Glioma cells on the run – the migratory transcriptome of 10 human glioma cell lines

<p>Abstract</p> <p>Background</p> <p>Glioblastoma multiforme (GBM) is the most common primary intracranial tumor and despite recent advances in treatment regimens, prognosis for affected patients remains poor. Active cell migration and invasion of GBM cells ultimately lead to ubiquitous tumor recurrence and patient death.</p> <p>To further understand the genetic mechanisms underlying the ability of glioma cells to migrate, we compared the matched transcriptional profiles of migratory and stationary populations of human glioma cells. Using a monolayer radial migration assay, motile and stationary cell populations from seven human long term glioma cell lines and three primary GBM cultures were isolated and prepared for expression analysis.</p> <p>Results</p> <p>Gene expression signatures of stationary and migratory populations across all cell lines were identified using a pattern recognition approach that integrates <it>a priori </it>knowledge with expression data. Principal component analysis (PCA) revealed two discriminating patterns between migrating and stationary glioma cells: i) global down-regulation and ii) global up-regulation profiles that were used in a proband-based rule function implemented in GABRIEL to find subsets of genes having similar expression patterns. Genes with up-regulation pattern in migrating glioma cells were found to be overexpressed in 75% of human GBM biopsy specimens compared to normal brain. A 22 gene signature capable of classifying glioma cultures based on their migration rate was developed. Fidelity of this discovery algorithm was assessed by validation of the invasion candidate gene, connective tissue growth factor (CTGF). siRNA mediated knockdown yielded reduced <it>in vitro </it>migration and <it>ex vivo </it>invasion; immunohistochemistry on glioma invasion tissue microarray confirmed up-regulation of CTGF in invasive glioma cells.</p> <p>Conclusion</p> <p>Gene expression profiling of migratory glioma cells induced to disperse <it>in vitro </it>affords discovery of genomic signatures; selected candidates were validated clinically at the transcriptional and translational levels as well as through functional assays thereby underscoring the fidelity of the discovery algorithm.</p

Derived from SAM analysis of union of and ; fast migrating cell lines colored in green, slow migrating cell lines colored in red ()

K-means (k = 3) identified three populations in malignant astrocytoma samples stratified by age that were visualized by multidimensional scaling (MDS); young (< median age) () and old patients (> median age) (). Kaplan-Meier survival analysis for clusters derived from k-means stratified by age; young (), old () show significant differences in overall survival.<p><b>Copyright information:</b></p><p>Taken from "Glioma cells on the run – the migratory transcriptome of 10 human glioma cell lines"</p><p>http://www.biomedcentral.com/1471-2164/9/54</p><p>BMC Genomics 2008;9():54-54.</p><p>Published online 29 Jan 2008</p><p>PMCID:PMC2275271.</p><p></p

Technical validation of microarray data by quantitative RT-PCR (QRT-PCR)

Average Log2 expression of relative mRNA copy numbers derived from three replicate microarray experiments and QRT-PCR of migratory (rim) over stationary (core) glioma cells (error bars = SD). Concordance between directionality of differential regulation between migratory and stationary cells for microarray and QRT-PCR data is displayed in parentheses (CYR61 = cystein rich 61, CTGF = connective tissue growth factor, RRAS2 = related RAS viral oncogene homolog 2, RhoA = ras homolog gene family member A, PCAF = p300/CBP-associated factor, ITM2B = integral membrane protein 2B, ZNF436 = zinc finger protein 436, MADH1 = mothers against decapentaplegic homolog 1 (). Expression pattern of () and () in comprehensive glioma expression data set (NB = normal brain, LGA = low grade astrocytoma, AA = anaplastic astrocytoma, GBM = glioblastoma multiforme). Bar indicates genes significantly (P < 0.05) differentially expressed between tumors and normal brain. Canonical pathways significantly over-represented in (black bars) and (white bar) ().<p><b>Copyright information:</b></p><p>Taken from "Glioma cells on the run – the migratory transcriptome of 10 human glioma cell lines"</p><p>http://www.biomedcentral.com/1471-2164/9/54</p><p>BMC Genomics 2008;9():54-54.</p><p>Published online 29 Jan 2008</p><p>PMCID:PMC2275271.</p><p></p

Hierarchical clustering of expression patterns of 20 core and rim samples ()

