The Origin of Meningiomas

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CHAPTER 3 The Origin of Meningiomas

Serdar Baki Albayrak, Peter M. Black

INTRODUCTION

Meningiomas account for approximately 30% of all primary brain tumors constituting the largest subset of all intracranial tumors.¹^–³ They can occur at any age, but most commonly in middle age. Women are more likely to develop intracranial meningiomas, with a female:male ratio of nearly 2:1. Even though it is generally agreed that meningiomas are of neuroectodermal in origin and arise from the arachnoidal (meningothelial, arachnoid cap) cells based on the ultrastructural and histologic similarities between meningiomas and arachnoid cells, the cellular origins of meningiomas still have not been identified clearly.⁴^–²¹ The histologic expression of diverse meningioma subtypes ranging from meningothelial to fibroblastic patterns matches well with the various non-neoplastic cells in the arachnoid villi in a similar range of meningeal to fibroblastic cells. Thus, the critical question merges at this point: Is there a universal pluripotent cell that gives rise to all different subtypes of meningiomas or does each meningioma subtype takes origin from different tumor initiating cells in various subsets of cells in the arachnoid villi? The answer to this questions still remains obscure because there is no as yet identified subset of meningioma cells with unique molecular signatures that may give rise to all meningioma subtypes.

Even though it was possible to characterize meningiomas well cytogenetically in the past several decades, they are still poorly understood and defined molecularly. Hence histopathologic grading of the tumor does not necessarily predict its clinical course, particularly in atypical meningiomas.^22,²³ Current findings in molecular genetics provide convincing evidence that meningiogenesis is a dynamic process whereas histopathologic grading, which reflects only a snapshot of tumor behavior, falls short in capturing the complexity of the underlying molecular dynamics of the neoplastic process.

Recently, in addition to the well known tumor suppressor NF-2 gene deletion on chromosome 22, several other genetic aberrations including the deletion of the INK4a-ARF locus have been discovered, and altered biological pathways that potentially promote tumor growth have been suggested.^22,²⁴^–²⁸

Even though these findings may provide more insight into the ongoing molecular alterations and thus various clinical courses of meningiomagenesis, the ultimate challenge still remains: the origin and evolution of meningiomas.

In this chapter, we report the latest findings regarding the cellular origins of meningiomas. As well known, the classically described “arachnoid-cell derived meningioma” concept is based on histopathologic and electron microscopic studies. In addition, recent molecular and genetic studies in animal models have shown that biallelic inactivation of the NF2 gene has resulted in meningioma formation, which further supports the concept of “arachoid cell-derived meningioma” at the molecular and genetic levels.^29,³⁰

The further objective of meningioma research in this sense is to identify whether there are any universal meningioma stem cells, and if so, what their molecular signatures would be. Isolating candidate meningioma “stem cells” from human meningioma tissue samples and establishing a novel in vivo meningioma animal model are the first steps in accomplishing this goal. The next step would be to demonstrate that the molecular and genetic profiles of the initial and in vivo formed tumor cells are identical, which would verify the presence of the meningioma stem cells.

HISTOLOGIC AND ULTRASTRUCTURAL SIMILARITIES BETWEEN ARACHNOID CELLS AND MENINGIOMAS

Arachnoid granulations, or arachnoid villi, are small projections of the arachnoid membrane into the superior sagittal sinus and its major tributaries, involved in the absorption process of cerebrospinal fluid (CSF). There is a general agreement that meningiomas take origin from these granulations. In 1831, Bright noticed the histologic similarities between meningioma cells and arachnoid villi cells. Cleland and Robin proposed for the first time that meningiomas derive from arachnoid cells. Soon after, Schmidt observed obvious histologic similarities between meningioma and arachnoid cells at the ultrastructural level, and with respect to cell adhesion mechanisms and the components of extracellular matrix ^11,¹³ (Table 3-1).

TABLE 3-1 Ultrastructural and histological features of non-neoplastic arachnoid cells and meningioma cells.

	Arachnoid cells	Meningioma cells
Arachnoid cap cell aggregates	Psammoma bodies	Psammoma bodies
Polygonal arachnoid cells	Numerous junctional complexes and interdigitations	Fewer junctional complexes and interdigitations
Phospholipid composition	Phosphatidyl choline-multilamellar bodies to lubricate the surfaces of arachnoid cells thus facilitating the flow or absorption of CSF	Phosphatidyl serine ribbonlike rings in meningioma whorls are thought to be the precursors of psammoma bodies
E-cadherin expression	Localized at the intermediate junctions and anchored to cytoskeleton via intracytoplasmic microfilaments in normal arachnoid cells	Distributed along the cell borders and variations exist between the expressions of E-cadherin in different meningioma subtypes
Prostaglandin D₂ synthase (PGDS)	Mainly localized in the rough endoplasmic reticulum of arachnoid cells and detected in higher concentrations in the core arachnoid cells suggesting that it may play role in the absorption process of CSF	The exact role of PGDS in meningioma cells is yet to be identified, besides being a candidate as a cell marker for meningiomas

