Genesis and biology of vestibular schwannomas

This review chapter is a synthesis of the recent literature about pathogenesis of schwannomas with emphasis on vestibular schwannomas (VSs). The cornerstone of cellular transformation and proliferation of Schwann cells toward schwannomas has been attributed to the nonexpression of normal schwannomin/merlin (S/M) by these cells. The understanding of this mechanism has been gained from molecular genetic studies of neurofibromatosis type 2 (NF2) patients, in whom mutations of a tumor suppressor gene (NF2 gene) was clearly identified. S/M is the normal NF2 gene product. Lack of normal S/M protein in the schwannoma cell is due to gene mutation in 50% of sporadic VSs. In the other cases, epigenetic factors or activation of protease cascade contribute to ineffective S/M. The exact interactions of S/M with extracellular matrix, membranous glycoprotein and cytoskeleton are not fully understood. However, it is recognized that these interactions activate several pathways that might regulate cell-cycle process, apoptosis and intercellular interaction. Apart from the involvement of the S/M pathway, the authors review the potential role of other genetic abnormalities and growing factors that are supposed to be involved in the pathogenesis of VS. Understanding the pathways of action and regulation of S/M may provide the basics for identifying potential therapeutic targets, which is of paramount importance for a better management of NF2 patients.