UMLS:C0017638 - FACTA Search

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Query: UMLS:C0017638 (glioma)
30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The collagen type IV cleavage fragment tumstatin and its active subfragments bind to integrin alpha(V)beta(3) and inhibit activation of focal adhesion kinase, phophoinositol-3 kinase, Akt, and mammalian target of rapamycin (mTOR) in what is thought to be an endothelial cell-specific manner. The resultant endothelial cell apoptosis accounts for the ability of tumstatin to function as an endogenous inhibitor of angiogenesis and an indirect suppressor of tumor growth. We hypothesized that the inability of tumstatin to directly suppress tumor cell growth might be the result of the constitutive activation of the Akt/mTOR pathway commonly seen in tumors. Consistent with this idea, several integrin alpha(V)beta(3)-expressing glioma cell lines with PTEN mutations and high levels of phospho-Akt (pAkt) were unaffected by exposure to an active fragment of tumstatin (T3), whereas alpha(V)beta(3)-expressing glioma cell lines with a functional PTEN/low levels of pAkt exhibited T3-induced growth suppression that could be bypassed by small interfering RNA-mediated suppression of PTEN, introduction of a constitutively expressed Akt, or introduction of the Akt and mTOR target eukaryotic translation initiation factor 4E. The direct tumor-suppressive actions of T3 were further shown in an alpha(V)beta(3)-deficient in vivo mouse model in which T3, while unable to alter the tumstatin-insensitive vasculature contributed by the alpha(V)beta(3)-deficient host, nonetheless suppressed the growth and proliferative index of i.c. implanted alpha(V)beta(3)-expressing PTEN-proficient glioma cells. These results show that tumstatin, previously considered to be only an endogenous inhibitor of angiogenesis, also directly inhibits the growth of tumors in a manner dependent on Akt/mTOR activation.
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PMID:The PTEN/Akt pathway dictates the direct alphaVbeta3-dependent growth-inhibitory action of an active fragment of tumstatin in glioma cells in vitro and in vivo. 1714 79

Secreted protein acidic and rich in cysteine (SPARC) is an extracellular glycoprotein expressed in several solid cancers, including malignant gliomas, upon adoption of metastatic or invasive behaviors. SPARC expression in glioma cells promotes invasion and survival under stress, the latter process dependent on SPARC activation of AKT. Here we demonstrate that downregulation of SPARC expression with short interfering RNA (siRNA) in glioma cells decreased tumor cell survival and invasion. SPARC siRNA reduced the activating phosphorylation of AKT and two cytoplasmic kinases, focal adhesion kinase (FAK) and integrin-linked kinase (ILK). We determined the contributions of FAK and ILK to SPARC effects using SPARC protein and cell lines engineered to overexpress SPARC. SPARC activated FAK and ILK in glioma cells previously characterized as responsive to SPARC. Downregulation of either FAK or ILK expression inhibited SPARC-mediated AKT phosphorylation, and targeting both FAK and ILK attenuated AKT activation more potently than targeting either FAK or ILK alone. Decreased SPARC-mediated AKT activation correlated with a reduction in SPARC-dependent invasion and survival upon the downregulation of FAK and/or ILK expression. These data further demonstrate the role of SPARC in glioma tumor progression through the activation of intracellular kinases that may provide novel therapeutic targets for advanced cancers.
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PMID:Targeting SPARC expression decreases glioma cellular survival and invasion associated with reduced activities of FAK and ILK kinases. 1721 7

