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PPAR Gamma Activators: Off-Target Against Glioma Cell Migration and Brain Invasion.

Seufert S, Coras R, Tränkle C, Zlotos DP, Blümcke I, Tatenhorst L, Heneka MT, Hahnen E - PPAR Res (2008)

Bottom Line: Today, there is increasing evidence that PPARgamma agonists, including thiazolidinediones (TDZs) and nonthiazolidinediones, block the motility and invasiveness of glioma cells and other highly migratory tumor entities.However, the mechanism(s) by which PPARgamma activators mediate their antimigratory and anti-invasive properties remains elusive.This letter gives a short review on the debate and adds to the current knowledge by applying a PPARgamma inactive derivative of the TDZ troglitazone (Rezulin) which potently counteracts experimental glioma progression in a PPARgamma independent manner.

View Article: PubMed Central - PubMed

Affiliation: Institute of Human Genetics, Institute of Genetics, and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Kerpener Street 34, 50931 Cologne, Germany.

ABSTRACT
Today, there is increasing evidence that PPARgamma agonists, including thiazolidinediones (TDZs) and nonthiazolidinediones, block the motility and invasiveness of glioma cells and other highly migratory tumor entities. However, the mechanism(s) by which PPARgamma activators mediate their antimigratory and anti-invasive properties remains elusive. This letter gives a short review on the debate and adds to the current knowledge by applying a PPARgamma inactive derivative of the TDZ troglitazone (Rezulin) which potently counteracts experimental glioma progression in a PPARgamma independent manner.

No MeSH data available.


Related in: MedlinePlus

Δ2-Troglitazone inhibitsglioma progression in an organotypic glioma transplantation model. (a) Organotypic hippocampal gliomainvasion assay was performed as described earlier [10, 12, 30]. In brief, enhanced greenfluorescent protein (eGFP) positive F98 rat glioma cells were transplanted intothe entorhinal cortex of organotypic rat brain slice cultures one day after preparation. DAI= days after implantation. DG = dentate gyrus. EC = entorhinal cortex. (b) Tumor progression was monitored by fluorescentmicroscopy over the time course of 12 days. Quantification of the tumorinfiltration area at day 1 to day 12 after transplantation derived from 3independent experiments is shown. For each experiment, the tumor infiltrationarea at DAI 1 was defined as 100%. Data are given as mean ± SD percentage. AtDAI 12, the tumor infiltration area significantly increased to 448 ± 71 % (P = .002, t-test) in solvent-matched controls butremained unchanged following Δ2-TRO treatment (75 ± 22 %; P = .18, t-test). Starting from DAI 2,differences in tumor progression (TRO versus Δ2-TRO) reachedstatistical significance (P < .01, t-test) (c) Acontinuous increase of the bulk tumor masses was observed in solvent-matchedcontrols while 10 μM concentrations of Δ2-TRO effectivelyblocked tumor progression. Right column: magnification of the indicated borderarea between bulk tumor mass and rat brain tissue. In controls, F98 gliomacells have diffusely migrated into the adjacent brain parenchyma, while a sharptumor border was observed following Δ2-TRO treatment (scale bar: 200 μm).
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fig3: Δ2-Troglitazone inhibitsglioma progression in an organotypic glioma transplantation model. (a) Organotypic hippocampal gliomainvasion assay was performed as described earlier [10, 12, 30]. In brief, enhanced greenfluorescent protein (eGFP) positive F98 rat glioma cells were transplanted intothe entorhinal cortex of organotypic rat brain slice cultures one day after preparation. DAI= days after implantation. DG = dentate gyrus. EC = entorhinal cortex. (b) Tumor progression was monitored by fluorescentmicroscopy over the time course of 12 days. Quantification of the tumorinfiltration area at day 1 to day 12 after transplantation derived from 3independent experiments is shown. For each experiment, the tumor infiltrationarea at DAI 1 was defined as 100%. Data are given as mean ± SD percentage. AtDAI 12, the tumor infiltration area significantly increased to 448 ± 71 % (P = .002, t-test) in solvent-matched controls butremained unchanged following Δ2-TRO treatment (75 ± 22 %; P = .18, t-test). Starting from DAI 2,differences in tumor progression (TRO versus Δ2-TRO) reachedstatistical significance (P < .01, t-test) (c) Acontinuous increase of the bulk tumor masses was observed in solvent-matchedcontrols while 10 μM concentrations of Δ2-TRO effectivelyblocked tumor progression. Right column: magnification of the indicated borderarea between bulk tumor mass and rat brain tissue. In controls, F98 gliomacells have diffusely migrated into the adjacent brain parenchyma, while a sharptumor border was observed following Δ2-TRO treatment (scale bar: 200 μm).