Ultrastructural Similarities

Human arachnoid villi are composed of five layers: endothelial layer, fibrous capsule, arachnoid cell layer, cap cells, and central core. The outermost layer, an endothelial lining has a pivotal role in the absorption process of CSF, and displays a number of micropinocytotic vesicles, intracytoplasmic vacuoles, and villous projections. Endothelial cells are interconnected to each other by tight junctions. The arachnoid cell layer of the villus is the direct continuation of arachnoid membrane itself. This arachnoid cell layer forms cap cell aggregates that contains calcified organelles (psammoma bodies), which are also one of the histopathologic features of meningiomas. The arachnoid cell layer contains numerous extracellular cisterns that may contain granular material and multilamellar phospholipids. These cisterns form channels from the central core into the venous lumen and are involved in the transport of CSF. In addition, polygonal arachnoid cells are tightly attached via junctional complexes that are less frequently seen in meningioma cells.¹³ Several studies in the literature revealed that syncytial areas of meningiomas and normal arachnoid villi are similar ultrastructurally; however, the ultrastructure of the meningioma cells are less organized and display fewer interdigitations.^11,^13,³¹

Yamashima and colleagues investigated two forms of phospholipids in arachnoid villi and meningiomas: phosphatidyl choline and phosphatidyl serine. Human arachnoid villi display multilamellar bodies that are similar to pulmonary surfactant and are assumed to lubricate the surfaces of arachoid cells thus facilitating the flow or absorption of CSF. Conversely, phosphatidyl serine appeared as ribbonlike rings in meningioma whorls that are thought to be the precursors of psammoma bodies.³²

Cell Adhesion Mechanisms

During formation of a tumor, the tumor cells attach to each other via adhesion molecules. Adhesion molecules are divided into subgroups including cadherins, immunoglobulins, selectins, integrins, and mucins. These molecules have a pivotal role in tumor cell–tumor cell adhesion, tumor cell–endothelial cell adhesion, or tumor cell–extracellular matrix adhesion, all of which are of paramount importance at different stages in primary tumor formation or metastasis. Here, we discuss some of the common adhesion molecules that are expressed in both non-neoplastic arachnoid tissue and meningioma cells.

Cadherins

Cadherins are a group of glycoproteins playing a crucial role in cell adhesion and known to be one of the fundamental elements in embryologic morphogenesis similar to immunoglobulins and integrins. Cadherins are divided into four subtypes based on the tissue distribution: epithelial (E), neuronal (N), placental (P), and vascular (V).

Epithelial (E)-cadherin is a transmembrane glycoprotein and functions in cell–cell adhesion via β-catenin that indirectly binds E-cadherin to actin filaments. This results in strong adhesive forces between the adjacent arachnoid cells in arachnoid villi, thus enabling individual arachnoid cells to undergo conformational changes during CSF absorption.^33,³⁴

E-cadherin–dependent cell adhesion is a calcium-dependent process and is regulated by a number of cytoplasmic proteins such as alpha-catenin, moesin, exrin, and radixin. Recent evidence has shown that cadherin-mediated cell–cell adhesion is also controlled by NF2 gene–coded merlin protein, which is lost or inactivated in the majority of meningioma cells.

Apart from their involvement in CSF absorption process in arachnoid villi, cadherins have profound roles in embryogenesis, normal tissue growth, and maintenance of the tumor cell nest. Shimoyama and colleagues reported that E-cadherin is expressed in all epithelial tissues and cancer cells, loss of which may contribute to the invasiveness of cancer cells. Interestingly, most meningiomas display en block growth, compressing the surrounding brain without infiltration. This growth pattern can be partly explained by the expression of E-cadherins, particularly in syncytial and transitional types of meningiomas. Several experimental studies reported an inverse correlation between the invasiveness of meningiomas and the expression of E-cadherins. Further, variations exist between the expressions of E-cadherin in different meningioma subtypes: It is expressed diffusely in syncytial type, less in transitional type, and not expressed in the fibroblastic type. This variation in the expression of E-cadherins in meningioma types correlates with the proposed corresponding cell types in arachnoid villi. Tohma and colleagues ³³ claimed that meningiomas may derive from arachnoid cells or fibroblasts (fibrous capsule) in the arachnoid villi rather than a single uniform cell based on the expression pattern of E-cadherin in different meningioma types. It is noteworthy that whereas fibrous capsule and the fibroblastic type of meningiomas do not express E-cadherin, the rest of the layers of arachnoid villi (cap cell cluster, arachnoid layer, and core arachnoid cells), and the proposed corresponding meningioma types do express E-cadherins. Tohma and colleagues also demonstrated ultrastructurally that E-cadherins are distributed along the cell borders in meningioma cells whereas they are localized at the intermediate junctions and anchored to cytoskeleton via intracytoplasmic microfilaments in normal arachnoid cells.³³ This change in the distribution of E-cadherin was thought to be at the receptor level, rendering the E-cadherin inactive and thus resulting in more arbitrary architecture and the increased motility of embryonic and meningioma cells.

Prostaglandin D₂ synthase

Prostaglandin D₂ synthase (PGDS or β-trace) is an enzyme playing a role in the synthesis of prostaglandin D₂ in the central nervous system (CNS).^9,³⁵ The function of PGDS in arachnoid and meningioma cells was reported in detail by Yamashima and colleagues in 1997. This study demonstrated that PGDS is localized mainly in the rough endoplasmic reticulum of arachnoid cells and detected in higher concentrations in the core arachnoid cells, suggesting that it may play role in the CSF absorption process.⁹

The authors also showed diffuse expression of PGDS in meningioma cells. However, the exact role of PGDS in meningioma cells is yet to be identified, besides its being a candidate universal cell marker for meningiomas as proposed by Yamashima and colleagues.