Brain Invasion and Trends in Molecular Research on Meningioma

Abstract

Meningiomas are the most common primary brain tumors in adults. The treatment of non-benign meningiomas remains a challenging task, and after the publication of the 2021 World Health Organization classification, the importance of molecular biological classification is emerging. In this article, we introduce the mechanisms of brain invasion in atypical meningioma and review the genetic factors involved along with epigenetic regulation. First, it is important to understand the three major steps for brain invasion of meningeal cells: 1) degradation of extracellular matrix by proteases, 2) promotion of tumor cell migration to resident cells by adhesion molecules, and 3) neovascularization and supporting cells by growth factors. Second, the genomic landscape of meningiomas should be analyzed by major categories, such as germline mutations in NF2 and somatic mutations in non- NF2 genes ( TRAF7 , KLF4 , AKT1 , SMO , and POLR2A ). Finally, epigenetic alterations in meningiomas are being studied, with a focus on DNA methylation, histone modification, and RNA interference. Increasing knowledge of the molecular landscape of meningiomas has allowed the identification of prognostic and predictive markers that can guide therapeutic decision-making processes and the timing of follow-up.

Meningiomas with CNS invasion

“…CNS invasion has been associated with AKT1 mutations as well as alterations of metalloproteases and adhesion molecule expression ( Jalali et al, 2015 ; Barresi et al, 2021 ; Qin et al, 2021 ). The pathophysiology of CNS invasion seems to undergo different stages ( Quintero-Fabian et al, 2019 ; Maggio et al, 2021 ; Furtak et al, 2023 ; Go and Kim, 2023 ). The crucial point for the initiation of meningioma cells invasion is the cleavage of the basement membrane and the following remodeling of the extracellular matrix (ECM) by specific matrix metalloproteinases ( MMPs ) ( Quintero-Fabian et al, 2019 ; Maggio et al, 2021 ; Furtak et al, 2023 ; Go and Kim, 2023 ).…”

“…The pathophysiology of CNS invasion seems to undergo different stages ( Quintero-Fabian et al, 2019 ; Maggio et al, 2021 ; Furtak et al, 2023 ; Go and Kim, 2023 ). The crucial point for the initiation of meningioma cells invasion is the cleavage of the basement membrane and the following remodeling of the extracellular matrix (ECM) by specific matrix metalloproteinases ( MMPs ) ( Quintero-Fabian et al, 2019 ; Maggio et al, 2021 ; Furtak et al, 2023 ; Go and Kim, 2023 ). Several activators of MMPs , like uPA have been linked to plasmin mediated matrix breakdown and cell adhesion ( Fleetwood et al, 2014 ).…”

“…In a further step, the migration of meningioma cells within the loose environment of the degraded ECM is promoted by adhesion agents, like integrins ( Wilisch-Neumann et al, 2013 ). Finally, well known growth factors, like EGFR, VEGFR or HGF contribute to neoangiogenesis and growth of the tumor cells ( Fleetwood et al, 2014 ; Go and Kim, 2023 ). In this regard, Pei et al reported lower expression of canstatin, an angiogenesis inhibitor, in WHO grade 3 brain invasive meningiomas ( Pei et al, 2023 ).…”

Modelling Meningioma Using Organoids: A Review of Methodologies and Applications

“…Krüppel-like factor 4 (KLF4) is involved in cell proliferation, growth, and differentiation [27,30]. RNA polymerase II subunit A (POLR2A) is commonly mutated in meningothelial meningiomas [31][32][33]. This somatic mutation is also associated with meningioma development in the tuberculum sellae [32].…”

“…RNA polymerase II subunit A (POLR2A) is commonly mutated in meningothelial meningiomas [31][32][33]. This somatic mutation is also associated with meningioma development in the tuberculum sellae [32]. TNF receptor-activated factor 7 (TRAF7), which is mutated in >20% of meningiomas, encodes an E3 ubiquitin ligase that oversees the degradation of other proteins [27,34].…”