Mentions: In agreement with the finding that TGF-β1 promotes glioma cell migration and braininvasion, treatment of glioma cells with micromolar doses of Δ2-troglitazoneeffectively blocks their migrative properties (Figure 2). Already 10 μM dosesof Δ2-troglitazone inhibit F98 glioma cell migration in a Boyden chamber assay, while migration was completelysuppressed at 20 μM. An intriguing question is whether inhibition of gliomacell migration alone is sufficient to counteract glioma progression. To addressthis issue we employed rat organotypic hippocampal brain slice cultures (OHSCs)to monitor glioma progression and brain invasion in the organotypic brainenvironment [12]. Here, eGFP-labelled F98 glioma cells were implanted into theentorhinal cortex of OHSCs (Figure 3(a)). The tumor infiltration area wasquantified up to 12 days by fluorescence microscopy. A continuous increase ofthe bulk tumor mass was observed in solvent-matched control experimentsat all time periods. 12 days after glioma cell implantation, the tumorinfiltration area increased approximately 4.5 fold compared to the initialtumor size at day 1 after implantation (Figures 3(b), 3(c)). In contrast, thetumor infiltration size remained stable over the period of 12 days aftertreatment with 10 μM Δ2-troglitazone. Thisfinding indicates that Δ2-troglitazone is notable to reduce existing tumor masses, but effectively inhibits tumorprogression and brain invasion in an organotypic environment. Given the factthat 10 μM doses of Δ2-troglitazonesignificantly affect TGF-β1 release (Figure 1(d)) and glioma cellmotility (Figure 2) but not glioma cell viability (Figure 1(c)), these data suggest that glioma cellmigration is an essential requirement for glioma progression in a system closely resembling extracellular matrix environment presentin the brain.


PPAR Gamma Activators: Off-Target Against Glioma Cell Migration and Brain Invasion.

Seufert S, Coras R, Tränkle C, Zlotos DP, Blümcke I, Tatenhorst L, Heneka MT, Hahnen E - PPAR Res (2008)

Δ2-Troglitazone inhibitsglioma progression in an organotypic glioma transplantation model. (a) Organotypic hippocampal gliomainvasion assay was performed as described earlier [10, 12, 30]. In brief, enhanced greenfluorescent protein (eGFP) positive F98 rat glioma cells were transplanted intothe entorhinal cortex of organotypic rat brain slice cultures one day after preparation. DAI= days after implantation. DG = dentate gyrus. EC = entorhinal cortex. (b) Tumor progression was monitored by fluorescentmicroscopy over the time course of 12 days. Quantification of the tumorinfiltration area at day 1 to day 12 after transplantation derived from 3independent experiments is shown. For each experiment, the tumor infiltrationarea at DAI 1 was defined as 100%. Data are given as mean ± SD percentage. AtDAI 12, the tumor infiltration area significantly increased to 448 ± 71 % (P = .002, t-test) in solvent-matched controls butremained unchanged following Δ2-TRO treatment (75 ± 22 %; P = .18, t-test). Starting from DAI 2,differences in tumor progression (TRO versus Δ2-TRO) reachedstatistical significance (P < .01, t-test) (c) Acontinuous increase of the bulk tumor masses was observed in solvent-matchedcontrols while 10 μM concentrations of Δ2-TRO effectivelyblocked tumor progression. Right column: magnification of the indicated borderarea between bulk tumor mass and rat brain tissue. In controls, F98 gliomacells have diffusely migrated into the adjacent brain parenchyma, while a sharptumor border was observed following Δ2-TRO treatment (scale bar: 200 μm).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2542841&req=5

