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)

Invasive behavior is the pathological hallmark of malignant gliomas, being responsible for the failure of surgery, radiation, and chemotherapy. Matrix metalloproteinases (MMPs) are essential for proper ECM remodeling and invasion. The tumor and metastasis suppressor RECK protein regulates at least three members of the MMPs family: MMP-2, MMP-9, and MT1-MMP. In order to mimic the in vivo invasion process, A172 and T98G, respectively, non-invasive and invasive human glioblastoma cell lines, were cultured onto uncoated (control) or type I collagen gel-coated surface, and maintained for up to 7 days to allow establishment of the invasive process. We show that the collagen substrate causes decreased growth rates and morphological alterations correlated with the invasive phenotype. Electronic transmission microscopy of T98G cells revealed membrane invaginations resembling podosomes, which are typically found in cells in the process of crossing tissue boundaries, since they constitute sites of ECM degradation. Real time PCR revealed higher RECK mRNA expression in A172 cells, when compared to T98G cells and, also, in samples obtained from cultures where the invasive process was fully established. Interestingly, the collagen substrate increases RECK expression in A172 cells and the same tendency is displayed by T98G cells. MMPs-2 and -9 displayed higher levels of expression and activity in T98G cells, and their activities are also upregulated by collagen. Therefore, we suggest that: (1) RECK downregulation is critical for the invasiveness process displayed by T98G cells; (2) type 1 collagen could be employed to modulate RECK expression in glioblastoma cell lines. Since a positive correlation between RECK expression and patients survival has been noted in several types of tumors, our results may contribute to elucidate the complex mechanisms of malignant gliomas invasiveness.
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PMID:Downregulation of the RECK-tumor and metastasis suppressor gene in glioma invasiveness. 1679 55

Toll-like receptor 9 (TLR9) recognizes microbial DNA. We show here that TLR9 protein is expressed in human breast cancer cells and clinical breast cancer samples. Stimulation of TLR9-expressing breast cancer cells with the TLR9 agonistic CpG oligonucleotides (1-10 mumol/L) dramatically increased their in vitro invasion in both Matrigel assays and three-dimensional collagen cultures. Similar effects on invasion were seen in TLR9-expressing astrocytoma and glioblastoma cells and in the immortalized human breast epithelial cell line MCF-10A. This effect was not, however, dependent on the CpG content of the TLR9 ligands because the non-CpG oligonucleotides induced invasion of TLR9-expressing cells. CpG or non-CpG oligonucleotide-induced invasion in MDA-MB-231 cells was blunted by chloroquine and they did not induce invasion of TLR9(-) breast cancer cells. Treatment of MDA-MB-231 cells with CpG or non-CpG oligonucleotides induced the formation of approximately 50-kDa gelatinolytic band in zymograms. This band and the increased invasion were abolished by a matrix metalloproteinase (MMP) inhibitor GM6001 but not by a serine proteinase inhibitor aprotinin. Furthermore, CpG oligonucleotide treatment decreased tissue inhibitor of metalloproteinase-3 expression and increased levels of active MMP-13 in TLR9-expressing but not TLR9(-) breast cancer cells without affecting MMP-8. Neutralizing anti-MMP-13 antibodies inhibited the CpG oligonucleotide-induced invasion. These findings suggest that infections may promote cancer progression through a novel TLR9-mediated mechanism. They also propose a new molecular target for cancer therapy, because TLR9 has not been associated with cancer invasiveness previously.
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PMID:Toll-like receptor 9 agonists promote cellular invasion by increasing matrix metalloproteinase activity. 1684 19

Glioblastoma, the most malignant form of brain cancer, is responsible for 23% of primary brain tumors and has extremely poor outcome. Confounding the clinical management of glioblastomas is the extreme local invasiveness of these cancer cells. The mechanisms that govern invasion are poorly understood. To gain insight into glioblastoma invasion, we conducted experiments on the patterns of growth and dispersion of U87 glioblastoma tumor spheroids in a three-dimensional collagen gel. We studied two different cell lines, one with a mutation to the EGFR (U87DeltaEGFR) that is associated with increased malignancy, and one with an endogenous (wild-type) receptor (U87WT). We developed a continuum mathematical model of the dispersion behaviors with the aim of identifying and characterizing discrete cellular mechanisms underlying invasive cell motility. The mathematical model quantitatively reproduces the experimental data, and indicates that the U87WT invasive cells have a stronger directional motility bias away from the spheroid center as well as a faster rate of cell shedding compared to the U87DeltaEGFR cells. The model suggests that differences in tumor cell dispersion may be due to differences in the chemical factors produced by cells, differences in how the two cell lines remodel the gel, or different cell-cell adhesion characteristics.
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PMID:A mathematical model of glioblastoma tumor spheroid invasion in a three-dimensional in vitro experiment. 1704 Sep 92

