Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macro- and microvascular endothelial cells (EC) formed tubular structures when cultured within a 3D fibrin matrix, a process that was enhanced by vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), hepatocyte growth factor/scatter factor (HGF/SF) and an angiogenic cocktail composed of nine angiogenic factors. Endothelial tubulogenesis was also increased in co-culture with tumour cells such as U87 glioma cells, but not with non-tumorigenic cell types such as Madin-Darby canine kidney (MDCK) epithelial cells. VEGF/FGF-2-stimulated tube formation was dependent on metalloproteinase function [it is inhibited by the addition of tissue inhibitor of metalloproteinases-2 (TIMP-2)], whereas aprotinin, E64 [trans-epoxysuccinyl-L-leucylamido (4-guanidino)-butane] and pepstatin had no effect. In addition, TIMP-4 also inhibited tubulogenesis, but TIMP-1 or the C-terminal haemopexin domain of matrix metalloproteinase-2 (MMP-2) (PEX) and an anti-MMP-2 function-blocking antibody were unable to block tube formation. This suggests that MMP-2 and other soluble MMPs are not essential for tubulogenesis in fibrin gels, instead TIMP-1-insensitive MMPs, such as members of the membrane type-MMPs (MT-MMP) sub-group (MT1-, MT2-, MT3- or MT5-MMP), are required for this process. Further support for a role for MT1-MMP in endothelial tubulogenesis is that recombinant Y36G N-terminal TIMP-2 mutant protein, which retains an essentially unaltered apparent inhibition constant (K(i)(app)) for several MMPs compared to wild-type N-TIMP-2 but is a 40-fold poorer inhibitor of MT1-MMP, was unable to block tubulogenesis. Furthermore, when EC were cultured within fibrin gels, the mRNA levels of several MMPs (including MT1-MMP, MT2-MMP, MT3-MMP and MMP-2) increased during tubulogenesis. Therefore MT-MMPs and specifically MT1-MMP are likely candidates for involvement during endothelial tubulogenesis within a fibrin matrix, and thus their blockade may be a viable strategy for inhibition of angiogenesis.
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PMID:Endothelial tubulogenesis within fibrin gels specifically requires the activity of membrane-type-matrix metalloproteinases (MT-MMPs). 1215 73

Increased expression of membrane-type matrix metalloproteinases (MT-MMPs) has previously been reported to correlate with increasing grade of malignancy in gliomas, a relationship shared with alterations in epidermal growth factor receptor (EGFR) signaling. To investigate the possibility of a causative role for EGFR signaling in increasing MT-MMP expression and subsequent peritumoral proteolysis, we characterized glioma cell lines for expression of MT1-MMP, MT2-MMP, MT3-MMP, and MT5-MMP by Western blotting and by quantitative real-time polymerase chain reaction analysis, and for MMP-2 activity following epidermal growth factor (EGF) stimulation. EGF stimulation of glioma cell lines resulted in a 2- to 4-fold increase in MT1-MMP mRNA levels. Although there were slight differences in MT2-, MT3-, and MT5-MMP mRNA expression following EGF stimulation, none of these demonstrated an increase similar to that of MT1-MMP expression. Treatment of high-grade glioma cell lines U251MG and IPSB-18 with EGF for 24 h resulted in a several-fold increase in MT1-MMP protein (2.5- and 5.1-fold, respectively) and in cyclin D1 (2.9-fold), as compared to untreated controls. No significant increase was detected in other MT-MMPs at the protein level. Although there was no detectable increase in proMMP-2 protein, there was an increase in MMP-2 activity. Furthermore, the MT1-MMP induction by EGF was prevented by pretreatment with the EGFR-specific tyrphostin inhibitor AG1478. Similarly, treatment with the phosphatidylinositol 3-kinase inhibitor LY294002 prevented the induction of MT1-MMP protein by EGF stimulation. These compounds additionally inhibited EGF-stimulated invasion in Matrigel Transwell assays. Our results indicate that one mechanism of EGFR-mediated invasiveness in gliomas may involve the induction of MT1-MMP.
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PMID:Induction of membrane-type-1 matrix metalloproteinase by epidermal growth factor-mediated signaling in gliomas. 1527 11