Meningioma achieves malignancy and erastin-induced ferroptosis resistance through FOXM1-AURKA-NRF2 axis.

The oncogene Aurora kinase A (AURKA) has been implicated in various tumor, yet its role in meningioma remains unexplored. Recent studies have suggested a potential link between AURKA and ferroptosis, although the underlying mechanisms are unclear. This study presented evidence of AURKA upregulation in high grade meningioma and its ability to enhance malignant characteristics. We identified AURKA as a suppressor of erastin-induced ferroptosis in meningioma. Mechanistically, AURKA directly interacted with and phosphorylated kelch-like ECH-associated protein 1 (KEAP1), thereby activating nuclear factor erythroid 2 related factor 2 (NFE2L2/NRF2) and target genes transcription. Additionally, forkhead box protein M1 (FOXM1) facilitated the transcription of AURKA. Suppression of AURKA, in conjunction with erastin, yields significant enhancements in the prognosis of a murine model of meningioma. Our study elucidates an unidentified mechanism by which AURKA governs ferroptosis, and strongly suggests that the combination of AURKA inhibition and ferroptosis-inducing agents could potentially provide therapeutic benefits for meningioma treatment.

[Methylthioadenosine phosphorylase and p16 as surrogate diagnostic markers for CDKN2A homozygous deletion in brain tumors].

Objective: To examine whether immunohistochemistry of methylthioadenosine phosphorylase (MTAP) and p16 could be used to predict the CDKN2A status in various brain tumors. Methods: A total of 118 cases of IDH-mutant astrocytomas, 16 IDH-wildtype glioblastoma, 17 polymorphic xanthoastrocytoma (PXA) and 20 meningiomas diagnosed at Xuanwu Hospital, Capital Medical University, Beijing, China from November 2017 to October 2023 were collected and analyzed. The CDKN2A status was detected by using fluorescence in situ hybridization or next-generation sequencing. Expression of MTAP and p16 proteins was detected with immunohistochemistry. The association of loss of MTAP/p16 expression with CDKN2A homozygous/heterozygous deletion was examined. Results: Among the 118 cases of IDH-mutant astrocytoma, 13 cases showed homozygous deletion of CDKN2A. All of them had no expression of MTAP while 9 cases had no expression of p16. Among the 16 cases of IDH wild-type glioblastoma, 6 cases showed homozygous deletion of CDKN2A. All 6 cases had no expression of MTAP, while 3 of these cases had no expression of p16 expression. Among the 17 PXA cases, 4 cases showed homozygous deletion of CDKN2A, and the expression of MTAP and p16 was also absent in these 4 cases. Among the 20 cases of meningiomas, 4 cases showed homozygous deletion of CDKN2A. Their expression of MTAP and p16 was also absent. Among the four types of brain tumors, MTAP was significantly correlated with CDKN2A homozygous deletion (P<0.05), with a sensitivity of 100%. However, it was only significantly correlated with the loss of heterozygosity (LOH) of CDKN2A in astrocytomas (P<0.001). P16 was associated with CDKN2A homozygous deletion in IDH-mutant astrocytoma and PXA (P<0.001), but not with the LOH of CDKN2A. Its sensitivity and specificity were lower than that of MTAP. Conclusions: MTAP could serve as a predictive surrogate for CDKN2A homozygous deletion in adult IDH-mutant astrocytoma, PXA, adult IDH-wildtype glioblastoma and meningioma. However, p16 could only be used in the first two tumor types, and its specificity and sensitivity are lower than that of MTAP.

The OTX2 Gene Induces Tumor Growth and Triggers Leptomeningeal Metastasis by Regulating the mTORC2 Signaling Pathway in Group 3 Medulloblastomas.

