Analysis of ADAM9 regulation and function in vestibular schwannoma primary cells.
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ABSTRACT:
SUBMITTER: Nattmann A
PROVIDER: S-EPMC7659081 | biostudies-literature | 2020 Nov
REPOSITORIES: biostudies-literature
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Analysis of ADAM9 regulation and function in vestibular schwannoma primary cells.
Nattmann Anja A Breun Maria M Monoranu Camelia M CM Matthies Cordula C Ernestus Ralf-Ingo RI Löhr Mario M Hagemann Carsten C
BMC research notes 20201111 1
<h4>Objective</h4>Recently, we described a disintegrin and metalloproteinase 9 (ADAM9) overexpression by Schwann cells of vestibular schwannoma (VS) and suggested that it might be a marker for VS tumor growth and invasiveness. This research note provides additional data utilizing a small cohort of VS primary cultures and tissue samples. We examined whether reconstitution of Merlin expression in VS cells regulates ADAM9 protein expression and performed lentiviral ADAM9 knock down to investigate p ...[more]
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Project description:A disintegrin and metalloproteinase 9 (ADAM9) is a member of the transmembrane ADAM family. It is expressed in different types of solid cancer and promotes tumor invasiveness. To the best of our knowledge, the present study was the first to examine ADAM9 expression in vestibular schwannomas (VS) from patients with and without neurofibromatosis type 2 (NF2) and to associate the data with clinical parameters of the patients. The aim of the present study was to evaluate if ADAM9 could be used as prognostic marker or therapeutic target. ADAM9 mRNA and protein levels were measured in VS samples (n=60). A total of 30 of them were from patients with neurofibromatosis. Healthy peripheral nerves from autopsies (n=10) served as controls. ADAM9 mRNA levels were measured by PCR, and protein levels were determined by immunohistochemistry (IHC) and western blotting (WB). The Hannover Classification was used to categorize tumor extension and hearing loss. ADAM9 mRNA levels were 8.8-fold higher in VS compared with in controls. The levels were 5.6-fold higher in patients with NF2 and 12-fold higher in patients with sporadic VS. WB revealed two mature isoforms of the protein, and according to IHC ADAM9 was mainly expressed by S100-positive Schwann cells. There was a strong correlation between ADAM9 mRNA expression and the level of functional impairment (r~1, p=0.01). Particularly, the secreted isoform of ADAM9 was expressed in patients with higher hearing impairment. ADAM9 mRNA was overexpressed in the tumor samples relative to healthy vestibular nerves, and there was an association between higher ADAM9 expression levels and greater hearing impairment. Therefore, ADAM9 may be a prognostic marker for VS, and ADAM9 inhibition might have the potential as a systemic approach for the treatment of VS.
| S-EPMC7039135 | biostudies-literature
Project description:BackgroundThe management of vestibular schwannoma has evolved over the past hundred years. In the last decades, surgery has been gradually replaced by radiation therapy as a primary treatment modality, particularly for small tumors, due to the less invasive nature and the compared reported outcomes in tumor control and hearing preservation. However, irradiation sometimes fails to stop tumor growth. In a long-term follow-up after primary fractionated stereotactic radiotherapy, the rate of treatment failure was reported as 3% and needed surgical salvage. For single-fraction modality, Hasegawa et al. reported salvage treatment after primary Gamma Knife radiosurgery in 8%, where 90% of these underwent surgery and 50% of those who were treated with a second gamma knife surgery required surgical intervention later. An increase in tumor volume by more than 10-20%, tumor growth after three years, and no return to pretreatment volume after transient swelling have been considered as tumor recurrence rather than pseudoprogression, a transient increase in tumor volume after radiotherapy that occurs up to 30% of cases. It has been reported that microsurgery after radiotherapy is more difficult, with most authors reporting a loss of defined arachnoid planes and worse cranial nerve outcomes, especially for hearing and facial nerve function.Case descriptionA 43-year-old female patient was incidentally (asymptomatic) diagnosed on a magnetic resonance imaging (MRI) scan harboring a left vestibular schwannoma, grade T2 (Hannover classification), in 2015. Neurologic examination was unremarkable, and audiometry testing was normal. She was initially treated with observation. Three years later, in 2018, the lesion had enlarged, becoming a grade T3a and reaching the cistern of the cerebellopontine angle. The tumor was then treated with fractionated stereotactic radiosurgery (5 sessions of 5 Gy). MRI scans in 2019 and 2020 showed slight tumor growth. This enlargement was attributed to a pseudoprogression after radiosurgery, and only observation was advocated. In 2022, 4 years later, after radiosurgery, the tumor was still growing, and the patient began to suffer from hearing loss. A failure treatment was considered, and microsurgery was indicated. The patient was counseled about the risk of functional nerve impairment, and surgical consent was obtained. A retro sigmoid approach was planned. A gross total resection was attempted due to the clear subperineural plane during tumor dissection and because it was the only option that would provide a cure for the patient. The adjacent neurovascular structures were firmly adhered to the tumor capsule, which represented a major challenge for microdissection. The tumor was soft, without significant bleeding. A total resection was achieved, and the facial nerve was anatomically preserved. The patient developed facial paresis (House-Brackmann III) in the immediate postoperative period, which improved at the 6-month follow-up. Hearing loss did not improve. Postoperative MRI showed total resection.ConclusionMicrosurgery after radiotherapy for vestibular schwannoma is challenging in terms of indication, when to indicate, resection target, difficulty in dissection due to local changes, and outcome. Gross total resection may be considered, as it is the only treatment that may provide a cure for the patient. However, the patient should be counseled about the risks.
