meningioma cell
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Author(s):  
Peter John ◽  
Natalie Waldt ◽  
Josephine Liebich ◽  
Christoph Kesseler ◽  
Stefan Schnabel ◽  
...  

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3298
Author(s):  
Philipp Selke ◽  
Kaya Bork ◽  
Tao Zhang ◽  
Manfred Wuhrer ◽  
Christian Strauss ◽  
...  

Meningiomas are the most common non-malignant intracranial tumors and prefer, like most tumors, anaerobic glycolysis for energy production (Warburg effect). This anaerobic glycolysis leads to an increased synthesis of the metabolite methylglyoxal (MGO) or glyoxal (GO), which is known to react with amino groups of proteins. This reaction is called glycation, thereby building advanced glycation end products (AGEs). In this study, we investigated the influence of glycation on sialylation in two meningioma cell lines, representing the WHO grade I (BEN-MEN-1) and the WHO grade III (IOMM-Lee). In the benign meningioma cell line, glycation led to differences in expression of sialyltransferases (ST3GAL1/2/3/5/6, ST6GAL1/2, ST6GALNAC2/6, and ST8SIA1/2), which are known to play a role in tumor progression. We could show that glycation of BEN-MEN-1 cells led to decreased expression of ST3Gal5. This resulted in decreased synthesis of the ganglioside GM3, the product of ST3Gal5. In the malignant meningioma cell line, we observed changes in expression of sialyltransferases (ST3GAL1/2/3, ST6GALNAC5, and ST8SIA1) after glycation, which correlates with less aggressive behavior.


Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5898
Author(s):  
Tao Yu ◽  
Junguo Cao ◽  
Montadar Alaa Eddine ◽  
Mahmoud Moustafa ◽  
Andreas Mock ◽  
...  

To date, there is no standard-of-care systemic therapy for the treatment of aggressive meningiomas. Receptor tyrosine kinases (RTK) are frequently expressed in aggressive meningiomas and are associated with poor survival. Ponatinib is a FDA- and EMA-approved RTK inhibitor and its efficacy in meningioma has not been studied so far. Therefore, we investigated ponatinib as a potential drug candidate against meningioma. Cell viability and cell proliferation of ponatinib-treated meningioma cells were assessed using crystal violet assay, manual counting and BrdU assay. Treated meningioma cell lines were subjected to flow cytometry to evaluate the effects on cell cycle and apoptosis. Meningioma-bearing mice were treated with ponatinib to examine antitumor effects in vivo. qPCR was performed to assess the mRNA levels of tyrosine kinase receptors after ponatinib treatment. Full-length cDNA sequencing was carried out to assess differential gene expression. IC50 values of ponatinib were between 171.2 and 341.9 nM in three meningioma cell lines. Ponatinib induced G0/G1 cell cycle arrest and subsequently led to an accumulation of cells in the subG1-phase. A significant induction of apoptosis was observed in vitro. In vivo, ponatinib inhibited meningioma growth by 72.6%. Mechanistically, this was associated with downregulation of PDGFRA/B and FLT3 mRNA levels, and mitochondrial dysfunction. Taken together, ponatinib is a promising candidate for targeted therapy in the treatment of aggressive meningioma.


Author(s):  
Masahiro Yamamoto ◽  
Tomomi Sanomachi ◽  
Shuhei Suzuki ◽  
Keita Togashi ◽  
Asuka Sugai ◽  
...  

