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Article ; Online: CXCR2-Blocking Has Context-Sensitive Effects on Rat Glioblastoma Cell Line Outgrowth (S635) in an Organotypic Rat Brain Slice Culture Depending on Microglia-Depletion (PLX5622) and Dexamethasone Treatment

Johannes Falter / Annette Lohmeier / Petra Eberl / Eva-Maria Stoerr / Janne Koskimäki / Lena Falter / Jakob Rossmann / Tobias Mederer / Nils Ole Schmidt / Martin Proescholdt

International Journal of Molecular Sciences, Vol 24, Iss 23, p

2023 Volume 16803

Abstract: In glioblastoma (GBM), the interplay of different immune cell subtypes, cytokines, and/or drugs shows high context-dependencies. Interrelations between the routinely applied dexamethasone (Dex) and microglia remain elusive. Here, we exploited rat ... ...

Abstract	In glioblastoma (GBM), the interplay of different immune cell subtypes, cytokines, and/or drugs shows high context-dependencies. Interrelations between the routinely applied dexamethasone (Dex) and microglia remain elusive. Here, we exploited rat organotypic brain slice co-cultures (OBSC) to examine the effects on a rat GBM cell line (S635) outgrowth resulting from the presence of Dex and pretreatment with the colony-stimulating factor receptor 1 (CSF1-R) inhibitor PLX5622: in native OBSC (without PLX5622-pretreatment), a diminished S635 spheroid outgrowth was observable, whereas Dex-treatment enhanced outgrowth in this condition compared to PLX5622-pretreated OBSC. Screening the supernatants of our model with a proteome profiler, we found that CXCL2 was differentially secreted in a Dex- and PLX5622-dependent fashion. To analyze causal interrelations, we interrupted the CXCL2/CXCR2-axis: in the native OBSC condition, CXCR2-blocking resulted in increased outgrowth, in combination with Dex, we found potentiated outgrowth. No effect was found in the PLX5622-pretreated. Our method allowed us to study the influence of three different factors—dexamethasone, PLX5622, and CXCL2—in a well-controlled, simplified, and straight-forward mechanistic manner, and at the same time in a more realistic ex vivo scenario compared to in vitro studies. In our model, we showed a GBM outgrowth enhancing synergism between CXCR2-blocking and Dex-treatment in the native condition, which was levelled by PLX5622-pretreatment.
Keywords	glioblastoma ; OBSC ; dexamethasone ; PLX5622 ; CXCL2 ; danirixin ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	630
Language	English
Publishing date	2023-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Diabetes, use of metformin, and the risk of meningioma.

Corinna Seliger / Christoph R Meier / Claudia Becker / Susan S Jick / Martin Proescholdt / Ulrich Bogdahn / Peter Hau / Michael F Leitzmann

PLoS ONE, Vol 12, Iss 7, p e

2017 Volume 0181089

Abstract: Metformin is a commonly used oral antidiabetic agent that has been associated with decreased cancer risk. However, data regarding the association between metformin use and the risk of meningioma are unavailable.We conducted a matched case-control ... ...

Abstract	Metformin is a commonly used oral antidiabetic agent that has been associated with decreased cancer risk. However, data regarding the association between metformin use and the risk of meningioma are unavailable.We conducted a matched case-control analysis using data from the U.K.-based Clinical Practice Research Datalink (CPRD) to analyse diabetes status, duration of diabetes, glycemic control, and use of metformin, sulfonylureas, and insulin in relation to the risk of meningioma. We conducted conditional logistic regression analyses to determine relative risks, estimated as odds ratios (ORs) with 95% confidence intervals (CIs) and adjusted for body mass index, smoking, history of arterial hypertension, myocardial infarction, and use of estrogens (among women).We identified 2,027 meningioma cases and 20,269 controls. For diabetes there was the suggestion of an inverse association with meningioma (OR = 0.89; 95%CI = 0.74-1.07), which was driven by an inverse relation among women (OR = 0.78; 95%CI = 0.62-0.98), in whom we also noted a suggestive inverse association with duration of diabetes (p-value for trend = 0.071). For metformin there was a suggestive positive relation, particularly after matching on duration of diabetes and HbA1c level (OR = 1.64; 95%CI = 0.89-3.04). Sulfonylureas showed no clear association (OR = 0.91; 95%CI = 0.46-1.80). For insulin there was the suggestion of an inverse relation, in particular when comparing a high vs. low number of prescriptions (OR = 0.58; 95%CI = 0.18-1.83).Further studies are needed to solidify a possible inverse association between diabetes and meningioma risk and to clarify the role of antidiabetics in this context.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Combined Modulation of Tumor Metabolism by Metformin and Diclofenac in Glioma

