In the 2016 WHO classification of CNS tumors, brain invasion became the sole criterion for grade 2 meningioma, as was the criterion for mitosis of ≥4 per 10 high-power fields [12]. In addition, a diagnosis can be made if three of the following five additional diagnostic criteria are met: spontaneous necrosis, sheeting (loss of whorling or fascicular architecture), prominent nucleoli, high cellularity, and small cells (tumor clusters with a high nuclear: cytoplasmic ratio) [12]. With the addition of this brain invasion-only criterion, brain-invasive otherwise benign, which was previously classified as grade 1, has been classified as grade 2 in atypical meningioma since the WHO classification in 2016. Brain invasion meningioma causes loss of interface with brain tissue on T2 weighted magnetic resonance imaging and causes prominent peripheral brain edema. Even in microscopic surgery, it penetrates the arachnoid interface or encases cerebral blood vessels [8]. An important structure that supports or prevents brain involvement is the so-called “brain-meningioma interface.” It can be divided into three types: bone invasion, perivascular growth along the Virchow-robin-spaces, and direct brain invasion [13].
Major process of meningioma brain invasions in three stepsDegeneration of extracellular matrix (<xref rid="F1-btrt-11-47" ref-type="fig">Fig. 1</xref>)First step is the degeneration of the extracellular matrix (ECM) by protease [8]. The ECM and basement membrane (BM) are rigid structures formed from macromolecules: type IV collagen, laminin, entactin, nidogen, fibronectin, and heparin sulfate proteoglycans (HSPG). Proteases can degrade BMs and connective tissues. Proteases result in a breakthrough interaction between the ECM and BM. Matrix metalloproteinases (MMPs), one of the proteases, are lysosomal endopeptidases that are categorized into four classes: category I, interstitial collagenases (MMP-1, MMP-8, and MMP-13), which degrade fibrillary collagens; category II, type IV collagenases (MMP-2 and MMP-9), which degrade the BM collagens gelatin and elastin; category III, stromelysins (MMP-3, MMP-10, and MMP-11), which degrade proteoglycans, fibronectin, laminin, gelatin, and globular proteins of type IV collagens; and category IV, membrane-type MMPs (MMP-14, MMP-15, MMP-16, and MMP-17), which contain a unique transmembrane domain in their C-terminus, localizing these MMPs to the cell surface. Jalali et al. [14] confirmed that MMP-16 knockdown tumors showed reduced invasion into brain tissue. In their experiments, they confirmed that MMP-16 expression was significantly elevated in bone- and brain-invasive meningiomas and that the number of cells passing through the BM and the mobility of knockdown cells were decreased [14]. MMP-16 is believed to promotes invasiveness of meningiomas [14]. Meningiomas may have a wide range of epithelial and mesenchymal properties, including the ability to produce collagen and other ECM proteins [15]. Immunoreactivity to MMP-2 and MMP-9 and their tissue inhibitors TIMP-1 and adhesion factor galectin-3 were found in most cases of benign meningiomas regardless of location [15]. This suggests that these compounds may serve as potential therapeutic targets.
Another potential target of MMP inhibitors, uPA and PAI-1, is tumor invasion. Kandenwein et al. [16] confirmed a significant correlation between WHO grade and the concentrations of uPA and PAI-1 proteins in meningiomas. In that study, uPA/PAI-1 levels were significantly increased in high-grade meningiomas and showed an inverse correlation between their expression levels and promoter methylation. In addition, brain involvement was frequent in tumors with higher PAI-1 expression (more frequent in tumors containing >6 ng/mL PAI-1), although the Simpson grade was not significant and there was a highly significant correlation with patient prognosis [16].
Lah et al. [17] reported that cysteine cathepsins and their inhibitors were involved in the early recurrence of meningiomas, regardless of histological classification. Lysosomal cysteine proteinases such as cathepsin D and cysteine cathepsins B and L initiate a proteolytic cascade by activating cysteine protease [17]. Subsequently, lysosomal cysteine proteinases activate cell membrane-associated pro-urokinase, inducing the extracellular release of plasmin from plasminogen, and finally activate various types of MMPs which degrade collagen and other basal lamina proteins [17].
