Tumor Biology of Vestibular Schwannoma: A Review of Experimental Data on the Determinants of Tumor Genesis and Growth Characteristics *†Maurits de Vries, †Andel G. L. van der Mey, and *Pancras C. W. Hogendoorn Departments of *Pathology and ÞOtolaryngology, Leiden University Medical Center, Leiden, The Netherlands Objective: Provide an overview of the literature on vestibular schwannoma biology with special attention to tumor behavior and targeted therapy. Background: Vestibular schwannomas are benign tumors originating from the eighth cranial nerve and arise due to inactiva- tion of the NF2 gene and its product merlin. Unraveling the biology of these tumors helps to clarify their growth pattern and is essential in identifying therapeutic targets. Methods: PubMed search for English-language articles on vestibular schwannoma biology from 1994 to 2014. Results: Activation of merlin and its role in cell signaling seem as key aspects of vestibular schwannoma biology. Merlin is regulated by proteins such as CD44, Rac, and myosin phosphatase-targeting subunit 1. The tumor-suppressive functions of merlin are related to receptor tyrosine kinases, such as the platelet-derived growth factor receptor and vascular endothelial growth factor receptor. Merlin mediates the Hippo pathway and acts within the nucleus by binding E3 ubiquiting ligase CRL4 DCAF1 . Angiogenesis is an important mechanism responsible for the progression of these tumors and is affected by processes such as hypoxia and inflammation. Inhibiting angiogenesis by targeting vascular endothelial growth factor receptor seems to be the most successful pharmacologic strategy, but additional therapeutic options are emerging. Conclusion: Over the years, the knowledge on vestibular sch- wannoma biology has significantly increased. Future research should focus on identifying new therapeutic targets by investi- gating vestibular schwannoma (epi)genetics, merlin function, and tumor behavior. Besides identifying novel targets, testing new combinations of existing treatment strategies can further improve vestibular schwannoma therapy. Key Words: Vestibular schwannoma V Acoustic neuroma VNeurofibrosis type 2VMerlinVTumor biologyV TherapyVTumor growthVAngiogenesis. Otol Neurotol 36:1128Y1136, 2015. Sporadic vestibular schwannomas (VSs) are benign tumors recapitulating the differentiation repertoire of the myelin-forming Schwann cells of the vestibular branch of the eighth cranial nerve. VSs derive within the internal auditory canal, often extending into the cerebellopontine angle. Associated symptoms are hearing loss, tinnitus, and vertigo. Large tumors can cause paralysis of adjacent cranial nerves and brainstem compression. Most VSs occur as unilateral sporadic tumors (990%) (1). Bilateral tumors are pathognomonic for the hereditary disorder neurofibrosis type 2 (NF2). In this review, we discuss both but mainly focus on the sporadic tumors. In recent years, the incidence of VSs has increased to approximately 20 per million people per year (2Y4). This is probably a consequence of the increased application of magnetic resonance imaging scanning resulting in the identification of more subclin- ical cases. Therapeutic management of VSs comprises three strat- egies, that is, microsurgery, radiotherapy, or serial radio- logic observation. So far, pharmacologic treatment options are scarce (5Y7). An important aspect determining the most suitable therapy is growth rate. Some tumors remain stable for years, whereas others grow relatively fast (Fig. 1). The biological background of this phenotypical heterogeneity is largely unknown. This review provides an overview of the literature on VS biology with special attention to tumor behavior and targeted therapy. NF2 Gene An essential contribution to the understanding of VS bi- ology was the isolation of the neurofibromatosis type 2 gene (NF2) (8,9). NF2 encodes for the tumor suppressor protein merlin. This gene is located on chromosome 22q12 and contains 17 exons. Loss of functional merlin is essential in schwannoma pathogenesis (10). Heterozygous germline Address correspondence and reprint requests to Maurits de Vries, M.D., Department of Otolaryngology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands; E-mail: w.m.de_vries@lumc.nl Conflicts of interest and source of funding: This study was supported by a departmental grant; the authors declare no conflict of interest. Supplemental digital content is available in the text. Otology & Neurotology 36:1128Y1136 Ó 2015, Otology & Neurotology, Inc. 1128 Copyright © 2015 Otology & Neurotology, Inc. Unauthorized reproduction of this article is prohibited.