Valeria Gerthofer / Marina Kreutz / Kathrin Renner / Birgit Jachnik / Katja Dettmer / Peter Oefner / Markus J. Riemenschneider / Martin Proescholdt / Arabel Vollmann-Zwerenz / Peter Hau / Corinna Seliger

International Journal of Molecular Sciences, Vol 19, Iss 9, p

2018 Volume 2586

Abstract: Glioblastoma remains a fatal diagnosis. Previous research has shown that metformin, which is an inhibitor of complex I of the respiratory chain, may inhibit some brain tumor initiating cells (BTICs), albeit at dosages that are too high for clinical use. ... ...

Abstract	Glioblastoma remains a fatal diagnosis. Previous research has shown that metformin, which is an inhibitor of complex I of the respiratory chain, may inhibit some brain tumor initiating cells (BTICs), albeit at dosages that are too high for clinical use. Here, we explored whether a combined treatment of metformin and diclofenac, which is a non-steroidal anti-inflammatory drug (NSAID) shown to inhibit glycolysis by interfering with lactate efflux, may lead to additive or even synergistic effects on BTICs (BTIC-8, -11, -13 and -18) and tumor cell lines (TCs, U87, and HTZ349). Therefore, we investigated the functional effects, including proliferation and migration, metabolic effects including oxygen consumption and extracellular lactate levels, and effects on the protein level, including signaling pathways. Functional investigation revealed synergistic anti-migratory and anti-proliferative effects of the combined treatment with metformin and diclofenac on BTICs and TCs. Signaling pathways did not sufficiently explain synergistic effects. However, we observed that metformin inhibited cellular oxygen consumption and increased extracellular lactate levels, indicating glycolytic rescue mechanisms. Combined treatment inhibited metformin-induced lactate increase. The combination of metformin and diclofenac may represent a promising new strategy in the treatment of glioblastoma. Combined treatment may reduce the effective doses of the single agents and prevent metabolic rescue mechanisms. Further studies are needed in order to determine possible side effects in humans.
Keywords	glioma ; BTICs ; metformin ; diclofenac ; lactate ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	572
Language	English
Publishing date	2018-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Use of statins or NSAIDs and survival of patients with high-grade glioma.

Corinna Seliger / Julia Schaertl / Michael Gerken / Christian Luber / Martin Proescholdt / Markus J Riemenschneider / Michael F Leitzmann / Peter Hau / Monika Klinkhammer-Schalke

PLoS ONE, Vol 13, Iss 12, p e

2018 Volume 0207858

Abstract: Background High-grade glioma (HGG) is associated with a limited prognosis. Drug repurposing has become of increasing interest to improve standard therapy. Statins and NSAIDs inhibit glioma cell growth in vitro and in vivo, but data on statin and NSAID ... ...

