Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0017636 (glioblastoma)
18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nestin is a member of intermediate filaments abundantly expressed in neural stem cells and glioblastomas. The nestin gene has four exons and three introns, and neural cell-specific expression is regulated by the second intron. We previously reported that nestin was invariably detected in the tumor endothelium in gliomas even though tumor cells were negative for nestin. In the present study, we further confirmed nestin immunostaining in tumor endothelium of a variety of common cancers, including lung, stomach, colon, and cervical carcinomas. We examined an endothelium-specific regulator using human umbilical vein endothelial cells (HUVECs) and human glioblastoma-derived U251 cells. In a luciferase reporter assay, the first intron plus 5' upstream promoter (5'UP) gave the highest activity, followed by 5'UP, and the second intron plus 5'UP. However, the assay values were much lower by HUVEC extracts than by U251 cell extracts. Although green fluorescent protein expression was positive over all U251 cells under either the first intron, second intron, or ubiquitously active CAG promoter, the fluorescence in HUVECs was limited to a few cells even under the first intron. This difference came from the growth feature of HUVECs which exhibit growth arrest by contact inhibition. We found that the nestin expression was specific to proliferative endothelium, by using proliferation markers in hemangioblastomas and in situ hybridization. Using an endothelial tube formation assay, tyrosine kinase domain-deleted VEGF receptor KDR effectively abolished the tube formation under the first intron. We suggest that the nestin expression in tumor endothelium is enhanced by the first intron.
...
PMID:Angiogenic endothelium-specific nestin expression is enhanced by the first intron of the nestin gene. 1550 61

We examined how the effect of topotecan is modulated by transient hypoxia in three different tumor lines, Lewis lung carcinoma (LLC), U87 human glioblastoma and DMS273 human small cell lung cancer. Four groups of tumor bearing mice were treated with saline or a single dose of topotecan, immediately followed by 6-h or 72-h exposure to a hypoxic environment (10% O(2)) or normal air. Topotecan + hypoxia resulted in significantly greater suppression of tumor growth than normoxic topotecan or hypoxia alone. Correspondingly, the sensitivity of LLC cells to topotecan in a clonogenic survival assay was significantly higher under hypoxia. This effect of hypoxia was not a general phenomenon, since the tumor growth inhibitory effect of the alkylating agent cisplatin was not changed by hypoxic environment. In a parallel series of in vitro experiments, cell cultures were exposed to hypoxia (0.1% or 0.7% O(2)) in a hypoxic chamber or normoxia for 24 h. We found a dose-dependent downregulation of HIF-1alpha by topotecan (30-270 nM). The hypoxic upregulation of Glucose transporter-1 and VEGF secretion to the culture medium was inhibited by the addition of topotecan, while doses up to 270 nM had no effect on VEGF under normoxia. VEGF protein levels in tumors were also reduced by topotecan. These data show that the effect of topotecan is increased by transient hypoxia, and this may be a direct effect on the ability of cells to survive under hypoxia as well as an antiangiogenic effect, mediated through the HIF-1 inhibitory effect of topotecan.
...
PMID:Augmenting tumor sensitivity to topotecan by transient hypoxia. 1589 31

Basigin/CD147, also named extracelluar matrix metalloproteinase inducer (EMMPRIN), has been implicated in playing very important roles in several aspects of tumor progression. In this study, we examined the inhibitory effects of antisense RNA of CD147 on invasion and angiogenesis of human glioblastoma U251 cells in vitro. The U251 cell line was transfected by a plasmid containing antisense CD147 cDNA. Gelatin zymography was used to determine the effect on reducing secretions of MMP-2 and MMP-9 of the transfected cells. Boyden chamber was employed to test the invasion of U251 cells in vitro. We found that downregulation of CD147 resulted in reducing secretions of MMP-2, MMP-9, and VEGF. Moreover, the invasion of stable antisense transfectants was inhibited. Wound-induced migration assay also showed decreased migration in stable antisense transfectants compare to parental- and empty vector-transfected cells. Taken together, these results provide evidence that invasion of human glioblastoma cells can be inhibited by antisense RNA of CD147. Basigin/CD147 may be used as a potential target of drugs for anti-invasion and metastasis of human glioblastoma cells.
...
PMID:Inhibition of basigin expression in glioblastoma cell line via antisense RNA reduces tumor cell invasion and angiogenesis. 1597 Jun 88

