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

The receptor protein tyrosine phosphatase beta (RPTPbeta/PTPzeta) is overexpressed in glioblastoma tumors and plays a functional role in tumor cell migration and adhesion. Glioblastomas express at least three splice variants of RPTPbeta, including long and short receptor forms and a secreted chondroitin sulfate proteoglycan called phosphacan. Here we explore the differences in the expression pattern and function of long RPTPbeta and short RPTPbeta. The short form of RPTPbeta lacks exon 12, which encodes 860 amino acids located in the extracellular domain. Until now, functional differences between long and short RPTPbeta have been difficult to elucidate. In this study, antibodies specific to the splice junction, unique to short RPTPbeta, allowed for the discrimination of the two receptors. A study of normal brain tissue and graded astrocytomas indicates that long and short RPTPbeta forms have an overlapping expression pattern. In order to study functional differences between long and short RPTPbeta, we created stable U87 glioblastoma cells that expressed these receptors. U87 stable cell lines overexpressing long or short RPTPbeta migrate faster and adhere more robustly than parental U87 cells. The two forms differ in that long-RPTPbeta-overexpressing cells migrate and adhere better than short-RPTPbeta-overexpressing cells. A study of the extracellular domain of short RPTPbeta indicates that it retains much of the functional capacity of phosphacan. Indeed, the action of recombinant, short-RPTPbeta extracellular domain protein is similar to that of phosphacan as a repulsive substrate for glioblastoma cells. Comparison of the signaling capacity of long RPTPbeta to that of short RPTPbeta reveals very similar abilities to activate transcription pathways. Moreover, transient transfection with either long or short RPTPbeta activates NF-kappaB reporter gene transcription. Because of their tumor-restricted and largely overlapping expression patterns in glioblastoma, both RPTPbeta splice forms are potential therapeutic targets. The involvement of long and short RPTPbeta in glioma tumor cell biology also contributes to the value of RPTPbeta as a cancer target.
 ...
PMID:Functional comparison of long and short splice forms of RPTPbeta: implications for glioblastoma treatment. 1583 Dec 33

Here we characterize the antitumor activity of a recombinant bispecific single-chain antibody isolated from the serum of cloned transgenic cows. The antibody, termed r28M, is directed to a melanoma-associated proteoglycan, also expressed on glioblastoma cells, and to human CD28. Bound to tumor cells, r28M induced exceedingly efficient supraagonistic T-cell activation via the CD28 molecule without an additional stimulus via the TCR/CD3 complex. In vitro, T cells and NK cells contributed to tumor cell killing after r28M-mediated activation of peripheral blood mononuclear cells. However, NK activity depended on T-cell-derived cytokines. In vivo, r28M markedly inhibited the growth of human glioblastoma cells in nude mice. The serum half-life of the protein after i.v. injection was approximately 6 hr. Thus, r28M is unique not only in inducing supraagonistic CD28-mediated T-cell activation against tumor cells in vitro and in vivo, it also meets 2 additional requirements that are critical for clinical application: a relatively long serum half-life and the possibility of obtaining large amounts of active material from cloned transgenic livestock.
 ...
PMID:Supraagonistic, bispecific single-chain antibody purified from the serum of cloned, transgenic cows induces T-cell-mediated killing of glioblastoma cells in vitro and in vivo. 1600 29

Brain tumors, in particular glioblastomas, have a high morbidity and mortality, mainly due to their invasive nature. A prerequisite for this invasiveness is cell migration based on increased expression of proteases digesting the extracellular matrix. Brevican, an important extracellular proteoglycan that is upregulated in glioblastomas, can be degraded by certain proteases. We demonstrate that in human glioblastomas secretory proteases like ADAMTS4 and ADAMTS5 (aggrecanases 1 and 2; ADAMTS = a disintegrin and metalloproteinase with thrombospondin motifs) are expressed on the mRNA and protein levels in considerable amounts. Real-time RT-PCR shows a higher levels of ADAMTS4 and 5 expressions in glioblastomas in situ, compared to cultured human glioblastoma cells. The upregulation of these proteases in vivo by cytokines may explain this difference. In vitro, transforming growth factor-beta induces ADAMTS4, but less ADAMTS5, and interleukin-1beta ADAMTS5, but not ADAMTS4. As demonstrated by immunohistochemistry and confocal microscopy in situ, ADAMTS5 expression is confined to proliferating glioblastoma cells of surgical tumor sections and with lower intensity to astroglial cells in normal brain sections, as opposed to brevican. In vitro, glioblastoma-derived ADAMTS5 degrades recombinant human brevican to several smaller fragments. Our results show that ADAMTS4 and 5 are upregulated on proliferating glioblastoma cells and these proteases may contribute to their invasive potential.
 ...
PMID:Matrix-degrading proteases ADAMTS4 and ADAMTS5 (disintegrins and metalloproteinases with thrombospondin motifs 4 and 5) are expressed in human glioblastomas. 1600 58