Glioblastomas are highly lethal cancers that resist current therapies. Novel therapies under development target molecular mechanisms that promote glioblastoma growth. In glioblastoma patient specimens, the non-receptor tyrosine kinase focal adhesion kinase (FAK) is overexpressed. Upon growth factor receptor stimulation or integrin engagement, FAK is activated by phosphorylation on critical tyrosine residues. Activated FAK initiates a signal transduction cascade which promotes glioma growth and invasion by increasing cellular adhesion, migration, invasion, and proliferation. We find that human glioma cell lines express different levels of total FAK protein and activating phosphorylation of tyrosine residues Tyr397, Tyr861, and Tyr925. As all glioma cell lines examined expressed phosphorylated FAK, we examined the efficacy of a novel low-molecular weight inhibitor of FAK, TAE226, against human glioma cell lines. TAE226 inhibited the phosphorylation of FAK as well as the downstream effectors AKT, extracellular signal-related kinase, and S6 ribosomal protein in multiple glioma cell lines. TAE226 induced a concentration-dependent decrease in cellular proliferation with an associated G(2) cell cycle arrest in every cell line and an increase in apoptosis in a cell-line-specific manner. TAE226 also decreased glioma cell adhesion, migration, and invasion through an artificial extracellular matrix. Together, these data demonstrate the potential benefit of TAE226 for glioma therapy.
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PMID:A novel low-molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth. 1721 39

High-grade gliomas comprise the most malignant type of primary brain tumor and are relatively frequent in adults. Recent studies have indicated that the loss of p16, an inhibitor of CDK4, promotes the acquisition of malignant characteristics in gliomas. A correlation between overexpression of urokinase-type plasminogen activator receptor (uPAR) and glioblastoma invasion has also been established. Moreover, uPAR/integrin binding has been shown to initiate or potentiate integrin signaling through focal adhesion kinase and/or src kinases. Our previous studies demonstrated that downregulation of uPAR expression and restoration of p16 regress glioma growth in nude mice and downregulate alphavbeta3 integrin receptor expression. Here, we show the effect of a bicistronic construct on alphavbeta5 integrin receptor expression, angiogenesis and the biochemical pathway that causes glioma cell death. The U251 glioblastoma and a glioblastoma xenograft cell line transduced with a recombinant replication-defective adenovirus vector containing the cDNA of wild-type p16 and antisense RNA of uPAR significantly inhibited human mammary epithelial cell capillary formation and vascular endothelial growth factor (VEGF) expression. Inactivation of anti-apoptotic molecules such as Akt, PARP, activation of caspases and accumulation of heteroduplex chromosomal DNA in pre-G1 phase of the cell cycle was demonstrated by Western blotting, caspase activity assay and FACS analysis. Nuclear DNA fragmentation upon induction of apoptosis was scored using the TUNEL assay. Significant downregulation of alphavbeta5 integrin receptor expression was also confirmed by FACS analysis, immunoprecipitation and RT-PCR. Taken together, the results demonstrate that the sense p16 and anti-sense uPAR bicistronic construct significantly inhibits angiogenesis, induces apoptosis by deregulation of the PI3K-Akt pathway and downregulates alphavbeta5 integrin receptor expression.
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PMID:Sense p16 and antisense uPAR bicistronic construct inhibits angiogenesis and induces glioma cell death. 1727 68

Eph receptors, the largest receptor tyrosine kinases, and their ephrin ligands play important roles in axon guidance and cell migration during development of the nervous system. Recently, these molecules are also found involved in tumorigenesis of different kinds of cancers. In this study, we demonstrated that expression of ephrin-A1 was dramatically down-regulated in glioma cell lines and in primary gliomas compared to the matched normal tissues. Forced expression of ephrin-A1 attenuated cell migration, cell proliferation, and adhesion-independent growth in human glioma U251 cells. EphA2, a receptor for ephrin-A1 and an oncoprotein, was greatly decreased in ephrin-A1-transfected glioma cells. Overexpression of ephrin-A1 stimulated activation of EphA2 by phosphorylation and led to its degradation. Furthermore, focal adhesion kinase (FAK), a known downstream molecule of EphA2, was also down-regulated in the ephrin-A1 transfected cells. These results suggested that ephrin-A1 serves as a critical negative regulator in the tumorigenesis of gliomas by down-regulating EphA2 and FAK, which may provide potential valuable targets for therapeutic intervention.
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PMID:Ephrin-A1 is a negative regulator in glioma through down-regulation of EphA2 and FAK. 1733 25