Medulloblastoma (MB) encompasses diverse subgroups, and leptomeningeal disease/metastasis (LMD) plays a substantial role in associated fatalities. Despite extensive exploration of canonical genes in MB, the molecular mechanisms underlying LMD and the involvement of the orthodenticle homeobox 2 (OTX2) gene, a key driver in aggressive MB Group 3, remain insufficiently understood. Recognizing OTX2's pivotal role, we investigated its potential as a catalyst for aggressive cellular behaviors, including migration, invasion, and metastasis. OTX2 overexpression heightened cell growth, motility, and polarization in Group 3 MB cells. Orthotopic implantation of OTX2-overexpressing cells in mice led to reduced median survival, accompanied by the development of spinal cord and brain metastases. Mechanistically, OTX2 acted as a transcriptional activator of the Mechanistic Target of Rapamycin (mTOR) gene's promoter and the mTORC2 signaling pathway, correlating with upregulated downstream genes that orchestrate cell motility and migration. Knockdown of mTOR mRNA mitigated OTX2-mediated enhancements in cell motility and polarization. Analysis of human MB tumor samples (N = 952) revealed a positive correlation between OTX2 and mTOR mRNA expression, emphasizing the clinical significance of OTX2's role in the mTORC2 pathway. Our results reveal that OTX2 governs the mTORC2 signaling pathway, instigating LMD in Group 3 MBs and offering insights into potential therapeutic avenues through mTORC2 inhibition.

Magnetic resonance and computed tomographic imaging characteristics and potential molecular mechanisms of feline meningioma associated calvarial hyperostosis.

Meningiomas are the most common feline primary brain tumours, and calvarial hyperostosis (CH) is frequently documented in association with this neoplastic entity. The clinical significance of and mechanisms driving the formation of CH in cats with meningiomas are poorly understood, although tumour invasion into the skull and tumour production of cytokines and enzymes have been implicated as causes of CH in humans. This retrospective study investigated relationships between signalment, MRI or CT imaging features, histopathologic tumour characteristics, alkaline phosphatase (ALP) isoenzyme concentrations, tumour expression of matrix metalloproteinases (MMP)-2, MMP-9, and interleukin-6 (IL-6), and progression free survival times (PFS) following surgical treatment in 27 cats with meningiomas with (n = 15) or without (n = 12) evidence of CH. No significant differences in breed, age, sex, body weight, tumour grade, tumour volume, peritumoral edema burden, ALP isoenzyme concentrations, tumour Ki-67 labelling indices or MMP-2 or MMP-9 expression and activity, or PFS were noted between cats with or without CH. There was a trend towards higher serum (p = .06) and intratumoral (p = .07) concentrations of IL-6 in cats with CH, but these comparisons were not statistically significant. Histologic evidence of tumour invasion into bone was observed in 5/12 (42%) with CH and in no (0/6) cats without CH, although this was not statistically significant (p = .07). Tumour invasion into bone and tumour production of IL-6 may contribute to the formation of meningioma associated CH in cats, although larger studies are required to further substantiate these findings and determine their clinical relevance.

Drug target therapy and emerging clinical relevance of exosomes in meningeal tumors.

Meningioma is the most common central nervous system (CNS) tumor. In recent decades, several efforts have been made to eradicate this disease. Surgery and radiotherapy remain the standard treatment options for these tumors. Drug therapy comes to play its role when both surgery and radiotherapy fail to treat the tumor. This mostly happens when the tumors are close to vital brain structures and are nonbenign. Although a wide variety of chemotherapeutic drugs and molecular targeted drugs such as tyrosine kinase inhibitors, alkylating agents, endocrine drugs, interferon, and targeted molecular pathway inhibitors have been studied, the roles of numerous drugs remain unexplored. Recent interest is growing toward studying and engineering exosomes for the treatment of different types of cancer including meningioma. The latest studies have shown the involvement of exosomes in the theragnostic of various cancers such as the lung and pancreas in the form of biomarkers, drug delivery vehicles, and vaccines. Proper attention to this new emerging technology can be a boon in finding the consistent treatment of meningioma.

