Molecular biology of unreresectable meningiomas: implications for new treatments and review of the literature

Abstract

Even though meningiomas are most often benign tumors, they can be locally invasive and can develop in locations that prevent surgical treatment. The molecular and biologic factors underlying meningioma development are only now beginning to be understood. Genetic factors such as mutations in the neurofibromatosis-2 gene and in chromosomes 1, 9, and 10 play important roles in meningioma development and may be responsible for atypical tumors in some cases. Cellular factors such as telomerase activation and tyrosine kinase receptor mutations may also play an important role. Finally, autocrine and paracrine factors including epidermal growth factor receptor, platelet-derived growth factor-1, and fibroblast growth factor have been implicated in the development of some tumors. Although the relationship between the various factors implicated in tumor development is unknown, understanding these factors will be critical in the treatment of malignant or surgically inaccessible tumors.

Keywords: Aggressive; atypical; biology; meningioma; treatment.

Figure 1

The interaction between the neurofibromatosis factor-2 tumor suppressor, merlin, and the meningioma growth demonstrates the effect of a tumor suppressor gene. Cytoskeleton-bound merlin attenuates Ras-mediated JNK activation and results in cellular transformation. Ras-induced phosphorylation of merlin inactivates the tumor suppressor and promotes its dissociation from the cytoskeleton and results in tumor growth. NF-2, neurofibromatosis-2; GTP, guanine triphosphate; JNK, jun N-terminal kinase.

Figure 2

The figure shows the role of CDKN2 and p14^ARF at 9p21 and p16 in suppression of proteins that mediate progression of G1 to S phase. Rb is phosphorylated to activate E2F which mediates transcription of genes necessary for G1 to S phase progression. Malignant meningiomas have been found to have inactivated CDKN2, p14^ARF, and p16, which rescinds tumor suppression. Solid lines represent progression of malignant meningioma whereas dotted lines are G1/S checkpoint pathways.