| S-EPMC10783665 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2014-11-30 | GSE56598 | GEO
Project description:Vestibular schwannoma (VS) is commonly accompanied by hearing loss, tinnitus, and dizziness and tends to be chronically progressive in nature. We report a case of VS presenting as left vestibular neuritis (VN) in a previously healthy 57-year-old patient. Right-beating horizontal-torsional spontaneous nystagmus was observed, and the bedside head impulse test revealed a left catch-up saccade. The bithermal caloric test showed left canal paresis, and pure-tone audiometry revealed an average threshold of 22.5 dB bilaterally. Brain magnetic resonance imaging (MRI) demonstrated a 0.7-cm enhancing mass in the left internal auditory canal, consistent with VS. The patient was administered with high-dose systemic corticosteroids and vestibular suppressants with antiemetic, which relieved acute vertigo. Although dizziness in VS is chronically progressive in nature, VS may present as an acute vestibular syndrome that mimics VN. VS should be considered a potential cause of acute vestibular syndrome, and thorough neurological examination with MRI may be helpful for accurate diagnosis.
| S-EPMC9830296 | biostudies-literature
Project description:AimVestibular schwannomas (VSs) are generally considered benign tumors, and malignant transformation of VSs (MTVSs) are rare findings. The clinical features, treatment strategy, outcomes and prognostic factors remain unclear. We endeavored to analyze the natural history, management, outcomes and prognostic factors of MTVSs.Materials and methodsThe clinical features, radiologic findings, pathological investigations and surgical outcomes of 4 patients with MTVSs treated at the authors' institution between 2010 and 2019 were retrospectively collected. Related literature published until December 2019 (63 articles, 67 patients) was evaluated. The authors also made a pooled analysis to evaluate the risk factors for overall survival (OS) time.ResultsOf the 4 cases in our series, 3 cases were malignant transformation following previous treatment (surgery and radiosurgery) and 1 was primary MTVS. Of the 71 MTVSs from the literature, 27 were male and 39 were female, with the mean age of 47.2 ± 17.5 years old. Twelve patients (18.5%) were diagnosed with NF2 (15.4%) or NF1 (3.1%). Forty-three (61.4%) patients underwent previous treatment (surgery and/or radiotherapy) prior to the pathological diagnosis of MTVSs. The mean size of the MTVSs was 35.1 ± 13.2mm. The mean Ki-67 index was 30.6% ± 18.8%. Twenty-four (49.0%) patients underwent gross total resection, 25 (51.0%) patients underwent incomplete resection. Twenty-five (44.6%) underwent adjuvant radiotherapy (RT) postoperatively. During the average follow-up of 9.9 ± 9.5 months (range, 0-40 months), 37 (82.2%) patients developed a local recurrence or metastasis. Forty-seven (73.4%) patients died of tumor progression or postoperative complications. The overall 1-year and 2-year survival rate was 42.3% and 18.6% respectively. Log-rank testing for Kaplan-Meier survival analysis identified that size (P = 0.047) and adjuvant radiotherapy (P=0.001) were significant prognostic factors for OS. Multivariate analysis revealed that adjuvant RT was the only prognostic factor for longer OS (P = 0.005).ConclusionsMTVSs are rare, fatal disease, prone to recur and metastasize rapidly, resulting in death in most of the cases. We found that GTR did not improve the survival in MTVSs but postoperative adjuvant RT can significantly improve the OS, and we recommend early postoperative RT in MTVSs regardless of extent of resection.