Expression of miRNA-451 and miRNA-885 in Meningiomas.

BACKGROUND/AIM: Meningiomas are one of the most common intracranial tumors, accounting for 30% of the tumors of the central nervous system. MicroRNAs (miRNAs) are noncoding RNAs containing approximately 18-22 nucleotides that regulate gene expression by interfering with transcription or inhibiting translation. Recent studies have reported that miRNAs could provide information about the molecular pathogenesis of several types of tumors. This study aimed to examine the expression levels of miRNA-885 and -451 and to determine their potential roles as biomarkers in meningioma. MATERIALS AND METHODS: In total, 29 patients with meningioma (9 males and 20 females) were included in this study. The expression levels of miRNA were determined using real-time polymerase chain reaction. In addition, receiver operating characteristic curve analysis was used to analyze the predictive potential of miRNAs. RESULTS: Our results indicated a significant increase in miRNA-451 expression levels (p=0.003); however, there was no significant change in miRNA-885 expression levels (p=0.139) in patients with meningioma compared with the control group. Moreover, miRNA-885 and miRNA-451 expression levels did not differ significantly based on the histopathological grade of meningioma. CONCLUSION: miRNA-451 may be a novel potential marker for the diagnosis and prognosis, and a target for meningioma treatment.

The usefulness of [68 Ga]Ga-DOTA-JR11 PET/CT in patients with meningioma: comparison with MRI.

PURPOSE: Clinical studies of PET imaging using SSTR2 agonists have demonstrated high accuracy and correlation with SSTR2 expression in meningiomas. However, the usefulness of the SSTR2 antagonist with [68 Ga]Ga-DOTA-JR11 is uncertain. To evaluate the diagnostic performance of [68 Ga]Ga-DOTA-JR11 PET/CT and to clarify tumor characteristics in patients with suspected meningiomas. MATERIALS AND METHODS: Patients with suspected de novo or recurrent meningioma in complex locations or atypical images were enrolled from August 2021 to October 2022 in prospective study. All patients underwent contrast-enhanced MRI (CE-MRI), [68 Ga]Ga-DOTA-JR11 PET/CT, and histopathological evaluation. Tumor uptake of [68 Ga]Ga-DOTA-JR11 was measured by SUVmax and tumor-endocranium ratio (TBR). Diagnostic performance was compared between PET and MRI. RESULTS: Of 36 (50.0 ± 13.0 years of age, 20 women) patients, 32 were histopathologically confirmed meningiomas and four with other tumors. [68 Ga]Ga-DOTA-JR11 uptake was significantly higher in meningioma patients than in those with other tumors (SUVmax: 13.6 ± 7.7 vs. 5.2 ± 3.0, P < 0.001; TBR: 64.2 ± 27.7 vs. 25.0 ± 18.9, P = 0.001). [68 Ga]Ga-DOTA-JR11 PET/CT detected 31 meningiomas, while CE-MRI detected 17 meningiomas of 25 initial diagnosis and 11 recurrent tumors; [68 Ga]Ga-DOTA-JR11 PET had an incremental diagnostic value of 24% (6/25) over MRI in the group of initial diagnosis. There was no statistically significant difference in diagnostic efficacy between PET and MRI (P = 0.45) for all 36 patients. In skull base meningiomas, PET provided a more definitive diagnosis of pituitary involvement (in 12, not in12), compared to MRI (in eight, possible in six, possible not in six, not in four). PET revealed bone involvement in all 14 patients proven by pathology, while MRI identified only 11. CONCLUSIONS: [68 Ga]Ga-DOTA-JR11 PET/CT provided high image quality and presented an ideal diagnostic performance in detecting meningioma and evaluating the involvement of the pituitary and bone. The study provides valuable evidence for the use of [68 Ga]Ga-DOTA-JR11 PET/CT as a complementary imaging modality to CE-MRI in the evaluation of meningiomas.