Glioblastoma (GBM) is a highly malignant glioma, which has the propensity to infiltrate throughout the brain in contrast to pilocytic astrocytoma (PA) of the posterior fossa, which does not spread and can be cured by surgery. We have used Suppression Subtractive Hybridization to define markers that better delineate the molecular basis of brain invasion and distinguish these tumor groups. We have identified 106 genes expressed in PA versus GBM and 80 genes expressed in GBM versus PA. Subsequent analysis identified a subset of 20 transcripts showing a common differential expression pattern for the two groups. GBM differs from PA by the expression of five genes involved in invasion and angiogenesis: fibronectin, osteopontin, chitinase-3-like-1 (YKL-40), keratoepithelin and fibromodulin. PA differs from GBM by the expression of genes related to metabolism (apolipoprotein D), proteolysis (protease-serine-11), receptor and signal transduction (PLEKHB1 for Pleckstrin-Homology-domain-containing-protein-family-B-member-1), transcription/translation (eukaryotic-translation-elongation-factor-1-alpha1) processes and cell adhesion (SPOCK1 for SPARC/Osteonectin-CWCV-kazal-like-domains-proteoglycan). The expression of these genes was confirmed by real-time quantitative RT-PCR and immunohistochemistry. This study highlights the crucial role of brain invasion in GBM and identifies specific molecules involved in this process. In addition, it offers a restricted list of markers that accurately distinguish PA from GBM.
 ...
PMID:Identification of genes differentially expressed in glioblastoma versus pilocytic astrocytoma using Suppression Subtractive Hybridization. 1631 30

Keratan sulfate (KS) proteoglycan is expressed in the extracellular matrix or cell surface in numerous tissues, predominantly in those of the cornea, cartilage, and brain. However, its structure, function, and regulation remain poorly understood. Our investigation of KS expression in glioblastoma cell lines using Western-blot and flow cytometry with anti-KS antibody (5D4) revealed that LN229 glioblastoma cell highly expresses KS on a cell surface. Real-time PCR analysis showed that LN229 expresses a high level of keratan sulfate Gal-6-sulfotransferase. Results of this study also demonstrate that recombinant 5D4-reactive aggrecan is produced in LN229. Taken together, these results suggest that LN229 produces 5D4-reactive highly sulfated KS and is useful to investigate the KS structure and function in glioblastoma.
 ...
PMID:Expression of highly sulfated keratan sulfate synthesized in human glioblastoma cells. 1821 4

Chemoresistance represents a major problem in the treatment of many malignancies. Overcoming this obstacle will require improved understanding of the mechanisms responsible for this phenomenon. The progenitor cell marker NG2/melanoma proteoglycan (MPG) is aberrantly expressed by various tumors, but its role in cell death signaling and its potential as a therapeutic target are largely unexplored. We have assessed cytotoxic drug-induced cell death in glioblastoma spheroids from 15 patients, as well as in five cancer cell lines that differ with respect to NG2/MPG expression. The tumors were treated with doxorubicin, etoposide, carboplatin, temodal, cisplatin and tumor necrosis factor (TNF)alpha. High NG2/MPG expression correlated with multidrug resistance mediated by increased activation of alpha3beta1 integrin/PI3K signaling and their downstream targets, promoting cell survival. NG2/MPG knockdown with shRNAs incorporated into lentiviral vectors attenuated beta1 integrin signaling revealing potent antitumor effects and further sensitized neoplastic cells to cytotoxic treatment in vitro and in vivo. Thus, as a novel regulator of the antiapoptotic response, NG2/MPG may represent an effective therapeutic target in several cancer subtypes.
 ...
PMID:The progenitor cell marker NG2/MPG promotes chemoresistance by activation of integrin-dependent PI3K/Akt signaling. 1846 52