The abnormal function of tyrosine kinase receptors is a hallmark of malignant gliomas. Tie2 receptor tyrosine kinase is a specific endothelial cell receptor whose function is positively regulated by angiopoietin 1 (Ang1). Recently, Tie2 has also been found in the nonvascular compartment of several tumors, including leukemia as well as breast, gastric, and thyroid cancers. There is, however, little information on the function of the Ang1/Tie2 pathway in the non-stromal cells within human tumors. We found that surgical glioblastoma specimens contained a subpopulation of Tie2+/CD31- and Tie2+/GFAP+ cells, suggesting that Tie2 is indeed expressed outside the vascular compartment of gliomas. Furthermore, analysis of a tissue array consisting of 116 human glioma samples showed that Tie2 expression in the neoplastic glial cells was significantly associated with progression from a lower to higher grade. Importantly, Ang1 stimulation of Tie2+ glioma cells resulted in increased adherence of the cells to collagen I and IV, suggesting that Tie2 regulates glioma cell adhesion to the extracellular matrix. Conversely, the down-regulation of Tie2 levels by small interference RNA or the addition of soluble Tie2 abrogated the Ang1-mediated effect on cell adhesion. In studying the expression of cell adhesion molecules, we found that Tie2 activation was related to the up-regulation of integrin beta1 levels and the formation of focal adhesions. These results, together with the reported fact that malignant gliomas express high levels of Ang1, suggest the existence of an autocrine loop in malignant gliomas and that a Tie2-dependent pathway modulates cell-to-extracellular matrix adhesion, providing new insights into the highly infiltrative phenotype of human gliomas.
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PMID:Expression of the receptor tyrosine kinase Tie2 in neoplastic glial cells is associated with integrin beta1-dependent adhesion to the extracellular matrix. 1718 82

Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is a membrane-bound serine proteinase inhibitor having two extracellular Kunitz-type proteinase inhibitor domains (KD) namely KD-1 and KD-2. It efficiently inhibits hepatocyte growth factor activator, matriptase, hepsin, prostasin and trypsin. We have previously reported that the expression of HAI-1 suppresses the in vitro invasive capability of human glioblastoma cells. In this study we examined the role of each KD in the anti-invasive effect of HAI-1. Engineered over-expression of the mature membrane-form HAI-1 suppressed in vitro fibrin gel invasion of two human glioblastoma cell lines, U251 and YKG-1. The migratory activity on type IV collagen was also suppressed by the HAI-1 expression. These effects were not affected by the deletion of intracytoplasmic domain of HAI-1. A truncated secreted form of HAI-1 also suppressed in vitro invasion of the cells, indicating that the extracellular portion of HAI-1 was responsible for the anti-invasive effect. To determine the roles of each KD in the anti-invasive effect of HAI-1 in vitro, we constructed expression plasmids for HAI-1 with or without mutation at the P1 position of the reactive site of each KD. The results revealed that the proteinase inhibitor activity of N-terminal KD (KD-1) is responsible for the anti-invasion effect of HAI-1.
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PMID:Roles of Kunitz domains in the anti-invasive effect of hepatocyte growth factor activator inhibitor type 1 in human glioblastoma cells. 1794 49

Glioblastomas are heterogeneous tumors displaying regions of necrosis, proliferation, angiogenesis, apoptosis and invasion. SPARC, a matricellular protein that negatively regulates angiogenesis and cell proliferation, but enhances cell deadhesion from matrix, is upregulated in gliomas (Grades II-IV). We previously demonstrated that SPARC promotes invasion while concomitantly decreasing tumor growth, in part by decreasing proliferation of the tumor cells. In other cancer types, SPARC has been shown to influence tumor growth by altering matrix production, and by decreasing angiogenesis via interfering with the VEGF-VEGFR1 signaling pathway. We therefore examined whether the SPARC-induced decrease in glioma tumor growth was also, in part, due to alterations in matrix and/or decreased vascularity, and assessed SPARC-VEGF interactions. The data demonstrate that SPARC upregulates glioma matrix, collagen I is a constituent of the matrix and SPARC promotes collagen fibrillogenesis. Furthermore, SPARC suppressed glioma vascularity, and this was accompanied by decreased VEGF expression and secretion, which was, in part, due to reduced VEGF165 transcript abundance. These data indicate that SPARC modulates glioma growth by altering the tumor microenvironment and by suppressing tumor vascularity through suppression of VEGF expression and secretion. These experiments implicate a novel mechanism, whereby SPARC regulates VEGF function by limiting the available growth factor. Because SPARC is considered to be a therapeutic target for gliomas, a further understanding of its complex signaling mechanisms is important, as targeting SPARC to decrease invasion could undesirably lead to the growth of more vascular and proliferative tumors.
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PMID:SPARC-induced increase in glioma matrix and decrease in vascularity are associated with reduced VEGF expression and secretion. 1835 May 69