Single-cell RNA sequencing identifies macrophage signatures correlated with clinical features and tumour microenvironment in meningiomas.

BACKGROUND: Meningiomas are common primary brain tumours, with macrophages playing a crucial role in their development and progression. This study aims to identify module genes correlated with meningioma-associated macrophages and analyse their correlation with clinical features and immune infiltration. METHODS: We analysed single-cell RNA sequencing (scRNA-seq) data from two paired meningioma and normal meninges to identify meningioma-associated macrophages. High-dimensional weighted gene co-expression network analysis (hdWGCNA) was employed to identify module genes linked to these macrophages, followed by functional enrichment and pseudotime trajectory analyses. A machine learning-based model using the module genes was developed to predict tumour grades. Finally, meningiomas were classified into two molecular subtypes based on the module genes, followed by a comparison of clinical characteristics and immune cell infiltration. RESULTS: Meningiomas exhibited a significantly higher proportion of macrophages than normal meninges, including novel macrophage clusters referred to as meningioma-associated macrophages. The hdWGCNA analysis of macrophages within meningiomas unveiled 12 distinct modules, with the blue, black, and turquoise modules closely correlated with the meningioma-associated macrophages. Hub genes within these modules were enriched in immune regulation, cellular communication, and metabolism pathways. Machine learning analysis identified 13 module genes (RSBN1, TIPRL, ATIC, SPP1, MALSU1, CDK1, MGP, DDIT3, SUPT16H, NFKBIA, SRSF5, ATXN2L, and UBB) strongly correlated with meningioma grade and constructed a predictive model with high accuracy and robustness. Based on the module genes, meningiomas were classified into two subtypes with distinct clinical and tumour microenvironment characteristics. CONCLUSIONS: Our findings provide insights into the molecular characteristics underlying macrophage infiltration in meningiomas. The molecular signatures of macrophages demonstrate correlations with clinical features and immune cell infiltration in meningiomas.

Tumor-selective Blockade of CD47 Signaling with CD47 Antibody for Enhanced Anti-tumor Activity in Malignant Meningioma.

BACKGROUND: Patients with WHO grade III meningioma have a poor prognosis with a median survival of less than two years and a high risk of recurrence. However, traditional treatment options have failed to improve prognosis. Therefore, development of novel immunotherapy targets is urgently needed. CD47 acting as a "don't eat me" signal to macrophages can trigger tumor immune escape. However, the role of CD47 in malignant meningioma is not well understood. METHODS: We collected 190 clinical meningioma samples and detected the expression of CD47 and immune infiltration in WHO grade I-III by immunohistochemistry, western blot, qPCR. We also examined the functional effects of anti-CD47 on cell proliferation, migration and invasion, macrophagemediated phagocytosis and tumorigenicity both in vitro and in vivo. RESULTS: We found that the expression of CD47 was increased in malignant meningioma along with a decreased number of T cells and an increase in CD68+ macrophages. Blocking CD47 with anti-CD47 antibody (B6H12) suppressed tumor cell growth, motility and promoted macrophage-mediated phagocytosis in IOMM-Lee cells in vitro. In vivo experiments showed that anti-CD47 antibody (B6H12 or MIAP301) significantly inhibited the tumor growth and this effect was partly blocked by the depletion of macrophages. Finally, p-ERK and EGFR showed higher expression in malignant meningioma with high expression of CD47, which was verified by western blot. CONCLUSION: Our results demonstrated that CD47 maybe involved in the meningioma progression and prognosis and offered a novel therapeutic option by targeting CD47 in malignant meningioma.

Polycystin-2 Associates With Malignancy in Meningiomas.