HSPG act as cellular switches to invasive meningiomas [18]. HSPG, a core protein of the ECM BM, and heparanase (HPSE), a major enzyme that degrades heparin sulfate, are important regulators of the ECM [18]. HPSE breaks the heparin sulfate chains of HSPG into 5–7 kD-sized fragments at specific HSPG sites [18].
Promotion of tumor cell migration to resident cells by adhesion molecules (<xref rid="F1-btrt-11-47" ref-type="fig">Fig. 1</xref>)Integrins are cell-surface adhesion molecules that are important for proliferation and migration. Recently, much interest has focused on the role of integrins in carcinomas. Each histological meningioma subtype has a specific spectrum of integrin expression, especially αVβ3 and αVβ5 integrins, which contribute to the invasive growth of meningiomas. αvβ5 is an integrin heterodimer that is predominantly expressed in meningiomas, whereas αvβ3 is mainly detected in tumor vessels [19]. Brain invasion is inhibited in meningioma cell lines and mouse models injected with cilengitide [19]. Integrins along with their inhibitor, cilengitide, could be a potential targeted therapy.
E-cadherin, a cell-surface glycoprotein, is essential for calcium-dependent cell–cell adhesion and structural rigidity. The extracellular N-terminus of E-cadherin forms a “zipperlike” structure that serves as a tight junction [20]. Additionally, the intracellular part is involved in the construction of the cytoskeleton indirectly to the cell–cell junction by catenin (α-catenin and β-catenin). Disruption of these junctions causes brain invasion, and the expression of E-cadherin and β-catenin is closely related to the meningioma grading criteria [20].
Selectin is a key protein involved in this process. Selectin mainly correlates with the binding, rotation, and extravasation of activated leukocytes, which commonly occurs on the endothelium and in inflammatory reactions. E-, P-, and L-selectins in turn have the following functions: E-selectin secretion is activated following local stimulation by endothelia of skin and bone marrow and subsequently induced by inflammatory cytokines, P-selectin exocytosis translocates to the cell surface of activated endothelial cells and platelets, and L-selectin functions by interacting with the selectin binding ligand (P-selectin glycoprotein ligand-1). Atukeren et al. [21] confirmed that these selectins are expressed at higher levels in meningiomas than in the control group, suggesting that selectins may be involved in the pathological mechanism of meningiomas.
Neovascularization and supporting meningioma tumor cells by growth factors (<xref rid="F1-btrt-11-47" ref-type="fig">Fig. 1</xref>)Growth factors play critical roles in brain invasion processes, including the promotion of migratory, proliferative, and angiogenic responses in meningioma cells [8]. The hepatocyte growth factor (HGF)/c-MET signaling pathway is one of the major pathways involved in this process. HGF is a multifunctional growth factor secreted by mesenchymal cells and has a strong mitogenic effect on hepatocytes. It consists of a heavy chain with four domains and a light chain, and binds to its tyrosine kinase receptor (RTK), a product of the proto-oncogene c-MET [22]. Mature c-MET is structurally distinct from most RTKs. It exists as a heterodimer containing an extracellularα-chain and transmembrane β-chain. Once activated by HGF binding, c-MET is auto-phosphorylated and recruits adaptor proteins, activating multiple downstream effector proteins and signaling cascades [22]. Dysregulation of the HGF/c-MET signaling pathway induces tumor cell proliferation, motility, and invasiveness in several human cancers, including breast cancer, lung cancer, and hepatocellular carcinoma (except for clinical trials in meningioma) [22].
Platelet-derived growth factor (PDGF) and endothelial growth factor receptors (EGFRs) (Ras/Raf/MAPK and PI3K pathways) are also potential therapeutic targets. PDGF acts as a proliferation driver during normal development and in multiple cancers, and all histological grades of meningiomas express PDGF ligands AA and BB [23]. Early studies have shown that normal arachnoid cells almost exclusively express β-type PDGF receptors [2425], which predominantly bind to PDGF-BB and stimulate meningioma growth, activate MAPK, and induce c-Fos expression [2627].
More than 60% of meningiomas highly express the EGFR [28]. EGFR activation by autocrine or paracrine mechanisms in meningiomas may promote tumor growth [8]. EGFR activation increases resistance to apoptosis, promotes angiogenesis, and impairs immune surveillance. Thus, EGFR inhibitors have the potential to reduce tumor progression [8].
