MEFs appeared to promote greater neural differentiation of hES cells than U87. We conclude hES cells grown on U87 feeders demonstrate greater numbers of apoptotic cells and BrdU-positive cells at day 19. Independent of the feeders, proliferation and apoptosis may be positively correlated. We speculate differences in proliferation, apoptosis, and neural differentiation may be due to differential elaboration of specific cytokines by MEFs and U87.
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PMID:Human embryonic stem cells (HSF-6) show greater proliferation and apoptoses when grown on glioblastoma cells than mouse embryonic fibroblasts at day 19 in culture: comparison of proliferation, survival, and neural differentiation on two different feeder cell types. 1761 Mar 70

The anti-neoplastic effects of histone deacetylase inhibitors (HDACi), Trichostatin A (TSA) and 4-phenylbutyrate (4-PB) on the human glioblastoma cell lines GBM-29, U-343 MG and U-343 MGa Cl. 2:6 were investigated. TSA and 4-PB induced apoptosis in the three cell lines in a dose- and time-dependent manner. Whereas caspase-3 activation was detected in all three cell lines, U-343 MG cells were more sensitive to the apoptotic effect of HDACi compared with U-343 MGa Cl. 2:6. TSA and 4-PB induced differentiation in the three cell lines, each cell line developing unique phenotypic characteristics. During long-term treatment with a low dose of HDACi U-343 MGa Cl. 2:6 cells developed an astrocytic morphology with expression of glial fibrillary acidic protein (GFAP). GFAP-negative U-343 MG cells changed their morphology in response to HDACi and down-regulated their expression of vimentin. The nestin and vimentin positive GBM-29 cells also showed a morphological differentiation, while the expression of the two malignancy markers decreased. In summary, our results showed that these three glioblastoma cell lines display unique phenotypes and differentiation patterns in response to HDACi.
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PMID:HDAC inhibitors effectively induce cell type-specific differentiation in human glioblastoma cell lines of different origin. 1836 Jul 9

Despite recent technical improvements in surgical excision techniques and adjuvant radio- and chemotherapy, the clinical outcome of patients with grade IV astrocytoma (glioblastoma) remains very poor, with a median survival of less than 12 months. A promising approach to therapy employs gene-engineered neural stem/progenitor cells (NSCs) as a cellular therapeutic delivery system, to track glioblastoma cells and deliver anticancer molecules. However, most results on their tumor tropism have been derived by immortalized NSCs. We now report that primary murine gene-engineered NSCs displayed in vivo tropism for glioblastoma cells. Ten days after injection into the brain, many NSCs continued to express the transgene and the NSC marker, nestin. NSCs transduced with a retroviral vector co-expressing a secretable form of human endostatin and eGFP (NSC/endo-eGFP) released potentially antiangiogenetic concentrations of endostatin into the culture medium. Conditioned medium of NSC/endo-eGFP cells inhibited the growth of mouse pulmonary microvascular endothelial cells (PMVECs). A good correlation between endostatin levels and PMVEC growth inhibition was observed. In NSCs co-expressing cytochrome P450 2B6 (CYP2B6) and eGFP (NSC/CYP2B6-eGFP), the forced expression of CYP2B6 resulted in intracellular activation of CPA and subsequent cell death. In the presence of NSC/CYP2B6-eGFP, we observed CPA cytotoxicity to DsRed-expressing U87Mg glioma cells. In vivo treatment of intracranial GL-261 glioblastoma with NSC/endo-eGFP caused a 65% reduction in tumor size, compared to untreated control mice or mice treated with NSC/eGFP cells. Our data suggest that primary NSCs transduced with retroviral vectors expressing endostatin and/or CYP2B6 have a potential role in glioblastoma therapy.
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PMID:Primary neural stem/progenitor cells expressing endostatin or cytochrome P450 for gene therapy of glioblastoma. 1842 9