The involvement of polycystin-2 (PC2) in cell survival pathways raises questions about its role in carcinogenesis. Aberrant expression of PC2 has been associated with malignancy in various tumors. No evidence exists referring to PC2 expression in meningiomas. The aim of this study was to investigate the expression levels of PC2 in meningiomas and compare them with normal brain samples including leptomeninges. PC2 immunohistochemical expression was quantitatively analyzed in archival tissue from 60 patients with benign (WHO grade 1) and 22 patients with high-grade (21: WHO grade 2 and 1: grade 3) meningiomas. Specifically, the labeling index [the percentage of positive (labeled) cells out of the total number of tumor cells counted] was determined. PC2 mRNA levels were evaluated by quantitative real-time polymerase chain reaction. PC2 immunostaining was not detected in the leptomeninges. Gene expression analysis revealed increased levels of PC2 in WHO grade 1 ( P = 0.008) and WHO grade 2 ( P = 0.0007) meningiomas compared with that of normal brains. PC2 expression was significantly associated with an ascending grade of malignancy by both immunohistochemistry and quantitative real-time polymerase chain reaction ( P < 0.05). Recurrent meningiomas displayed higher levels of PC2 compared with primary meningiomas ( P = 0.008). Although no significant association of PC2 with the overall survival of the patients was found ( P > 0.05), it was noticed that the patients with WHO grade 2 meningiomas with low expression of PC2 survived longer compared with the patients with WHO grade 1 meningioma with high expression of PC2 (mean survival 49.5 and 28 months, respectively). The above results indicate a possible association of PC2 with malignancy in meningiomas. However, the mechanisms underlying PC2 implication in meningioma pathogenesis should be further elucidated.

Novel Human Meningioma Organoids Recapitulate the Aggressiveness of the Initiating Cell Subpopulations Identified by ScRNA-Seq.

High-grade meningioma has an unsatisfactory outcome despite surgery and postoperative radiotherapy; however, the factors driving its malignancy and recurrence remain largely unknown, which limits the development of systemic treatments. Single-cell RNA sequencing (scRNA-Seq) technology is a powerful tool for studying intratumoral cellular heterogeneity and revealing the roles of various cell types in oncogenesis. In this study, scRNA-Seq is used to identify a unique initiating cell subpopulation (SULT1E1+ ) in high-grade meningiomas. This subpopulation modulates the polarization of M2-type macrophages and promotes meningioma progression and recurrence. A novel patient-derived meningioma organoid (MO) model is established to characterize this unique subpopulation. The resulting MOs fully retain the aggressiveness of SULT1E1+ and exhibit invasiveness in the brain after orthotopic transplantation. By targeting SULT1E1+ in MOs, the synthetic compound SRT1720 is identified as a potential agent for systemic treatment and radiation sensitization. These findings shed light on the mechanism underlying the malignancy of high-grade meningiomas and provide a novel therapeutic target for refractory high-grade meningioma.

Innovative treatments for meningiomas.

Multi-recurrent high-grade meningiomas remain an unmet medical need in neuro-oncology when iterative surgeries and radiation therapy sessions fail to control tumor growth. Nevertheless, the last 10years have been marked by multiple advances in the comprehension of meningioma tumorigenesis via the discovery of new driver mutations, the identification of activated intracellular signaling pathways, and DNA methylation analyses, providing multiple potential therapeutic targets. Today, Anti-VEGF and mTOR inhibitors are the most used and probably the most active drugs in aggressive meningiomas. Peptide radioactive radiation therapy aims to target SSTR2A receptors, which are strongly expressed in meningiomas, but have an insufficient effect in most aggressive meningiomas, requiring the development of new techniques to increase the dose applied to the tumor. Based on the multiple potential intracellular targets, multiple targeted therapy clinical trials targeting Pi3K-Akt-mTOR and MAP kinase pathways as well as cell cycle and particularly, cyclin D4-6 are ongoing. Recently discovered driver mutations, SMO, Akt, and PI3KCA, offer new targets but are mostly observed in benign meningiomas, limiting their clinical relevance mainly to rare aggressive skull base meningiomas. Therefore, NF2 mutation remains the most frequent mutation and main challenging target in high-grade meningioma. Recently, inhibitors of focal adhesion kinase (FAK), which is involved in tumor cell adhesion, were tested in a phase 2 clinical trial with interesting but insufficient activity. The Hippo pathway was demonstrated to interact with NF2/Merlin and could be a promising target in NF2-mutated meningiomas with ongoing multiple preclinical studies and a phase 1 clinical trial. Recent advances in immune landscape comprehension led to the proposal of the use of immunotherapy in meningiomas. Except in rare cases of MSH2/6 mutation or high tumor mass burden, the activity of PD-1 inhibitors remains limited; however, its combination with various radiation therapy modalities is particularly promising. On the whole, therapeutic management of high-grade meningiomas is still challenging even with multiple promising therapeutic targets and innovations.