Tumor cells respond to hypoxic stress by upregulating a variety of genes involved in glucose uptake, glycolysis, and angiogenesis, all essential to maintaining nutrient availability and intracellular ATP levels. Adenosine monophosphate-dependent kinase (AMPK) is a key sensor for cellular homeostasis and is highly sensitive to changes in AMP:ATP ratios. The two catalytic AMPK alpha isoforms (AMPKalpha1, AMPKalpha2) were investigated with respect to their expression, cellular distribution, and contribution to VEGF expression under hypoxic stress in human U373 glioblastoma cells. Quantitative real-time PCR analysis showed AMPKalpha1 mRNA to be constitutively expressed in normoxia and hypoxia, whereas AMPKalpha2 mRNA levels were low in normoxia and significantly induced in hypoxia. Fluorescent immunohistochemistry showed that AMPKalpha2 protein redistributed to the nucleus under hypoxia, whereas AMPKalpha1 remained distributed throughout the cell. The AMPK chemical inhibitor, 5-iodotubericidin, effectively repressed the hypoxic induction of VEGF mRNA levels and hypoxia inducible factor-1 dependent transcription. AMPKalpha2 repression with RNA interference reduced hypoxia-induced VEGF mRNA and HIF-1 transcription, whereas AMPKalpha1 repression did not. Human glioblastoma cell lines U118 and U138 also showed hypoxia-induction of AMPKalpha2 as well as VEGF. Immunohistochemistry analysis of human astrocytoma/glioma samples revealed AMPKalpha2 present in high grade gliomas within hypoxic pseudopalisading microenvironments. These data suggest that prolonged hypoxia promotes the expression and functional activation of AMPKalpha2 and VEGF production in glioma cell lines and glioblastoma multiform tumors, thus contributing to tumor survival and angiogenesis in high grade human gliomas.
...
PMID:AMP-dependent protein kinase alpha 2 isoform promotes hypoxia-induced VEGF expression in human glioblastoma. 1651 31

cAMP has been shown to reverse the transformed phenotype of various cancer cells. Human glioblastoma U87MG cells exposed to 500 microM dB-cAMP for 6 days showed reduced proliferation, attenuated invasiveness, and inability to induce angiogenic responses in human brain endothelial cells (HBECs) grown in Matrigeltrade mark. VEGF was the principal mediator of angiogenic actions of U87MG conditioned media (CM), since VEGF neutralizing antibody completely inhibited U87MG-induced angiogenic responses and no detectable levels of IGF, bFGF, and PlGF were found in U87MG CM. VEGF release was induced ( approximately 20%) in dB-cAMP-treated U87MG cells, suggesting a simultaneous induction of anti-angiogenic mediators. Down-stream effectors of dB-cAMP actions in U87MG were investigated by microarray gene expression analysis. Detected increases in differentiation genes, staniocalcin-1 and Wnt-5a, and angiogenesis-related genes, PAI-1, SPARC, IGFBP-4, IGFBP-7, PAPP-A, and PRSS-11 in dB-cAMP-treated U87MG cells were validated by real-time PCR, Western blot, and/or ELISA. A subsequent series of experiments identified IGFBP-4 as the principal anti-angiogenic mediator secreted by glioblastoma cells in response to dB-cAMP. Human recombinant IGFBP-4 inhibited the angiogenic response of HBEC induced by U87MG CM, whereas anti-human IGFBP-4 antibody restored the pro-angiogenic activity of dB-cAMP-treated U87MG CM. Since neither U87MG nor HBEC cells secreted detectable levels of IGF-I, and there are no known cellular IGFBP-4 receptors, the anti-angiogenic effect of IGFBP-4 was likely IGF-I-independent and indirect. IGFBP-4 also antagonized angiogenic effects of VEGF(165), PlGF, and bFGF, and reduced U87MG colony formation in soft-agar. IGFBP-4 is a novel dB-cAMP-induced anti-angiogenic and anti-tumorigenic mediator that may be a promising candidate for glioblastoma therapy.
...
PMID:Insulin-like growth factor binding protein-4 (IGFBP-4) is a novel anti-angiogenic and anti-tumorigenic mediator secreted by dibutyryl cyclic AMP (dB-cAMP)-differentiated glioblastoma cells. 1658 92

We present a small series of patients with primary glioblastoma multiforme (GBM), and combine individual genetic data with pathohistologic characteristics and clinical outcome. Eighteen patients (12 men, 6 women, median age 51 years) with histologically proven GBM underwent surgical debulking followed by radiotherapy. Fifteen received concomitant chemotherapy. Histologic typing, immunohistochemistry for CD34, karyotypic analysis, and classification of the pattern of neovascularization was done in all patients. In 12/18, we performed methylation-specific polymerase chain reaction of the MGMT gene (O-6-methylguanine-DNA methyltransferase). The survival duration of patients spanned 3-58 months. By classical banding methods, 15/18 patients showed at least one aberration characteristic for primary glioblastoma (+7 in 7/18, deletions of 9p in 10/18 and -10 or deletions from 10q in 8/18 patients). We could not assess whether patients who survived for longer periods showed less complex or fewer aberrations than the patients who survived less than one year. Losses of 6p21(VEGF), 4q27(bFGF), and 12p11 approximately p13 (ING4) were associated with the "bizarre" pattern of neoangiogenesis. Methylation of the MGMT promoter was found in 3/12 patients. Even in this small series, the main characteristic of GBM was its diversity regarding all investigated histologic and genetic characteristics. This extreme diversity should be considered in the design of targeted therapies in GBM.
...
PMID:Diversity of cytogenetic and pathohistologic profiles in glioblastoma. 1661 11