Glioblastomas (GBMs) are highly malignant tumors characterized by microvascular proliferation and the pseudopalisading pattern of necrosis. Investigations have, therefore, focused on vascular and endothelial cell biology in GBM. Endocan, also called endothelial cell-specific molecule-1, is a proteoglycan that is secreted by endothelial cells and upregulated by proangiogenic factors. We found that endocan is not only expressed in vitro by endothelial cells but also in the T98G and U118MG human GBM cell lines. In U118MG cells, tumor necrosis factor and fibroblast growth factor 2 upregulated endocan production, whereas exposure to hypoxia or cobalt chloride, an inducer of hypoxia inducible factor 1, increased endocan release without affecting cell viability. Endocan expression in 82 brain tumors was studied by immunohistochemistry. Endocan immunoreactivity was detected in hyperplastic endothelial cells in high-grade gliomas, mostly at the tumor margins; endothelial cells were mostly endocan negative in low-grade gliomas, and it was never detected in the cerebral cortex distant from the tumors. Tumor cells in high-grade but not low-grade gliomas also expressed endocan, and it was detected in palisading cells surrounding areas of necrosis in GBM. Endothelial cell endocan immunoreactivity also correlated with shorter survival in glioma patients. Taken together, these results suggest that endocan is associated with abnormal vasculature in high-grade gliomas.
 ...
PMID:Endocan expression and localization in human glioblastomas. 1945 46

Glial tumors exhibit a high morbidity and mortality because of their invasive nature. Matrix metalloproteinase 19 (MMP19) is a secreted protease that together with epilysin (MMP28) forms a structural subgroup of MMPs. We analyzed their expression by quantitative reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry in tumor and normal control brain tissues and in glioblastoma (GB) cells and performed MMP19 silencing functional assays. Matrix metalloproteinase 28 was transcribed to the same extent in normal brain samples and gliomas but was undetectable in GB cell lines. In contrast, MMP19 was detected by immunohistochemistry in normal brain samples only in endothelial cells but was found at high levels in astrocytomas of different World Health Organization grades in situ and in GB cells in vitro. Matrix metalloproteinase 19 was upregulated in GB cells after exposure to proinflammatory cytokines. In Transwell invasion assays, MMP19-silenced cells migrated more slowly through laminin-, basal lamina-, and brevican-coated membranes than controls. Matrix metalloproteinase 19-silenced GB cells also migrated into brain tissue slices compared with control cells. Brevican, a brain-specific proteoglycan and major component of brain extracellular matrix, was degraded by recombinant human MMP19. Taken together, these results indicate that MMP19 is highly expressed in proliferating astrocytoma/glioma cells, and that its expression may facilitate their invasion through brain extracellular matrix components.
 ...
PMID:Matrix metalloproteinase-19 is highly expressed in astroglial tumors and promotes invasion of glioma cells. 2014 69

Versican is a proteoglycan expressed in the extracellular matrix, where it regulates a variety of cell activities and affects tumor development. With alternative splicing, there are four versican isoforms, denoted V0, V1, V2 and V3. The V2 isoform is highly expressed in the mature brain but its function in the mature brain has not yet been elucidated. Since brain tumors are among the most angiogenic of human tumors, we investigated whether or not the V2 isoform plays a role in angiogenesis and found that the glioblastoma cell line U87 stably transfected with V2 formed tumors containing extensive vasculature. Although the V2-expressing cells grew slowly, they survived well in serum-free medium. They also displayed high adhesive ability to endothelial cells and facilitated tube-like structure formation. Importantly, fibronectin was up-regulated by V2 and mediated V2 function. Thus, versican V2 could be a potential target for intervention of brain tumor angiogenesis.
 ...
PMID:Versican V2 isoform enhances angiogenesis by regulating endothelial cell activities and fibronectin expression. 2320 Dec 64

Glioblastoma, a malignant brain cancer, is characterized by abnormal activation of receptor tyrosine kinase signalling pathways and a poor prognosis. Extracellular proteoglycans, including heparan sulfate and chondroitin sulfate, play critical roles in the regulation of cell signalling and migration via interactions with extracellular ligands, growth factor receptors and extracellular matrix components, as well as intracellular enzymes and structural proteins. In cancer, proteoglycans help drive multiple oncogenic pathways in tumour cells and promote critical tumour-microenvironment interactions. In the present review, we summarize the evidence for proteoglycan function in gliomagenesis and examine the expression of proteoglycans and their modifying enzymes in human glioblastoma using data obtained from The Cancer Genome Atlas (http://cancergenome.nih.gov/). Furthermore, we demonstrate an association between specific proteoglycan alterations and changes in receptor tyrosine kinases. Based on these data, we propose a model in which proteoglycans and their modifying enzymes promote receptor tyrosine kinase signalling and progression in glioblastoma, and we suggest that cancer-associated proteoglycans are promising biomarkers for disease and therapeutic targets.
 ...
PMID:Proteoglycans and their roles in brain cancer. 2328 50


<< Previous 1 2 3 4 Next >>