The relationship between connexin-43 expression and Ki67 in non-glial central nervous system tumors.

BACKGROUND: Advanced intercellular communication is a known oncogenic factor. In the central nervous system, Connexin-43 (Cx43) forms this junctional networking. Moreover, it correlates with the proliferation rate, and thus behavior, of gliomas. We assessed the expression of Cx43 and its relationship to Ki67 in other common central nervous system tumors. METHODS: The expression of Cx43 and Ki67 were assessed in formalin-fixed paraffin embedded samples of human brain metastases, meningiomas, and neurinomas using immunohistochemistry. Neurinomas and meningiomas were jointly evaluated due to similar non-malignant behavior. RESULTS: A total of 14 metastases of different extracerebral carcinomas, 6 meningiomas, and 10 neurinomas were evaluated. Five (36%) metastases and 5 (31%) meningiomas/neurinomas showed minor expression, whereas 6 (43%) metastases and 2 (13%) meningiomas/neurinomas showed no Cx43 expression at all. In 3 (21%) metastases and 9 (56%) meningiomas/neurinomas, moderate or strong expression of Cx43 was identified. The higher expression of Cx43 in meningiomas and neurinomas directly correlated with Ki67, r = 0.53 (P = 0.034). For metastases no significant correlation was found. Mitotic index in meningiomas/neurinomas correlated with Ki67 expression, r = 0.74 (P < 0.001), but did not show statistically significant correlation with Cx43 expression in these tumors. CONCLUSIONS: The expression of Cx43 as a marker of cell-to-cell networking exposed a significant correlation with the Ki67-defined proliferation index in case of primary central nervous system neuroectodermal neoplasms. However, it does not seem to play a comparable role in metastases with extracerebral origin.

Peritumoral edema in meningiomas: pathophysiology, predictors, and principles for treatment.

Meningiomas is a tumor of the meninges and is among the most common intracranial neoplasms in adults, accounting for over a third of all primary brain tumors in the United States. Meningiomas can be associated with peritumoral brain edema (PTBE) which if not managed appropriately can lead to poor clinical outcomes. In this review, we summarize the relevant pathophysiology, predictors, and principles for treatment of PTBE. The results of various case-reports and case-series have found that meningioma-associated PTBE have patterns in age, tumor size, and hormone receptor positivity. Our study describes how increased age, increased tumor size, tumor location in the middle fossa, and positive expression of hormone receptors, VEGF, and MMP-9 can all be predictors for worse clinical outcomes. We also characterize treatment options for PTBE such as glucocorticoids and VEGF inhibitors along with the ongoing clinical trials attempting to alleviate PTBE in meningioma cases. The trends summarized in this review can be used to better predict the behavior of meningioma-associated PTBE and establish prognosis models to identify at risk patients.

Programmed death ligand 1 and tumor-infiltrating CD8+ T lymphocytes are associated with the clinical features in meningioma.