Epidermal growth factor (EGF) receptor-mediated cell migration plays a vital role in invasion of many tumor types. EGF receptor ligands increase invasiveness in vivo, but it remains unclear how consequent effects on intrinsic cell motility behavior versus effects on extrinsic matrix properties integrate to result in net increase of translational speed and/or directional persistence of migration in a 3D environment. Understanding this convolution is important for therapeutic targeting of tumor invasion, as key regulatory pathways for intrinsic versus extrinsic effects may not be coincident. Accordingly, we have undertaken a quantitative single-cell imaging study of glioblastoma cell movement in 3D matrices and on 2D substrata across a range of collagen densities with systematic variation of protease-mediated matrix degradation. In 3D, EGF induced a mild increase in cell speed and a strong increase in directional persistence, the latter depending heavily on matrix density and EGF-stimulated protease activity. In contrast, in 2D, EGF induced a similarly mild increase in speed but conversely a decrease in directional persistence (both independent of protease activity). Thus, the EGF-enhanced 3D tumor cell migration results only partially from cell-intrinsic effects, with override of cell-intrinsic persistence decrease by protease-mediated cell-extrinsic reduction of matrix steric hindrance.
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PMID:Epidermal growth factor-induced enhancement of glioblastoma cell migration in 3D arises from an intrinsic increase in speed but an extrinsic matrix- and proteolysis-dependent increase in persistence. 1863 79

Live-cell imaging of glioblastoma U373 and U87 cells transfected with actin cytoskeleton markers has been used to study there-arrangements that are associated with migration in two- and three-dimensional matrices and in brain tissue. In collagen gels and in brain slices, both cell types developed neuronal-like processes with ruffling membranes and filopodia. Blebbing cells were also observed, but these were mainly immobile. The retraction of trailing cell processes in a tissue environment was associated with the transient development and contraction of bundles of axial stress fibers. The inhibition of Rho-kinase caused glioblastoma cells in brain slices to become immobile and develop neurite-like processes at random, which indicates the requirement of Rho signaling and contractility for migration. Actin stress fibers were also observed in glioblastoma cells injected into the brains of living mice. Thus, invading glioblastoma cells use neurite-like extensions to penetrate between neuronal fibers and contractile actin bundles for traction of the cell body.
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PMID:Live imaging of glioblastoma cells in brain tissue shows requirement of actin bundles for migration. 1863 84

The poor prognosis of glioblastoma patients is related to diffuse brain invasion and interaction of tumor cells with extracellular matrices (ECM). We describe expression and function of the FACIT-collagen XVI in glioblastomas. We found upregulation of collagen XVI mRNA as well as protein in glioblastomas as compared to normal cortex. SiRNA knockdown resulted in decreased cell adhesion whereas increased adhesion was observed on surfaces coated with collagen XVI. The migration of glioblastoma cells on this substrate remained unchanged. Our results demonstrate de-novo expression of collagen XVI in glioblastomas as part of the tumor specific remodeling of the ECM.
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PMID:Collagen XVI expression is upregulated in glioblastomas and promotes tumor cell adhesion. 1880 7

High-grade gliomas release excitotoxic concentrations of glutamate, which has been shown to enhance tumor proliferation and migration. alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate receptors are abundantly expressed at the invading edge of glioblastoma specimens, suggesting they may play an important biologic role in tumor invasion. In this study, we examined potential mechanisms by which AMPA receptor (AMPAR) expression and stimulation promote glioma cell migration and invasion. Overexpression of GluR1, the most abundant AMPAR subunit in gliomas, positively correlated with glioma cell adhesion to type I and type IV collagen, which was decreased in cells with knockdown of GluR1 and with blocking antibodies to beta1 integrin. Furthermore, stimulation of the AMPAR led to detachment of cells from the extracellular matrix (ECM). Immunoprecipitation studies showed that GluR1 associated with the actin cytoskeleton-linked protein band 4.1B (brain type), which may serve as a link between GluR1 and integrins. Overexpression of GluR1 correlated with increased cell-surface expression of beta1 integrin, increased phosphorylation of focal adhesion kinase (FAK-Y397), and enhanced numbers of focal adhesion (FA) complexes. Cells overexpressing GluR1 had increased colocalization of actin and paxillin at FAs and, in several glioma cell lines, significantly increased invasion in an in vitro Matrigel transwell assay. Likewise, in an intracranial xenograft model, overexpression of GluR1 led to perivascular and subependymal glioma cell invasion similar to patterns of tumor dissemination described in human glioblastoma. Together, these results suggest that AMPARs may link signals from the ECM to sites of FA, where signal integration promotes tumor invasion.
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PMID:AMPA receptors promote perivascular glioma invasion via beta1 integrin-dependent adhesion to the extracellular matrix. 1895 20


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