Scatterplot of principal component (PC) 9 against PC10 reveals two clouds representing core (black symbols) and rim samples (white symbols), respectively (). Proband gene AK098354 shows strong correlation with PC9, containing genes down-regulated in rim population () while cystein rich 61 (Cyr61) exhibits strong correlation with up-regulation pattern of PC10 (). GABRIEL was used to detect genes with similar expression patterns to proband genes AK098354 and Cyr61 ().<p><b>Copyright information:</b></p><p>Taken from "Glioma cells on the run – the migratory transcriptome of 10 human glioma cell lines"</p><p>http://www.biomedcentral.com/1471-2164/9/54</p><p>BMC Genomics 2008;9():54-54.</p><p>Published online 29 Jan 2008</p><p>PMCID:PMC2275271.</p><p></p

Search for top quark decays t → qH with H → γγ using the ATLAS detector

A search is performed for flavour-changing neutral currents in the decay of a top quark to an up-type (c, u) quark and a Higgs boson, where the Higgs boson decays to two photons. The proton-proton collision data set used corresponds to 4.7 fb-1 at √ = 7TeV and 20.3fb-1 at √ = 8TeV collected by the ATLAS experiment at the LHC. Top quark pair events are searched for in which one top quark decays to qH and the other decays to bW. Both the hadronic and the leptonic decay modes of the W boson are used. No significant signal is observed and an upper limit is set on the t → qH branching ratio of 0.79 at the 95% confidence level. The corresponding limit on the tqH coupling combination λtcH 2 + λtuH 2 is 0.17

Measurements of the Total and Differential Higgs Boson Production Cross Sections Combining the H??????? and H???ZZ*???4??? Decay Channels at s\sqrt{s}=8??????TeV with the ATLAS Detector

Measurements of the total and differential cross sections of Higgs boson production are performed using 20.3~fb$^{-1}$ of $pp$ collisions produced by the Large Hadron Collider at a center-of-mass energy of $\sqrt{s} = 8$ TeV and recorded by the ATLAS detector. Cross sections are obtained from measured $H \rightarrow \gamma \gamma$ and $H \rightarrow ZZ ^{*}\rightarrow 4\ell$ event yields, which are combined accounting for detector efficiencies, fiducial acceptances and branching fractions. Differential cross sections are reported as a function of Higgs boson transverse momentum, Higgs boson rapidity, number of jets in the event, and transverse momentum of the leading jet. The total production cross section is determined to be $\sigma_{pp \to H} = 33.0 \pm 5.3 \, ({\rm stat}) \pm 1.6 \, ({\rm sys}) \mathrm{pb}$. The measurements are compared to state-of-the-art predictions.Measurements of the total and differential cross sections of Higgs boson production are performed using 20.3  fb-1 of pp collisions produced by the Large Hadron Collider at a center-of-mass energy of s=8  TeV and recorded by the ATLAS detector. Cross sections are obtained from measured H→γγ and H→ZZ*→4ℓ event yields, which are combined accounting for detector efficiencies, fiducial acceptances, and branching fractions. Differential cross sections are reported as a function of Higgs boson transverse momentum, Higgs boson rapidity, number of jets in the event, and transverse momentum of the leading jet. The total production cross section is determined to be σpp→H=33.0±5.3 (stat)±1.6 (syst)  pb. The measurements are compared to state-of-the-art predictions.Measurements of the total and differential cross sections of Higgs boson production are performed using 20.3 fb$^{-1}$ of $pp$ collisions produced by the Large Hadron Collider at a center-of-mass energy of $\sqrt{s} = 8$ TeV and recorded by the ATLAS detector. Cross sections are obtained from measured $H \rightarrow \gamma \gamma$ and $H \rightarrow ZZ ^{*}\rightarrow 4\ell$ event yields, which are combined accounting for detector efficiencies, fiducial acceptances and branching fractions. Differential cross sections are reported as a function of Higgs boson transverse momentum, Higgs boson rapidity, number of jets in the event, and transverse momentum of the leading jet. The total production cross section is determined to be $\sigma_{pp \to H} = 33.0 \pm 5.3 \, ({\rm stat}) \pm 1.6 \, ({\rm sys}) \mathrm{pb}$. The measurements are compared to state-of-the-art predictions