OBJECTIVE: To investigate the expression of programmed death ligand-1 (PD-L1) and the levels of CD8+ tumor-infiltrating lymphocytes (TILs) in meningioma as well as determine the association between their levels and the clinical outcomes. METHODS: We performed a retrospective case-control study on 93 patients with meningioma. The patients showed tumor recurrence and were matched with the control patients without recurrence in their age, gender, admission time, tumor sites, tumor volume, peritumoral brain edema (PTBE), Simpson grade resection, WHO grade, postoperative radiotherapy, and the follow-up duration. We reviewed the clinical data of patients and performed immunohistochemistry analysis to investigate the PD-L1 expression and the levels of CD8+ TILs. Multivariate logistic regression was performed to analyze the association between clinical features and immune markers. The conditional logistic regression models were used to calculate the odds ratios (ORs) with 95% confidence intervals (CIs), and Kaplan-Meier analysis was performed to analyze tumor recurrence. RESULTS: Tumor volume was correlated with the PD-L1 expression (P = 0.003, HR = 5.288, 95%CI, 1.786-15.651). PTBE served as an independent predictor of CD8+ TIL levels (P = 0.001, HR = 0.176, 95%CI 0.065-0.477). The levels of CD8+ TILs were associated with tumor recurrence (P = 0.020, OR = 0.325, 95%CI, 0.125-0.840). CONCLUSION: Tumor volume was associated with PD-L1 expression, and PTBE was an independent predictor of CD8+ TIL levels in meningioma. CD8+ TIL levels correlated with tumor recurrence in meningioma.

P53 Suppressor Gene Tissue Microarray-based Protein Expression Analysis in Meningiomas.

BACKGROUND/AIM: Meningiomas represent the main intracranial primary central nervous system (CNS) tumour in adults worldwide. Oncogenes' over-activation combined with suppressor genes' silencing affect negatively the biological behavior of these neoplasms. This study aimed to explore the impact of p53 suppressor gene expression in meningiomas' clinic-pathological features based on a combination of sophisticated techniques. MATERIALS AND METHODS: Fifty (n=50) meningiomas were included in the study, comprising a broad spectrum of histopathological subtypes. An immunohistochemistry assay was applied on tissue microarray cores followed by digital image analysis. RESULTS: p53 protein over-expression (high staining intensity levels) was observed in 27/50 (54%) cases, whereas the rest (23/50-/46%) demonstrated moderate to low levels of the protein. p53 over-expression was statistically significantly correlated to the mitotic index of the examined cases (p-value=0.001). Interestingly, the atypical/anaplastic group of histotypes demonstrated the strongest p53 expression rates compared to the others (p-value=0.001). CONCLUSION: p53 overexpression is observed in a broad spectrum of meningiomas. High expression levels lead to an aggressive biological behavior of the malignancy (combined with increased mitotic rates), especially in atypical and anaplastic sub-types that also have a high recurrence rate.

Acid and Alkaline Phosphatases Specific activities and Expression as Biomarkers in Brain Tumor Grading and Correlation of Anaplastic Oligodendroglioma G-III to Meningiomas G-I among Brain Tumors and their primary culture.

