Meningiomas account for about 40% of all primary brain tumors. How ever effective treatments for recurrent or inoperable cases remain limited. We previously demonstrated that culturing cancer cells on specific hydrogels efficiently induces cancer stem cells across multiple cancer types, a process we termed hydrogel activated reprogramming (HARP) phenomenon. In this study, we aimed to identify key molecules involved in the induction of meningioma stem cells through hydrogel-based culture. Meningioma cells cultured on hydrogels were analyzed for expression of established stem cell markers and for tumorigenicity. Microarray analysis was performed to identify meningioma stem cell specific markers and to evaluate the application of these marker molecules as a therapeutic targets or as diagnostic tools for pathological grading. Canonical stem cell markers including Nanog, and Oct3/4 were upregulated in culturing meningioma cells on hydrogels. Comprehensive gene expression analysis identified some molecules involved in cancer stem cell activity among which CXCR4 was selected as a potential therapeutic target. Stimulation of CXCR4 with its ligand CXCL12 resulted in increased expression of stem cell markers. In human meningioma pathological specimens and cultured cell lines, there was a correlation between CXCR4 expression levels and NF2 mutations and/or deletions. CXCR4 immunohistochemistry was frequently positive in cases with brain invasion along with brain invasion area. These findings suggest that CXCR4 immunohistochemistry may be useful in suggesting typical CNS WHO grade 1 meningiomas without the need for molecular analysis. We have defined meningioma stem cell signature via HARP phenomenon and identified CXCR4 with biological significance as being diagnostic target. IMPORTANCE OF THE STUDY: In addition to morphological evaluation, immunohistochemistry and genetic alteration increasingly incorporated into the diagnostic criteria for central nervous system (CNS) tumors. From the CNS WHO 5th edition onwards, epigenetic features including DNA methylation profiling, have also been adopted as diagnostic criteria. In this study, we induced epigenetic changes in meningioma cells and successfully promoted cancer stemness highlighting the potential importance of this approach for both meningioma research and meningioma diagnostic development. Furthermore, microarray analysis identified CXCR4 as a molecule consistently upregulated during stem cell induction across all three hydrogel conditions. Subsequent analysis revealed that CXCR4 immunohistochemistry may reflect the distribution of meningioma stem cells, supporting its potential utility as a diagnostic marker. By integrating basic experimental findings with histopathological evaluation of clinical specimens, this report will contribute to the advancement of meningioma research and diagnostic strategies.
Oda et al. (Fri,) studied this question.