Edited by: Toshihisa Murofushi, Teikyo University, Japan
Reviewed by: Angel Batuecas-Caletrio, University of Salamanca Health Care Complex, Spain; Takeshi Tsutsumi, Tokyo Medical and Dental University, Japan
This article was submitted to Neuro-Otology, a section of the journal Frontiers in Neurology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Vestibular schwannomas (VSs) are benign tumors composed of differentiated neoplastic Schwann cells. They can be classified into two groups: sporadic VS and those associated with neurofibromatosis type 2 (NF2). VSs usually grow slowly, initially causing unilateral sensorineural hearing loss (HL) and tinnitus. These tumors cause HL both due to compression of the auditory nerve or the labyrinthine artery and due to the secretion of different substances potentially toxic to the inner ear or the cochlear nerve. As more and more patients are diagnosed and need to be managed, we are more than ever in need of searching for biomarkers associated with these tumors. Owing to an unknown toxic substance generated by the tumor, HL in VS may be linked to a high protein amount of perilymph. Previous studies have identified perilymph proteins correlated with tumor-associated HL, including μ-Crystallin (CRYM), low density lipoprotein receptor-related protein 2 (LRP2), immunoglobulin (Ig) γ-4 chain C region, Ig κ-chain C region, complement C3, and immunoglobulin heavy constant γ 3. Besides, the presence of specific subtypes of heat shock protein 70 has been suggested to be associated with preservation of residual hearing. It has been recently demonstrated that chemokine receptor-4 (CXCR4) is overexpressed in sporadic VS as well as in NF2 tumors and that hearing disability and CXCR4 expression may be correlated. Further, the genetic profile of VS and its relationship with poor hearing has also been studied, including DNA methylation, deregulated genes, growth factors, and
Vestibular schwannomas (VSs), previously termed acoustic neuromas, are non-malignant tumors composed of Schwann cells of the vestibulocochlear nerve (VIII cranial nerve), arising from either the internal auditory canal (IAC) or the cerebellopontine angle (CPA). They can be classified into two groups: sporadic VS and those associated with neurofibromatosis type 2 (NF2) (
The mortality rate of VS ranges from 0.2 to 1% (
Diagnosis of VS may be either from cranial MRI performed for unrelated complaints or, usually, due to unilateral hearing loss or tinnitus (
Audiological tests including audiometry and auditory brainstem response are not reliable predictors of CPA pathology (
Approximately three of each of the four VSs exhibit no growth, leading to an observation strategy (wait and scan). Mean growth is about 2–4 mm/year in growing tumors (
As more and more patients are diagnosed and need to be managed, we are more than ever in need of searching for biomarkers associated with these tumors, in order to help with the choice of selecting between a “wait-and-scan” approach and surgery (
Due to the lack of biopsy sampling without the destruction of the organ, little is known about the cellular and molecular correlates in inner ear pathology (
In recent years, considerable progress in proteomics has been enabled by modern technology. By a shotgun proteomics approach, the identification of proteins with high sensitivity is enabled (
Perilymph, an extracellular fluid of the inner ear, is found within the scala tympani and vestibuli of the cochlea. During an apoptotic or necrotic episode inside the inner ear, the proteins that are secreted can be found at high concentrations in this fluid (
In 2011, Lysaght et al. identified 15 proteins from perilymph specimens (selected by comparing VS and cochlear implant samples) with differential expression and biological function. They suggested the use of this list in future research focused on distinguishing between better vs. worse hearing in patients with VS (see
Proposed biomarkers of human VSs related to worse hearing.