BACKGROUND: Acid Phosphatase (ACP) and Alkaline Phosphatases (ALP) are hydrolases that remove phosphate groups from protein and nucleic acid respectively for regulation of cell function from ACP as lysosomal defence function and ALP membrane-bound as a barrier of the cell. The ACP and ALP-specific activities of Meningiomas (n = 75) and gliomas (n = 81) were compared among brain tumors, normal brain, and derived primary cell culture. METHODS: Total Protein and Phosphatases assays estimated by Spectrophotometer and Native PAGE Gel Electrophoresis. Brain tumor and primary explant lysosome studies were performed with an electron microscope. RESULTS: Average ACP specific activity exhibited 9.32617 ± 4.1144 for meningiomas (n = 55) and 5.91 ± 5.8305 for gliomas (n = 60) respectively as compared to normal brain 7.104 ± 1.33 (n = 120) nm/min/mg of protein. Average ALP exhibited 37.1862 ± 39.91 (n = 36) for meningiomas and 5.91 ± 5.83 (n = 60) for gliomas respectively as compared to normal brain (n = 117) 2.463 ± 1.01 nm/min/mg of protein. ACP and ALP exhibited higher activities for meningiomas but not for gliomas as compared to normal brain, in contrast, both expressed more activities in the majority of glioma cell lines and lower in meningioma cell lines. Interestingly gliomas exhibited similar average specific activities for ACP and ALP. While GBM IV exhibits lower ALP activities due to cell migration and higher ACP activity correlate too many storage lysosomes from Electron microscopic observation as compared to meningiomas. CONCLUSIONS: Higher ALP activities can be surrogate markers from meningiomas G-I, G-II to G-III respectively. However meningiomas G-III are similar to gliomas excluding Anaplastic Oligodendroglioma G- III which is similar to Meningiomas G-I even for cells growth patterns. Therefore, an ALP level in meningiomas indicates complementary diagnosis as antibody-ALP conjugates with anticancer drugs for efficiency in targeting brain tumor reduction.

Antiangiogenic Molecules Suppressed Meningioma-Induced Neovascularization: A Corneal Angiogenesis Study.

AIM: To investigate the angiogenic effects of bevacizumab and imatinib on different meningioma tissue grades. MATERIAL AND METHODS: In this study, in silico analysis of angiogenesis-related gene expression was carried out using previously reported datasets. Messenger ribonucleic acid expressions of VEGFA, VEGFB, PDGFRA, and PDGFRB genes were obtained from two different meningioma transcriptome datasets. The effect of antiangiogenic drugs, bevacizumab and imatinib, on meningiomainduced vascularization was assessed by using rat corneal angiogenesis assay (CAA). RESULTS: Bevacizumab and imatinib both significantly reduced meningioma-induced neovascularization in the CAA model. CONCLUSION: The angiogenic characteristics of meningiomas may be suppressed by using antiangiogenic drugs to prevent neovascularization, thus improving prognosis.

miR-127-5p Targets JAM3 to Regulate Ferroptosis, Proliferation, and Metastasis in Malignant Meningioma Cells.

Objective: Meningiomas are one of the most common primary tumors of the central nervous system. Most of them are benign and can be cured by surgery, while a few meningiomas are malignant. Ferroptosis gene characteristics might be associated with drug therapy and survival in patients with clinically aggressive, unresectable meningiomas. This study explored the mechanism of differentially expressed miRNAs and ferroptosis in meningioma to provide a new reference to treat meningioma. Methods: Bioinformatics analysis of differential miRNA profiles and functions in patients with meningioma was performed. The contents of lactate dehydrogenase (LDH), malondialdehyde (MDA), and Fe2+ were determined. Reactive oxygen species (ROS) values, as well as cell cycle changes, were analyzed by flow cytometry. The targets of miR-127-5p and JAM3 were detected by dual luciferase assays. Cell counting kit-8 (CCK8) and Transwell assays were used to analyze cell activity. Ki67 expression was analyzed by immunohistochemistry. Expression levels of miR-127-5p and JAM3 were analyzed by RT-qPCR. GPX4 expression was quantified by western blotting. Results: miR-127-5p was expressed at low levels in IOMM-Lee cells, while JAM3 was highly expressed in IOMM-Lee cells. A dual luciferase assay demonstrated that miR-127-5p could target JAM3. Upregulation of miR-127-5p in IOMM-Lee cells resulted in cell cycle arrest and inhibition of cell activity. Upregulation of miR-127-5p increased LDH, MDA, and ROS levels and Fe2+ content and inhibited the expression of GPX4 protein. Upregulation of JAM3 reversed the results of miR-127-5p upregulation. Conclusion: miR-127-5p regulated meningioma formation and ferroptosis through JAM3, providing insights for the development of new treatments for meningioma.