Abstract	Background High-grade glioma (HGG) is associated with a limited prognosis. Drug repurposing has become of increasing interest to improve standard therapy. Statins and NSAIDs inhibit glioma cell growth in vitro and in vivo, but data on statin and NSAID treatment in relation to survival of patients with HGG are sparse. Methods We performed multivariable adjusted Cox-regression analyses among 1,093 patients with HGG from a regional cancer registry to obtain Hazard Ratios (HRs) with 95% Confidence Intervals (CIs) for overall survival (OS) and progression-free survival (PFS) according to treatment with statins or NSAIDs. Data on dose and duration of treatment was mostly lacking in our analysis, therefore we were not able to perform dose-response analyses. Results Use of statins was unrelated to OS or PFS of glioma patients. Use of aspirin was associated with prolonged OS and PFS in patients with WHO grade III, but not WHO grade IV glioma. Use of other NSAIDs (diclofenac, ibuprofen) or non-NSAID analgesics (paracetamol) was mostly unrelated to survival of glioma patients. Use of selective COX-2 inhibitors and metamizol was related to inferior patient survival in parts of the analyses. Conclusions Use of statins or NSAIDS, including aspirin, was not associated with prolonged OS or PFS of patients with WHO grade IV glioma in our selected cohort. There was an indication for improved survival in patients with WHO grade III glioma using aspirin, but further studies are needed to confirm our first observation.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2018-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Morphology of Middle Cerebral Artery Aneurysms

Karl-Michael Schebesch / Martin Proescholdt / Kathrin Steib / Odo-Winfried Ullrich / Andreas Herbst / Janine Rennert / Alexander Brawanski

ISRN Stroke, Vol

Impact on Surgical Strategy and on Postoperative Outcome

2013 Volume 2013

Keywords	Diseases of the circulatory (Cardiovascular) system ; RC666-701 ; Specialties of internal medicine ; RC581-951 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Cardiovascular ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Hindawi Publishing Corporation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Validation Study

Sylvia Moeckel / Arabel Vollmann-Zwerenz / Martin Proescholdt / Alexander Brawanski / Markus J Riemenschneider / Ulrich Bogdahn / Anja-Katrin Bosserhoff / Rainer Spang / Peter Hau

PLoS ONE, Vol 11, Iss 3, p e

Response-Predictive Gene Expression Profiling of Glioma Progenitor Cells In Vitro.

2016 Volume 0151312

Abstract: In a previous publication we introduced a novel approach to identify genes that hold predictive information about treatment outcome. A linear regression model was fitted by using the least angle regression algorithm (LARS) with the expression profiles of ...

Abstract	In a previous publication we introduced a novel approach to identify genes that hold predictive information about treatment outcome. A linear regression model was fitted by using the least angle regression algorithm (LARS) with the expression profiles of a construction set of 18 glioma progenitor cells enhanced for brain tumor initiating cells (BTIC) before and after in vitro treatment with the tyrosine kinase inhibitor Sunitinib. Profiles from treated progenitor cells allowed predicting therapy-induced impairment of proliferation in vitro. Prediction performance was validated in leave one out cross validation.In this study, we used an additional validation set of 18 serum-free short-term treated in vitro cell cultures to test the predictive properties of the signature in an independent cohort. We assessed proliferation rates together with transcriptome-wide expression profiles after Sunitinib treatment of each individual cell culture, following the methods of the previous publication.We confirmed treatment-induced expression changes in our validation set, but our signature failed to predict proliferation inhibition. Neither re-calculation of the combined dataset with all 36 BTIC cultures nor separation of samples into TCGA subclasses did generate a proliferation prediction.Although the gene signature published from our construction set exhibited good prediction accuracy in cross validation, we were not able to validate the signature in an independent validation data set. Reasons could be regression to the mean, the moderate numbers of samples, or too low differences in the response to proliferation inhibition in the validation set. At this stage and based on the presented results, we conclude that the signature does not warrant further developmental steps towards clinical application.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Response-predictive gene expression profiling of glioma progenitor cells in vitro.

Sylvia Moeckel / Katharina Meyer / Petra Leukel / Fabian Heudorfer / Corinna Seliger / Christina Stangl / Ulrich Bogdahn / Martin Proescholdt / Alexander Brawanski / Arabel Vollmann-Zwerenz / Markus J Riemenschneider / Anja-Katrin Bosserhoff / Rainer Spang / Peter Hau

PLoS ONE, Vol 9, Iss 9, p e

2014 Volume 108632

Abstract: BACKGROUND:High-grade gliomas are amongst the most deadly human tumors. Treatment results are disappointing. Still, in several trials around 20% of patients respond to therapy. To date, diagnostic strategies to identify patients that will profit from a ... ...