fig3: Δ2-Troglitazone inhibitsglioma progression in an organotypic glioma transplantation model. (a) Organotypic hippocampal gliomainvasion assay was performed as described earlier [10, 12, 30]. In brief, enhanced greenfluorescent protein (eGFP) positive F98 rat glioma cells were transplanted intothe entorhinal cortex of organotypic rat brain slice cultures one day after preparation. DAI= days after implantation. DG = dentate gyrus. EC = entorhinal cortex. (b) Tumor progression was monitored by fluorescentmicroscopy over the time course of 12 days. Quantification of the tumorinfiltration area at day 1 to day 12 after transplantation derived from 3independent experiments is shown. For each experiment, the tumor infiltrationarea at DAI 1 was defined as 100%. Data are given as mean ± SD percentage. AtDAI 12, the tumor infiltration area significantly increased to 448 ± 71 % (P = .002, t-test) in solvent-matched controls butremained unchanged following Δ2-TRO treatment (75 ± 22 %; P = .18, t-test). Starting from DAI 2,differences in tumor progression (TRO versus Δ2-TRO) reachedstatistical significance (P < .01, t-test) (c) Acontinuous increase of the bulk tumor masses was observed in solvent-matchedcontrols while 10 μM concentrations of Δ2-TRO effectivelyblocked tumor progression. Right column: magnification of the indicated borderarea between bulk tumor mass and rat brain tissue. In controls, F98 gliomacells have diffusely migrated into the adjacent brain parenchyma, while a sharptumor border was observed following Δ2-TRO treatment (scale bar: 200 μm).
Mentions: In agreement with the finding that TGF-β1 promotes glioma cell migration and braininvasion, treatment of glioma cells with micromolar doses of Δ2-troglitazoneeffectively blocks their migrative properties (Figure 2). Already 10 μM dosesof Δ2-troglitazone inhibit F98 glioma cell migration in a Boyden chamber assay, while migration was completelysuppressed at 20 μM. An intriguing question is whether inhibition of gliomacell migration alone is sufficient to counteract glioma progression. To addressthis issue we employed rat organotypic hippocampal brain slice cultures (OHSCs)to monitor glioma progression and brain invasion in the organotypic brainenvironment [12]. Here, eGFP-labelled F98 glioma cells were implanted into theentorhinal cortex of OHSCs (Figure 3(a)). The tumor infiltration area wasquantified up to 12 days by fluorescence microscopy. A continuous increase ofthe bulk tumor mass was observed in solvent-matched control experimentsat all time periods. 12 days after glioma cell implantation, the tumorinfiltration area increased approximately 4.5 fold compared to the initialtumor size at day 1 after implantation (Figures 3(b), 3(c)). In contrast, thetumor infiltration size remained stable over the period of 12 days aftertreatment with 10 μM Δ2-troglitazone. Thisfinding indicates that Δ2-troglitazone is notable to reduce existing tumor masses, but effectively inhibits tumorprogression and brain invasion in an organotypic environment. Given the factthat 10 μM doses of Δ2-troglitazonesignificantly affect TGF-β1 release (Figure 1(d)) and glioma cellmotility (Figure 2) but not glioma cell viability (Figure 1(c)), these data suggest that glioma cellmigration is an essential requirement for glioma progression in a system closely resembling extracellular matrix environment presentin the brain.

Bottom Line: Today, there is increasing evidence that PPARgamma agonists, including thiazolidinediones (TDZs) and nonthiazolidinediones, block the motility and invasiveness of glioma cells and other highly migratory tumor entities.However, the mechanism(s) by which PPARgamma activators mediate their antimigratory and anti-invasive properties remains elusive.This letter gives a short review on the debate and adds to the current knowledge by applying a PPARgamma inactive derivative of the TDZ troglitazone (Rezulin) which potently counteracts experimental glioma progression in a PPARgamma independent manner.

View Article: PubMed Central - PubMed

Affiliation: Institute of Human Genetics, Institute of Genetics, and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Kerpener Street 34, 50931 Cologne, Germany.

ABSTRACT
Today, there is increasing evidence that PPARgamma agonists, including thiazolidinediones (TDZs) and nonthiazolidinediones, block the motility and invasiveness of glioma cells and other highly migratory tumor entities. However, the mechanism(s) by which PPARgamma activators mediate their antimigratory and anti-invasive properties remains elusive. This letter gives a short review on the debate and adds to the current knowledge by applying a PPARgamma inactive derivative of the TDZ troglitazone (Rezulin) which potently counteracts experimental glioma progression in a PPARgamma independent manner.

No MeSH data available.


Related in: MedlinePlus