Urokinase plasminogen activator (uPA) and its receptor (uPAR) play a major role in invasion and proliferation. A growing body of evidence has suggested that the uPA system promotes tumor metastasis by several different mechanisms, and not just solely by breaking down the ECM. In this study we have used RNAi-mediated simultaneous down-regulation of uPAR and uPA to determine the signaling pathway molecules and caspase-mediated apoptosis. From our in vitro experiments, we have observed that plasmid-based RNAi-mediated down-regulation of uPAR and uPA in SNB19 human glioma cells caused a decrease in the levels of uPAR protein and uPA enzyme activities. In addition, we observed a decrease in the phosphorylation of the Ras-activated pathway molecules such as FAK, p38MAPK, JNK and ERK1/2, as well as the MEK-activated phosphatidylinositol 3-kinase (PI3k) pathway, and also retarded the dephosphorylation of p-AKTser473 and p-mTORser2448, indicative of a feedback signaling mechanism of the uPAR-uPA system. Activation of caspase 8 accompanied by the release of cytochrome c and cleavage of PARP was also observed and indicative of Fas-mediated apoptosis. The use of FMK-VAD-FAK peptides coupled with FITC indicated activation of polycaspases, which was accompanied by the presence of fragmented nuclei. Our studies provide evidence for the presence of a feedback response of the uPAR-uPA system indicative of the multifaceted role of uPAR, and also the therapeutic potential of simultaneously targeting uPAR and uPA in cancer patients.
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PMID:Down-regulation of uPAR and uPA activates caspase-mediated apoptosis and inhibits the PI3K/AKT pathway. 1754 1

Given our previous findings that human cytomegalovirus (HCMV) nucleic acids and proteins are expressed in human malignant glioma in vivo, we investigated cellular signaling events associated with HCMV infection of human glioma and astroglial cells. HCMV infection caused rapid activation of the phosphatidylinositol-3 kinase (PI-3K) effector AKT kinase in human astro-glial and fibroblast cells, and induced tyrosine phosphorylation of phospholipase Cgamma (PLCgamma). Co-immunoprecipitation experiments revealed association of the p85 regulatory subunit of PI-3K with a high-molecular weight protein phosphorylated on tyrosine, following short-term exposure to HCMV. In contrast to a previous report, we were unable to confirm the identity of this high-molecular weight protein as being the epidermal growth factor receptor (EGFR). Stimulation of glioma and fibroblast cell lines over-expressing EGFR with HCMV (whole virus) or soluble glycoprotein B did not induce tyrosine phosphorylation of the receptor, as did the genuine ligand, EGF. Furthermore, we found that expression levels of the human ErbB1-4 receptors were not rate-limiting for HCMV infection. Dispensability of EGFR function during early HCMV infection was substantiated by demonstration of viral immediate early gene expression in cells lacking the EGFR gene, indicating that HCMV may promote oncogenic signaling pathways independently of EGFR activation. Among non-receptor cellular kinases, HCMV infection induced phosphorylation of focal adhesion kinase (FAK) Tyr397, which is indispensable for integrin-mediated cell migration and invasion. HCMV-induced FAK activation was paralleled by increased extracellular matrix-dependent migration of human malignant glioma but not normal astro-glial cells, suggesting that HCMV can selectively augment glioma cell invasiveness.
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PMID:Human cytomegalovirus induces cellular tyrosine kinase signaling and promotes glioma cell invasiveness. 1758 4