Besides the role of normal stem cells in organogenesis, cancer stem cells are thought to be crucial for tumorigenesis. Most current research on human tumors is focused on molecular and cellular analysis of the bulk tumor mass. However, evidence in leukemia and, more recently, in solid tumors suggests that the tumor cell population is heterogeneous. In recent years, several groups have described the existence of a cancer stem cell population in different brain tumors. These neural cancer stem cells (NCSC) can be isolated by cell sorting of dissociated suspensions of tumor cells for the neural stem cell marker CD133. These CD133+ cells -which also express nestin, an intermediate filament that is another neural stem cell marker- represent a small fraction of the entire brain tumor population. The stem-like cancer cells appear to be solely responsible for propagating the disease in laboratory models. A promising new approach to treating glioblastoma proposes targeting cancer stem cells. Here, we summarize progress in delineating NCSC and the implications of the discovery of this cell population in human brain tumors.
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PMID:Cancer stem cells and brain tumors. 1849 Feb 42

Glioblastomas often show activation of epidermal growth factor receptor (EGFR) and loss of PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor, but it is not known if these two genetic lesions act together to transform cells. To answer this question, we infected PTEN-/- neural precursor cells with a retrovirus encoding EGFRvIII, which is a constitutively activated receptor. EGFRvIII PTEN-/- cells formed highly mitotic tumors with nuclear pleomorphism, necrotic areas, and glioblastoma markers. The transformed cells showed increased cell proliferation, centrosome amplification, colony formation in soft agar, self-renewal, expression of the stem cell marker CD133, and resistance to oxidative stress and ionizing radiation. The RAS/mitogen-activated protein kinase (ERK) and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathways were activated, and checkpoint kinase 1 (Chk1), the DNA damage regulator, was phosphorylated at S280 by Akt, suppressing Chk1 phosphorylation at S345 in response to ionizing irradiation. The PTEN-/- cells showed low levels of DNA damage in the absence of irradiation, which was increased by EGFRvIII expression. Finally, secondary changes occurred during tumor growth in mice. Cells from these tumors showed decreased tumor latencies and additional chromosomal aberrations. Most of these tumor lines showed translocations of mouse chromosome 15. Intracranial injections of one of these lines led to invasive, glial fibrillary acidic protein-positive, nestin-positive tumors. These results provide a molecular basis for the occurrence of these two genetic lesions in brain tumors and point to a role in induction of genomic instability.
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PMID:EGFRvIII expression and PTEN loss synergistically induce chromosomal instability and glial tumors. 1881 21

Transcriptional targeting of viral genes is a promising strategy to achieve tumor-specific replication of oncolytic viruses. Due to its natural tropism, herpes simplex virus type 1 (HSV-1) may be an ideal tool for oncolytic therapy of brain tumors such as malignant glioblastoma. To study whether glioma-specific gene expression can be accomplished within the HSV-1 genome, four cellular regulatory elements were exemplarily studied. Whereas the human telomerase reverse transcriptase (hTERT) and survivin promoters and the nestin and vascular endothelial growth factor A (VEGF-A) enhancers displayed pronounced glioma specificity after plasmid transfection, only the nestin enhancer conferred a certain selectivity for glioma cells and notable activity when transferred into the viral genome. The nestin enhancer was also found to be highly useful for tumor cell-specific expression of a therapeutically relevant gene (interleukin-2) when tested in combination with the hTERT or simian virus 40 (SV40) early promoter in the HSV-1 genome. Because activity of the chosen promoter in a tumor is a prerequisite for the successful application of an oncolytic virus, we examined whether the activity of a promoter can be deduced from the amounts of cellular mRNA or protein expressed under its control. We found little correlation between promoter activity and mRNA levels of the corresponding gene, whereas protein expression was more closely related to promoter activity. We conclude that the cellular elements are differently regulated in the viral and cellular genomes. Mechanistic insight into the differential regulation is required to improve and refine the design of transcriptionally targeted HSV vectors.
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PMID:Tumor-specific activity of cellular regulatory elements is down-regulated upon insertion into the herpes simplex virus genome. 1897 78


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