EGF and transforming growth factor-α (TGF-α) activate their receptors, which promote the proliferation of meningioma cells in an in vitro study [29]. In addition, upregulation of TGF-α activity in meningioma and tumor specimens has been demonstrated to be associated with aggressive growth [29]. Signal transduction activated by RTK, including PDGF receptor (PDGFR) and EGFR, is mediated by Ras/Raf/MAPK and PI3K pathways [30]. Imatinib is an oral tyrosine kinase inhibitor that targets BCR-ABL, PDGFR, and c-Kit receptors [8]. Meningiomas frequently overexpress PDGFR-α and PDGFR-β, which could be potential targets for imatinib therapy [8].
Vascular endothelial growth factor (VEGF) and the VEGF receptor (VEGFR) are highly expressed in meningiomas [31]. This is related to the extent of peritumoral edema. Moreover, the strong correlation between meningioma grade and VEGF suggests that anti-angiogenic therapy may be beneficial for the treatment of invasive meningiomas. An anti-VEGF monoclonal antibody (bevacizumab) improves the survival of several malignancies, including those of colorectum, lung, breast, and glioblastomas [3233]. This has been studied in several retrospective analyses and in two phase II trials involving patients with refractory meningiomas [34]. Sunitinib, a wide-spectrum tyrosine kinase inhibitor, targets VEGFR, PDGFR, and several other oncogenic pathways and is currently being used in clinical practice for several cancers [31].
Promising treatment for brain-invasive meningiomasImmunotherapyA recent study revealed reduced expression of PD-1-expressing T lymphocytes, such as CD4+ and CD8+, in anaplastic meningiomas [35]. Immunotherapy using PD-1/PD-L1 has been approved by the United States Food and Drug Administration; however, much remains unknown about the meningioma microenvironment [8]. However, recent clinical trials are ongoing, and current immunotherapy strategies for meningioma, anti-PD1 drugs pembrolizumab, and nivolumab are undergoing clinical trials for recurrent or residual high-grade meningiomas [8].
Depending on the grade of meningioma, the expression pattern of PD-L1 is different [35]. In grade 1 meningiomas, the overall expression level of PD-L1 is very low, and CD68 is expressed in a small number of cells. In grade 2 meningiomas, a significant PD-L1+population shows CD68+ expression, in addition to a separate population with CD68+/PD-L1–cells. In grade 3 meningiomas, PD-L1 expression is predominant in CD68 cells.
Hormone therapyThe epidemiological incidence of meningioma is high in women, particularly during pregnancy and breast cancer [3637]. The functions of progesterone and estrogen can be considered as regulatory mechanisms and potential therapeutic targets.
In a large-scale study, estrogen-alone hormonal replacement treatment (HRT) in postmenopausal women increased the incidence of meningioma, but not with estrogen plus progesterone HRT [383940]. Additionally, HRT without oral contraceptives plays an important role in meningioma formation [41].
Progesterone receptors are found in 58%–83% of meningiomas, but estrogen receptors are found in only 0%–8% [42]. Therefore, since meningiomas have a higher expression rate of progesterone receptors, they may be potential therapeutic targets for growth factor inhibition [8]. However, a recent double-blind phase 3 clinical trial using mifepristone, an anti-progesterone drug, failed to control unresectable meningioma [43].
Tumor treating fieldTumor-treating fields (TTFs) are antimitotic treatments that selectively affect dividing glioblastoma cells by delivering a low-intensity, medium-frequency (200 kHz) alternating electric field through transducer arrays applied to the scalp, and their safety and effectiveness have been reported [444546]. In the same way, it can be considered that TTF is applied to meningioma cells to interfere with the mitosis process and induce violent membrane blebbing, which subsequently induces immunogenic cell death [8].
WafersWafer treatment is a method of integrating chemotherapeutic agents into biodegradable polymers and continuously releasing them locally. The results of a placebo-controlled trial of wafer treatment using biodegradable polymers impregnated with carmustine for recurrent malignant gliomas have been reported [47]. Therefore, potentially biodegradable copolymers can be considered as impregnated chemotherapies for brain-invasive meningiomas.