Geldanamycin is a naturally occurring benzoquinone ansamycin product of Streptomyces geldanus that binds the protein chaperone heat shock protein 90. As geldanamycin binds to heat shock protein 90 interfering with its function and heat shock protein 90 is overexpressed in many cancers, heat shock protein 90 has become a target for cancer therapy. As the geldanamycin analogue 17-allylamino-17-demethoxygeldanamycin has a favorable toxicity profile, it is being tested extensively in clinical trials in patients with advanced cancer. In this study, GL261 glioma cells from C57BL/6 mice were used to investigate the anti-tumor effect of 17-allylamino-17-demethoxygeldanamycin both in vitro and in vivo. Heat shock protein 90 inhibitors possess potent anti-proliferative activity, usually at low nanomolar ranges, owing to their pharmacological characteristics of binding tightly to heat shock protein 90, coupled with a slow dissociation rate. We found that 17-allylamino-17-demethoxygeldanamycin at doses as low as 200 nmol/l showed anti-tumor activity within 24 h of treatment. Treatment with 17-allylamino-17-demethoxygeldanamycin arrested GL261 cells in the G2 phase of the cell cycle associated with the downregulation of cyclin B1. Low doses of 17-allylamino-17-demethoxygeldanamycin significantly inhibited migration of GL261 cells within 16 h of treatment, concomitant with the downregulation of phosphorylated focal adhesion kinase and matrix metalloproteinase 2 secretion. Using an orthotopic glioma model with well-established intracranial tumors, 3 weekly cycles of 17-allylamino-17-demethoxygeldanamycin significantly reduced tumor volumes of treated animals compared with untreated controls (P=0.002). Given these promising results, clinical testing of 17-allylamino-17-demethoxygeldanamycin or other novel heat shock protein 90 inhibitors being developed should be considered for glioma patients whose tumors remain refractory to most current treatment regimens.
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PMID:The geldanamycin analogue 17-allylamino-17-demethoxygeldanamycin inhibits the growth of GL261 glioma cells in vitro and in vivo. 1766 92

The extracellular matrix in animal tissues usually provides a three-dimensional structural support to cells in addition to performing various other important functions. In the present study, wavy submicrometer laser-irradiated periodic surface structures (LIPSS) were produced on a smooth polystyrene film by polarized laser irradiation with a wavelength of 266 nm. Rat C6 glioma cells exhibited directional migration and oriented division on laser-irradiated polystyrene, which was parallel to the direction of LIPSS. However, rat C6 glioma cells on smooth polystyrene moved in a three-step invasion cycle, with faster migration speed than that on laser-irradiated polystyrene. In addition, focal adhesions examined by immunostaining focal adhesion kinase in human epithelial carcinoma HeLa cells were punctuated on smooth polystyrene, whereas dash-like on laser-irradiated polystyrene. We hypothesized that LIPSS on laser-irradiated polystyrene acted as an anisotropic and persistent mechanical stimulus to guide cell anisotropic spreading, migration and division through focal adhesions.
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PMID:Cell directional migration and oriented division on three-dimensional laser-induced periodic surface structures on polystyrene. 1827 16

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is mutated or lost in 60% to 70% of advanced gliomas and is associated with malignant phenotypic changes such as migration, which contribute to the morbidity and mortality of this disease. Most of the tumor suppressor function of PTEN has been attributed to its ability to dephosphorylate the second messenger, phosphatidylinositol 3,4,5-triphosphate, resulting in the biological control of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. Despite recent work suggesting that the protein phosphatase activity of PTEN controls glioma cell migration, the mechanisms by which this occurs are unclear. Herein, we show using glioma cell lines (U87MG and U373MG) stably transfected with wild-type PTEN or catalytically altered mutants of PTEN that PTEN controls integrin-directed migration in a lipid phosphatase, PI3K/AKT-independent manner. Confirming this observation, we show that the stable overexpression of COOH-terminal Src kinase, the physiologic negative regulator of SRC family kinases (SFK), or treatment with the SFK inhibitor PP1 abrogates glioma migration. The results provide direct evidence that the downstream effect of the protein phosphatase activity of PTEN is to suppress SFK and FYN, and to regulate RAC-GTPase activity after alpha(v) integrin stimulation. Furthermore, studying vitronectin-directed migration using (a) Fyn small interfering RNA and (b) astrocytes from Fyn heterozygous (+/-) mice, Pten heterozygous (+/-) mice, Pten and Fyn double heterozygous (+/-) mice, or Fyn knockout (-/-) mice confirmed a role of FYN in alpha(v) integrin-mediated haptotaxis in glial cells. Our combined results provide direct biochemical and genetic evidence that PTEN's protein phosphatase activity controls FYN kinase function in glioma cells and regulates migration in a PI3K/AKT-independent manner.
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PMID:The protein phosphatase activity of PTEN regulates SRC family kinases and controls glioma migration. 1833 67

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