Abstract Background Malignant meningioma is an aggressive tumor that requires adjuvant radiotherapy after surgery, yet there has been no standard systemic therapy established so far. We recently reported that malignant meningioma cells are highly sensitive to gemcitabine; however, it remains unknown whether or how gemcitabine interacts with ionizing radiation (IR) in malignant meningioma cells. Methods We examined radiosensitization effects of gemcitabine using malignant meningioma cell lines and xenografts and explored the underlying mechanisms. Results Gemcitabine sensitized malignant meningioma cells to IR through the induction of senescence both in vitro and in vivo. Gemcitabine augmented the intracellular production of reactive oxygen species (ROS) by IR, which, together with cell growth suppression/senescence induced by this combination, was inhibited by N-acetyl-cysteine, suggesting a pivotal role for ROS in these combinatorial effects. Navitoclax, a senolytic drug that inhibits Bcl-2 proteins, further enhanced the effects of the combination of gemcitabine and IR by strongly inducing apoptotic cell death in senescent cells. Conclusion These results not only indicate the potential of gemcitabine as a candidate radiosensitizer for malignant meningioma, but also reveal a novel role for gemcitabine radiosensitization as a means to create a therapeutic vulnerability of senescent meningioma cells to senolytics.


2021 ◽  
Vol 10 (14) ◽  
pp. 3150
Author(s):  
Philip D. Tatman ◽  
Tadeusz H. Wroblewski ◽  
Anthony R. Fringuello ◽  
Samuel R. Scherer ◽  
William B. Foreman ◽  
...  

Background: Meningiomas are the most common primary central nervous system tumors. 20–30% of these tumors are considered high-grade and associated with poor prognosis and high recurrence rates. Despite the high occurrence of meningiomas, there are no FDA-approved compounds for the treatment of these tumors. Methods: In this study, we screened patient-cultured meningiomas with an epigenetic compound library to identify targetable mechanisms for the potential treatment of these tumors. Meningioma cell cultures were generated directly from surgically resected patient tumors and were cultured on a neural matrix. Cells were treated with a library of compounds meant to target epigenetic functions. Results: Although each tumor displayed a unique compound sensitivity profile, Panobinostat, LAQ824, and HC toxin were broadly effective across most tumors. These three compounds are broad-spectrum Histone Deacetylase (HDAC) inhibitors which target class I, IIa, and IIb HDACs. Panobinostat was identified as the most broadly effective compound, capable of significantly decreasing the average cell viability of the sample cohort, regardless of tumor grade, recurrence, radiation, and patient gender. Conclusions: These findings strongly suggest an important role of HDACs in meningioma biology and as a targetable mechanism. Additional validation studies are necessary to confirm these promising findings, as well to identify an ideal HDAC inhibitor candidate to develop for clinical use.


2021 ◽  
Vol 35 (S1) ◽  
Author(s):  
Erik White ◽  
Jesus Romero ◽  
Michael Prabhu ◽  
Samantha Beck ◽  
Vikram Prabhu ◽  
...  

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Philipp Selke ◽  
Philip Rosenstock ◽  
Kaya Bork ◽  
Christian Strauss ◽  
Rüdiger Horstkorte ◽  
...  

Abstract Meningiomas are the most common non-malignant intracranial tumors. Like most tumors, meningiomas prefer anaerobic glycolysis for energy production (Warburg effect). This leads to an increased synthesis of the metabolite methylglyoxal (MGO). This metabolite is known to react with amino groups of proteins. This reaction is called glycation, thereby building advanced glycation endproducts (AGEs). In this study, we investigated the influence of glycation on two meningioma cell lines, representing the WHO grade I (BEN-MEN-1) and the WHO grade III (IOMM-Lee). Increasing MGO concentrations led to the formation of AGEs and decreased growth in both cell lines. When analyzing the influence of glycation on adhesion, chemotaxis and invasion, we could show that the glycation of meningioma cells resulted in increased invasive potential of the benign meningioma cell line, whereas the invasive potential of the malignant cell line was reduced. In addition, glycation increased the E-cadherin- and decreased the N-cadherin-expression in BEN-MEN-1 cells, but did not affect the cadherin-expression in IOMM-Lee cells.


2020 ◽  
pp. 1-10
Author(s):  
Louise Stögbauer ◽  
Christian Thomas ◽  
Andrea Wagner ◽  
Nils Warneke ◽  
Eva Christine Bunk ◽  
...  

