Caspase 8 Expression Patterns in Meningiomas

Caspases (cysteine-aspartic proteases) represent a family of enzymes that critically influence cellular homeostasis by being involved in the mechanisms of inflammation and apoptosis. Meningiomas are the most common primary intracranial central nervous system tumors in adults worldwide.

Objective: Our objective was to explore the role of caspase 8 expression in the pathological characteristics of meningiomas.

Materials and methods: A total of 50 cases of meningioma were included in the study, comprising a wide range of histopathological subtypes. An immunohistochemistry test was applied on tissue chip cores followed by digital image analysis.

Results: Overexpression of caspase 8 protein was observed in 21/50 (42%) cases, while the others (29/50, 58%) had moderate to low levels of the molecule. Overall caspase 8 expression was statistically significantly correlated with the grade of tumors examined and the mitotic index (p=0.001, p=0.002, respectively).

Conclusions: An aberrant expression of caspase 8 is observed in meningiomas associated with their grade of differentiation and their mitotic activity. Targeted therapeutic strategies focused on enhancing caspase 8 expression and inducing global apoptotic activity should be a very promising approach to rationally manage subgroups of patients with meningioma.

Apoptosis is the genetically programmed variant of cell death mediated by a complex of proteins that positively or negatively influence intrinsic and extrinsic signaling pathways [1]. In cancerous tissues, programmed cell death is inhibited by dysregulated expression of apo- and anti-apoptotic proteins. This genetic imbalance pushes the cancer cell to immortalize itself, inducing aberrant tissue proliferation. For this reason, caspases and other mitochondria-dependent (or not) apoptotic molecules, such as bcl2/bax, are considered important agents for specific targeted therapeutic strategies aimed at improving apoptosis rates in malignant cells. [2].

Regarding central nervous system (CNS) tumors, meningioma is the second most common brain tumor and the most common primary intracranial tumor in adults. Interestingly, recurrent dedifferentiated meningiomas are correlated with aggressive biological behavior. They negatively affect response rates to surgical/radiation therapy regimens [3]. The histological substrate of meningiomas consists of the cells of the arachnoid cap of the meninges at the periphery of the brain.

Histopathologically, meningiomas include a wide spectrum of histopathological subtypes (meningotheliomatous, psammomatous, transitional, fibrous, angiomatous, atypical and anaplastic) [4].

Invasion of brain tissue is the most critical histopathological evidence of the tumor's aggressive biological behavior. In addition, extracranial metastatic potential and penetration of meningiomas are rare. Some molecular studies have reported - by analyzing large series of meningiomas - a variety of specific chromosomal and genetic aberrations (rearrangements/intra- or inter-translocations, gains, deletions/insertions by frameshift, point driver mutations or fusions in the frame ).

These imbalances are associated with a progressive differentiation of the corresponding malignant tumors (Grade I to III) [5,6]. Numerical imbalances also affect chromosomes other than chromosome 22. Fragment deletions were detected on chromosomes 1p and 2q33-q35. Regional amplifications occur on chromosome 6p21-p22 and on chromosomes 13q33, 17, and 19.

In conjunction with the chromosomal and gene instability described above, meningiomas are characterized by a broad spectrum of single-nucleotide somatic variants , demonstrated specific single-nucleotide polymorphism [7].Interestingly, there is limited evidence for viral involvement in the development of meningiomas, including human cytomegalovirus (HCMV)

Epstein-Barr virus (EBV), herpes simplex virus (HSV) 6/ 7, human papillomavirus (HPV) and hepatitis B virus (HBV) [8]. In the present research study, we explored the role of caspase 8, also called FLICE, in meningioma expression and its potential impact on its specific clinical-pathological features.