Tumour growth is tightly related to new blood vessel formation, tissue remodelling and invasiveness capacity. A number of tissular factors fuel the growth of glioblastoma multiforme, the most aggressive brain neoplasm. In fact, gene array analyses demonstrated that the proapoptotic cytokine tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) inhibited mRNA expression of VEGF, along with those of matrix metalloproteinase-2 (MMP-2), its inhibitor tissue inhibitor of matrix metalloproteinases-2 (TIMP-2), as well as the tumour invasiveness-related gene secreted protein acid rich in cysteine (SPARC) in different human glioblastoma cell lines. Particularly, VEGF mRNA and protein expression and release from glioblastoma cells were also inhibited by TRAIL. The latter also exerted antimitogenic effects on human umbilical vein endothelial cells (HUVECs). With the same cells, TRAIL inhibited new vessel formation in the in vitro matrigel model, as well as it exerted powerful inhibition of blood vessel formation induced by an angiogenic cocktail administered in subcutaneous pellets in vivo in the C57 mouse. Moreover, the expression of MMP-2, its inhibitor TIMP-2 and the tumour invasiveness-related protein SPARC were effectively inhibited by TRAIL in glioblastoma cell lines. In conclusion, our data indicate that TRAIL inhibits the orchestra of factors contributing to glioblastoma biological aggressiveness. Thus, the TRAIL system could be regarded as a molecular target to exploit for innovative therapy of this type of tumour.
...
PMID:TRAIL inhibits angiogenesis stimulated by VEGF expression in human glioblastoma cells. 1662 57

Glioblastoma (GBM) is a highly malignant, rapidly progressive astrocytoma that is distinguished pathologically from lower grade tumors by necrosis and microvascular hyperplasia. Necrotic foci are typically surrounded by "pseudopalisading" cells-a configuration that is relatively unique to malignant gliomas and has long been recognized as an ominous prognostic feature. Precise mechanisms that relate morphology to biologic behavior have not been described. Recent investigations have demonstrated that pseudopalisades are severely hypoxic, overexpress hypoxia-inducible factor (HIF-1), and secrete proangiogenic factors such as VEGF and IL-8. Thus, the microvascular hyperplasia in GBM that provides a new vasculature and promotes peripheral tumor expansion is tightly linked with the emergence of pseudopalisades. Both pathologic observations and experimental evidence have indicated that the development of hypoxia and necrosis within astrocytomas could arise secondary to vaso-occlusion and intravascular thrombosis. This emerging model suggests that pseudopalisades represent a wave of tumor cells actively migrating away from central hypoxia that arises after a vascular insult. Experimental glioma models have shown that endothelial apoptosis, perhaps resulting from angiopoetin-2, initiates vascular pathology, whereas observations in human tumors have clearly demonstrated that intravascular thrombosis develops with high frequency in the transition to GBM. Tissue factor, the main cellular initiator of thrombosis, is dramatically upregulated in response to PTEN loss and hypoxia in human GBM and could promote a prothrombotic environment that precipitates these events. A prothrombotic environment also activates the family of protease activated receptors (PARs) on tumor cells, which are G-protein-coupled and enhance invasive and proangiogenic properties. Vaso-occlusive and prothrombotic mechanisms in GBM could readily explain the presence of pseudopalisading necrosis in tissue sections, the rapid peripheral expansion on neuroimaging, and the dramatic shift to an accelerated rate of clinical progression resulting from hypoxia-induced angiogenesis.
...
PMID:'Pseudopalisading' necrosis in glioblastoma: a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis. 1678 63

Clinical assessment of the response to antiangiogenic therapy has been cumbersome. A study in this issue of Cancer Cell demonstrates that a combination of magnetic resonance imaging (MRI) for quantification of normalized vessels with measurements of circulating levels of proangiogenic factors, including FGF2, SDF1, and viable circulating endothelial cells, provides an effective means to evaluate the response of recurrent glioblastoma to a prototypical pan-VEGF receptor tyrosine kinase inhibitor, AZD2171.
...
PMID:Tracking normalization of brain tumor vasculature by magnetic imaging and proangiogenic biomarkers. 1722 92

Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171-an oral tyrosine kinase inhibitor of VEGF receptors-has rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1alpha, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor.
...
PMID:AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. 1760 54


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---