OBJECTIVEChemotherapeutic options for meningiomas refractory to surgery or irradiation are largely unknown. Human telomerase reverse transcriptase (hTERT) promoter methylation with subsequent TERT expression and telomerase activity, key features in oncogenesis, are found in most high-grade meningiomas. Therefore, the authors investigated the impact of the demethylating agent decitabine (5-aza-2ʹ-deoxycytidine) on survival and DNA methylation in meningioma cells.METHODShTERT promoter methylation, telomerase activity, TERT expression, and cell viability and proliferation were investigated prior to and after incubation with decitabine in two benign (HBL-52 and Ben-Men 1) and one malignant (IOMM-Lee) meningioma cell line. The global effects of decitabine on DNA methylation were additionally explored with DNA methylation profiling.RESULTSHigh levels of TERT expression, telomerase activity, and hTERT promoter methylation were found in IOMM-Lee and Ben-Men 1 but not in HBL-52 cells. Decitabine induced a dose-dependent significant decrease of proliferation and viability after incubation with doses from 1 to 10 μM in IOMM-Lee but not in HBL-52 or Ben-Men 1 cells. However, effects in IOMM-Lee cells were not related to TERT expression, telomerase activity, or hTERT promoter methylation. Genome-wide methylation analyses revealed distinct demethylation of 14 DNA regions after drug administration in the decitabine-sensitive IOMM-Lee but not in the decitabine-resistant HBL-52 cells. Differentially methylated regions covered promoter regions of 11 genes, including several oncogenes and tumor suppressor genes that to the authors’ knowledge have not yet been described in meningiomas.CONCLUSIONSDecitabine decreases proliferation and viability in high-grade but not in benign meningioma cell lines. The effects of decitabine are TERT independent but related to DNA methylation changes of promoters of distinct tumor suppressor genes and oncogenes.


2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii101-ii101
Author(s):  
Christoph Kesseler ◽  
Julian Kahr ◽  
Natalie Waldt ◽  
Nele Stroscher ◽  
Josephine Liebig ◽  
...  

Abstract PURPOSE To evaluate the role of the small GTPases RhoA, Rac1 and Cdc42 in meningiomas as therapeutic targets and their interactions in meningiomas. EXPERIMENTAL DESIGN We analyzed expression of GTPases in human meningioma samples and meningioma cell lines of various WHO grades. Malignant IOMM-Lee meningioma cells were used to generate shRNA mediated knockdowns of GTPases RhoA, Rac1 or Cdc42 and to study knockdown effects on proliferation and migration, as well as analysis of cell morphology by confocal microscopy. The same tests were used to investigate effects of the two inhibitors Fasudil and EHT-1864 of malignant IOMM-Lee, KT21 and benign Ben-Men cells and the effects of these drugs on IOMM-Lee knockdown cells. The effects of GTPase knockdowns and Fasudil treatment were studied in terms of overall survival by intracranial xenografts of mice. Potential interactions of GTPases regarding NF2, mTOR and FAK-Paxillin were examined. RESULTS Small GTPases were upregulated in meningiomas of higher tumor grades. Reduced proliferation and migration could be achieved by GTPase knockdown in IOMM-Lee cells. Additionally, the ROCK-inhibitor Fasudil and Rac1-inhibitor EHT-1864 reduced proliferation in different meningioma cell lines and reduced proliferation and migration independent of GTPase knockdowns/status. Moreover, overall survival in vivo could also be increased by knockdowns of RhoA and Rac1 as well as Fasudil treatment. GTPase expression was affected dependent on the NF2 status but effects were not very distinct, indicating that NF2 is not strongly involved in GTPase regulation in meningiomas. In terms of mTOR and FAK-Paxillin signaling, each GTPase changes those pathways in a different manner. CONCLUSION Small GTPases are important effectors in meningioma proliferation and migration in vitro as well as survival in vivo and their inhibition should be considered as potential treatment option.


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