Abstract	BACKGROUND:High-grade gliomas are amongst the most deadly human tumors. Treatment results are disappointing. Still, in several trials around 20% of patients respond to therapy. To date, diagnostic strategies to identify patients that will profit from a specific therapy do not exist. METHODS:In this study, we used serum-free short-term treated in vitro cell cultures to predict treatment response in vitro. This approach allowed us (a) to enrich specimens for brain tumor initiating cells and (b) to confront cells with a therapeutic agent before expression profiling. RESULTS:As a proof of principle we analyzed gene expression in 18 short-term serum-free cultures of high-grade gliomas enhanced for brain tumor initiating cells (BTIC) before and after in vitro treatment with the tyrosine kinase inhibitor Sunitinib. Profiles from treated progenitor cells allowed to predict therapy-induced impairment of proliferation in vitro. CONCLUSION:For the tyrosine kinase inhibitor Sunitinib used in this dataset, the approach revealed additional predictive information in comparison to the evaluation of classical signaling analysis.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Correction

Corinna Seliger / Petra Leukel / Sylvia Moeckel / Birgit Jachnik / Claudio Lottaz / Marina Kreutz / Alexander Brawanski / Martin Proescholdt / Ulrich Bogdahn / Anja-Katrin Bosserhoff / Arabel Vollmann-Zwerenz / Peter Hau

PLoS ONE, Vol 9, Iss

Lactate-Modulated Induction of THBS-1 Activates Transforming Growth Factor (TGF)-beta2 and Migration of Glioma Cells In Vitro

2014 Volume 1

Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Correction

PLoS ONE, Vol 9, Iss

Lactate-Modulated Induction of THBS-1 Activates Transforming Growth Factor (TGF)-beta2 and Migration of Glioma Cells.

2014 Volume 1

Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Lactate-modulated induction of THBS-1 activates transforming growth factor (TGF)-beta2 and migration of glioma cells in vitro.

PLoS ONE, Vol 8, Iss 11, p e

2013 Volume 78935

Abstract: Background An important phenomenon observed in glioma metabolism is increased aerobic glycolysis in tumor cells, which is generally referred to as the Warburg effect. Transforming growth factor (TGF)-beta2, which we previously showed to be induced by ... ...

Abstract	Background An important phenomenon observed in glioma metabolism is increased aerobic glycolysis in tumor cells, which is generally referred to as the Warburg effect. Transforming growth factor (TGF)-beta2, which we previously showed to be induced by lactic acid, is a key pathophysiological factor in glioblastoma, leading to increased invasion and severe local immunosuppression after proteolytic cleavage from its latency associated peptide. In this study we tested the hypothesis, that lactate regulates TGF-beta2 expression and glioma cell migration via induction of Thrombospondin-1 (THBS-1), a TGF-beta activating protein. Methods Lactate levels were reduced by knockdown of LDH-A using specific small interfering RNA (siRNA) and competitive inhibition of LDH-A by sodium oxamate. Knockdown of THBS-1 was performed using specific siRNA. Western Blot, qRT-PCR, and ELISA were used to investigate expression levels of LDH-A, LDH-B, TGF-beta2 and THBS-1. Migration of cells was examined by Spheroid, Scratch and Boyden Chamber assays. Results Knockdown of LDH-A with subsequent decrease of lactate concentration leads to reduced levels of THBS-1 and TGF-beta2 in glioma cells. Lactate addition increases THBS-1 protein, leading to increased activation of TGF-beta2. Inhibition of THBS-1 reduces TGF-beta2 protein and migration of glioma cells. Addition of synthetic THBS-1 can rescue reduced TGF-beta2 protein levels and glioma cell migration in siLDH-A treated cells. Conclusion We define a regulatory cascade between lactate, THBS-1 and TGF-beta2, leading to enhanced migration of glioma cells. Our results demonstrate a specific interaction between tumor metabolism and migration and provide a better understanding of the mechanisms underlying glioma cell invasion.
Keywords	Medicine ; R ; Science ; Q
Subject code	500
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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