| S-EPMC8079768 | biostudies-literature
Project description:Wide methylation analysis in vestibular schwannoma
| PRJNA244045 | ENA
Project description:Vestibular schwannomas are tumors arising from the vestibulocochlear nerve at the cerebellopontine angle. Their proximity to eloquent brainstem structures means that the pathology itself and the treatment thereof can be associated with significant morbidity. The vast majority of these tumors are sporadic, with the remainder arising as a result of the genetic syndrome Neurofibromatosis Type 2 or, more rarely, LZTR1-related schwannomatosis. The natural history of these tumors is extremely variable, with some tumors not displaying any evidence of growth, others demonstrating early, persistent growth and a small number growing following an extended period of indolence. Emerging evidence now suggests that far from representing Schwann cell proliferation only, the tumor microenvironment is complex, with inflammation proposed to play a key role in their growth. In this review, we provide an overview of this new evidence, including the role played by immune cell infiltration, the underlying molecular pathways involved, and biomarkers for detecting this inflammation in vivo. Given the limitations of current treatments, there is a pressing need for novel therapies to aid in the management of this condition, and we conclude by proposing areas for future research that could lead to the development of therapies targeted toward inflammation in vestibular schwannoma.
| S-EPMC7212860 | biostudies-literature
Project description:Vestibular schwannomas are intracranial tumors that affects unilateral and sporadically or bilateral when is associated to Neurofibromatosis type 2 syndrome. The hallmark of the disease is the biallelic inactivation by NF2 gene mutation or LOH of chromosome 22q, where this gene harbors. In this work, we used Infinium HumanMethylation 450K BeadChip microarrays in a series of 36 vestibular schwannomas, 4 non-vestibular schwannomas and 5 healthy nerves. Our results shows a trend to hypomethylation in schwannomas. Furthermore, HOX genes, located at 4 clusters in the genome, displayed hypomethylation in numerous CpG sites in vestibular but not in non-vestibular schwannomas. Additionally, several microRNA and protein-coding genes were found hypomethylated at promoter regions and confirmed by expression analysis; including miRNA-199a1, miRNA-21, MET and PMEPA1. We also detected methylation patterns that might be involved in alternative transcripts of several genes such as NRXN1 or MBP; that would increase the complexity of methylation-expression. Overall, our results shows specific epigenetic signatures in several coding genes and microRNA that could be used in the finding of potential therapeutic targets.
2014-11-30 | GSE56597 | GEO
Project description:Vestibular schwannomas are intracranial tumors that affects unilateral and sporadically or bilateral when is associated to Neurofibromatosis type 2 syndrome. The hallmark of the disease is the biallelic inactivation by NF2 gene mutation or LOH of chromosome 22q, where this gene harbors. In this work, we used Infinium HumanMethylation 450K BeadChip microarrays in a series of 36 vestibular schwannomas, 4 non-vestibular schwannomas and 5 healthy nerves. Our results shows a trend to hypomethylation in schwannomas. Furthermore, HOX genes, located at 4 clusters in the genome, displayed hypomethylation in numerous CpG sites in vestibular but not in non-vestibular schwannomas. Additionally, several microRNA and protein-coding genes were found hypomethylated at promoter regions and confirmed by expression analysis; including miRNA-199a1, miRNA-21, MET and PMEPA1. We also detected methylation patterns that might be involved in alternative transcripts of several genes such as NRXN1 or MBP; that would increase the complexity of methylation-expression. Overall, our results shows specific epigenetic signatures in several coding genes and microRNA that could be used in the finding of potential therapeutic targets.
2014-11-30 | GSE56596 | GEO
Project description:Objectives:The present study aimed to replicate the finding that vestibular schwannoma (VS) patients with facial paresis experience lower health related quality of life (QoL) than those without facial paresis in a Dutch sample, and to extend these findings by measuring VS patients' overall satisfaction with life, social function, and emotion. Methods:Forty-seven VS patients, differing in degree of facial functioning, half of them with and half of them without a facial paresis, answered questionnaires about health related QoL (SF-36 and PANQOL), overall satisfaction with life, fear of being evaluated negatively by others, social avoidance and distress, and characteristics and symptoms of depression. Results:We observed that VS patients with facial paresis experience lower health-related QoL as well negatively impacted social function and emotion compared to VS patients without facial paresis. VS patients with facial paresis experienced lower overall satisfaction with life, more characteristic symptoms of depression, and more fear of being evaluated negatively by others than VS patients without facial paresis. Conclusion:These findings corroborate previous research showing an association between impaired facial functioning and lower QoL, but also extend them by showing differences on the quality of social function and emotion. Being aware of this difference between VS patients with and without facial paresis informs health practitioners regarding the specific support these patients might need. Moreover, it is also relevant to consider the influence of a facial paresis on patients' life when deciding between treatment options and in case of surgery the type of resection. Level of evidence:3.
| S-EPMC7314489 | biostudies-literature