Abstract
Introduction: Meningioma affects thousands of people worldwide. Women are twice as likely to be affected than men, increasing to 3:1 during reproductive years. Previous studies have attributed this difference to hormone levels; however, the formation, progression, and sexual dimorphism of meningioma remains largely unknown. Therefore, meningothelial and atypical meningiomas display differentially expressed hormone levels as well as molecular and metabolic pathways that can affect drug metabolism in a sex-specific manner.
Methods: Immunohistochemistry (SSRT2A, EMA, PR and ER alpha) and untargeted proteomics study of patient-derived tissue, 3D spheres, and 2D cell lines were conducted. Western blots and PCRs were done to identify specific key molecules from each pathway. Meningioma spheres were treated with different concentrations of progesterone and beta-oestradiol to measure the effects of these hormones on invasion.
Results: SSRT2A, EMA and PR were present in all samples, while ER-alpha was not detected. Proteomics showed three significant pathways. The Oestrogen Receptor Signalling Pathway was predicted to be upregulated in all meningothelial models (tissue P<0.001; 3D P<0.004, 2D P<0.001), while the Mitochondrial Dysfunctional Pathway showed prediction of upregulation in atypical tissue and 3D model (P<0.001in both cases). DHCR24 Signalling Pathway showed prediction of downregulation in females vs males in all meningothelial models (tissue, 3D and 2D (P<0.001in all cases)). PCR of molecules from the Oestrogen Receptor Pathway showed significant differences when comparing meningothelial vs atypical: upregulated CKB, ESR2, FOS, IGFBP5, MAFF, NR0B2, PGR, VEGFA, CCN5 (p<0.05in all cases); downregulated CAV1, IRS1 and SPP1 (p<0.05in all cases).
Conclusion: We show that meningioma molecular and metabolic profiles differ according to the subtype and sex. Metabolomics, molecular analysis, cytotoxicity and viability assays are currently being performed and will examine the hormonal effect and the differences in drug metabolism between subtype and sex.