μ-Crystallin | |
Fibronectin 1 | |
Keratin 10 | |
APOC3 | Apolipoprotein C-III |
VCAN | Versican |
DCD | Dermcidin |
SERPINB12 | Serpin family B member 12 |
CTSD | Cathepsin D |
SERPINB3 | Serpin family B member 3 |
SERPINA5 | Serpin family A member 5 |
SOD3 | Superoxide dismutase 3, extracellular |
PARK7 | Parkinson disease protein 7 |
SERPINF1 | Serpin family F member 1 |
CHI3L1 | Cartilage glycoprotein 39 |
Low-density lipoprotein receptor-related protein 2 |
μ-Crystallin (CRYM) or nicotinamide adenine dinucleotide phosphate (NADPH)-regulated thyroid hormone binding protein is located within the cytoplasm, where it promotes transcription of the thyroid hormone triiodothyronine (T3) (
Low density lipoprotein receptor-related protein 2 (LRP2) or megalin is a trans-membrane receptor protein, which can be found in certain epithelial cells such as those of the ear. LRP2 has the ability to bind several ligands, being essential in the process of endocytosis of different elements such as sterols, lipoproteins, hormones, and vitamin binding proteins. Two well-known conditions, Donnai-Barrow and facio-oculo-acoustico-renal (FOAR) syndromes (
On the other hand, of the 91 commonly identified perilymph proteins of patients with VS on an individual level, Rasmussen et al. described four proteins that were significantly associated with tumor-related deafness: Immunoglobulin (Ig) γ-4 chain C region, Ig κ chain C region, complement C3, and immunoglobulin heavy constant γ 3. These 91 proteins were identified in 12 out of 15 samples they used in the study (
Moreover, alpha-2-HS-glycoprotein, a suggested inflammatory and immunological intermediary in perilymph, was suggested to be associated with deafness in patients with SVs. It was also discovered in samples from VS patients in 2017 (
Heat shock proteins (HSPs) are stress proteins, which mediate cell survival under critical environmental conditions (
HSP90 is the most important chaperone for cellular stress. It is involved in pathological processes, such as cancer development (
Recently, Schmitt et al. found that HSP90 was determined in the perilymph of half of the patients (
On the other hand, HSP70 has been identified as an otoprotective agent and protects hair cells from stress-induced apoptosis (
According to these findings, more data on the regulation of these proteins and perilymph proteomics are mandatory to demonstrate the role of these HSPs in patients with VS and hearing loss.
Increased signal intensity of the fluid on three-dimensional fluid-attenuated inversion recovery (3D-FLAIR) MRI has been reported in various diseases, including SNHL, and VS (
Kim et al. demonstrated a correlation between a higher cochlear signal on 3D FLAIR images and hearing loss in patients with VS (
Ipsilateral inner ear alterations, including endolymphatic hydrops (EH) and acidophilic-staining precipitate, have been observed in temporal bone histopathological studies from patients with VS (
A large number of cytokines are produced by tumors (
Chemokine receptor-4 (CXCR4) is implicated in several pathological processes, including autoimmune disease, infection, and tumor development (
C-X-C Motif Chemokine Ligand 12 (CXCL12), a ligand for CXCR4, cooperates with metastatic cells to CXCL12-expressing organs. The Ras/Raf/MEK and the PI3K/Akt/mTOR pathways can be activated by CXCL12 binding to the CXCR4 receptor. In a similar way, the loss of Merlin (
Recently, Breun et al. have described that CXCR4 could play a role in the pathogenesis of both sporadic and NF2-associated VS. In their study CXCR4 was overexpressed in these tumors, with no significant differences found between the two groups. CXCR4 mRNA expression increased with the degree of hearing loss when compared with the control group, with the results lacking statistical difference (
Although tumor extension may be related to hearing impairment in VS (
According to Celis-Aguilar et al.'s review (
Epigenetic alterations are found across many solid cancers, and although most efforts in VS are limited to the controversial DNA methylation of the
In a study searching for associations between the molecular basis of VS and hearing loss (
The development of VS has also been associated with abnormal expression of growth factors. In a study of tumor samples from 11 subjects with VS, Lassaletta et al. described an inverse correlation between the expression of platelet-derived growth factor A and deafness (
Selvanathan et a1. analyzed the impact of age of onset on the existence of several NF2-related symptoms, including hearing impairment or tinnitus, and found that there was a significantly younger age of onset of symptoms in patients with nonsense or frameshift mutation (i.e., mutations that produce protein truncation). They hypothesized that a younger age of onset of VS could explain the younger age of onset of hearing loss (and tinnitus) (
Halliday et al. proposed a genetic severity score (1, tissue mosaic; 2A, mild classic; 2B, moderate classic; and 3, severe) in order to predict morbidity for NF2 subjects in certain dimensions including hearing status (
So far, no reliable methods are able to predict the evolution of hearing loss in subjects with VS. Several markers such as perilymph proteins have been associated with tumor hearing loss. Also, specific subtypes of HSP70 have been correlated with hearing outcomes. Cytokines produced by VS, especially CXCR4 expression, have been related to hearing impairment. DNA methylation, deregulated genes, growth factors, and
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.