Cyclooxygenase-2 supports tumor proliferation in vestibular schwannomas.

BACKGROUND: Recent studies have shown that cyclooxygenase-2 (COX-2) plays an important role in tumor growth and neovascularization. However, COX-2 expression in vestibular schwannomas (VSs) has not been investigated. OBJECTIVE: To analyze the pattern of COX-2 expression in sporadic and neurofibromatosis type 2 (NF2)-associated VSs and its relationship with tumor proliferation and microvessel density. METHODS: Fifteen sporadic and 15 NF2-associated VSs were examined for COX-2 expression, microvessel density, and proliferation rate by immunohistochemical methods. Immunohistochemical scores were used to interpret the extent and intensity of COX-2 staining. Microvessel density (MVD) was determined using von Willebrand factor (vWf). Proliferation rate was quantified using Ki-67. The relationship among COX-2 expression, MVD, and proliferation rate was statistically analyzed. RESULTS: COX-2 expression was detected in 29 (96.67%) of 30 VSs, with no significant difference between sporadic and NF2-associated VSs (P = .722). In 6 (20%) VSs, COX-2 expression was graded as strong, in 12 (40%) as moderate, and in 11 (36.7%) as weak. VSs with high proliferation showed significantly higher COX-2 expression (P = .015) than VSs with low proliferation. COX-2 expression and MVD did not show specific biological correlations (P = .035). CONCLUSION: Our data demonstrate that COX-2 is expressed in VSs. High COX-2 expression in VSs with high proliferation rates suggests that the COX-2 pathway may be involved in the development and growth of VSs.

Angiogenesis in vestibular schwannomas: expression of extracellular matrix factors MMP-2, MMP-9, and TIMP-1.

OBJECTIVES/HYPOTHESIS: Vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) are potent mediators of tumor angiogenesis. It has been demonstrated that vestibular schwannoma VEGF expression correlates with tumor growth pattern, whereas knowledge on the expression of MMPs is lacking. This study targets the angiogenic process by investigation of tumor expression of MMP-2, MMP-9, and tissue inhibitors of metalloproteinase (TIMP)-1. A possible correlation with gender, patient age, symptom duration, tumor size, and the absolute and relative growth rate is explored. STUDY DESIGN: Prospective vestibular schwannoma tissue sampling for ELISA and immunohistochemical determination of MMP-2, MMP-9 and TIMP-1. METHODS: Thirty-four patients with a sporadic, noncystic, vestibular schwannoma were selected prospectively. Repeated, preoperative magnetic resonance imaging determined the tumor growth pattern. Following translabyrinthine resection, an enzyme-linked immunosorbent assay was used for determination of the MMP-2, MMP-9, and TIMP-1 concentration in tumor sample homogenates. Immunohistochemical labeling was performed in 12 randomly selected tumors. RESULTS: : All tumor homogenates expressed measurable MMP-9, MMP-2, and TIMP-1. Immunolabeling localized MMP-9 expression to the tumor cells, whereas MMP-2 and TIMP-1 was found interstitially. A significant correlation existed between the concentration MMP-9 and absolute tumor growth rate, whereas a weak correlation occurred for the relative growth rate. CONCLUSIONS: Vestibular schwannomas express MMP-2, MMP-9, and TIMP-1 and the tumor concentration of MMP-9 correlates with absolute tumor growth rate, but not with age, gender, symptom duration, or preoperative tumor size. No correlations existed between any clinical parameter and MMP-2 or TIMP-1 expression. We conclude that MMP-9 appears to be involved in the growth of vestibular schwannomas.

Sulfotransferase 1A1 (SULT1A1) polymorphism and susceptibility to primary brain tumors.

PURPOSE: Sulfotransferase 1A1 is a member of sulfotransferase family that plays an important role in the biotransformation of numerous carcinogenic and mutagenic compounds through sulfation. The present study has investigated the association between SULT1A1 polymorphism and primary brain tumor incidence. METHODS: SULT1A1 genotypes were successfully detected using the PCR-RFLP assay in 60 primary brain tumor patients and 156 hospital-based healthy control individuals with no history of cancer or precancerous disorder. RESULTS: There was a significant difference in genotypes distribution (GG vs. GA + AA) between brain tumor patients (GG genotype frequency = 48.3%) and control population (GG genotype frequency = 65.4%; OR = 2.019, 95% CI = 1.103-3.695; P = 0.022). In order to determine the association between SULT1A1 polymorphism and specific types of brain tumors, the patients were classified according to the type of brain tumors they suffer from: glial and non-glial. Results of the statistical analyses of each group of patients in comparison with the control individuals showed a significant difference only between SULT1A1 polymorphism and non-glial brain tumors (OR = 2.615; 95% CI = 1.192-5.739; P = 0.014) but glial tumors (OR = 1.535; 95% CI = 0.688-3.425; P = 0.293). When non-glial tumors were classified as meningiomal and others (pituitary adenoma, craniopharyngioma, acoustic neuroma and hemangioblastoma), statistical analysis showed that this significance is only due to the meningiomal tumors (OR = 3.238; CI = 1.205-8.704; P = 0.015). We also estimated a reduced risk of brain tumor in non-smokers (OR = 1.700; CI = 0.800-3.615) in comparison to smokers (OR = 2.773; CI = 0.993-7.749), but this was not statistically significant. CONCLUSION: Our findings have suggested that there was a significant association between brain tumor and SULT1A1*2 allele (A allele that is also known as His allele) and this allele is an important risk factor in the development of meningiomal brain tumors.

Association of cavernous malformation within vestibular schwannoma: immunohistochemical analysis of matrix metalloproteinase-2 and -9.

A 65-year-old man presented with a rare case of cavernous malformation with hemorrhage located within vestibular schwannoma. He had suffered hearing impairment for 20 years, and was admitted to our hospital with vertigo and ataxic gait. Neurological examination revealed hearing loss, facial nerve paresis, and left cerebellar ataxia. Magnetic resonance imaging demonstrated a left vestibular schwannoma 35 mm in diameter, as well as a heterogeneous area associated with hypointense rim within the tumor, indicating intratumoral hemorrhage. Subtotal removal of the tumor together with the fibrously encapsulated hematoma was performed through a left retrosigmoid craniotomy. Histological examination of the surgical specimen revealed cavernous malformation within vestibular schwannoma. Immunohistochemistry for matrix metalloproteinase (MMP)-2 and -9, and tissue inhibitors of metalloproteinase-2 showed strong expression in the endothelial cells of the cavernous malformation, but not in the interstitial structures. His symptoms significantly improved after surgery and he underwent gamma-knife therapy for the residual tumor. Cavernous malformations may show dynamic characteristics such as repeated hemorrhage and de novo formation. MMP-2 and -9, which are implicated in angiogenesis and hemorrhage, may be upregulated in such tumors.

Role of antioxidant enzymes in brain tumours.

Erythrocyte antioxidant enzymes were analysed in 100 patients with intracranial neoplasm and in 47 controls. There was a significant decrease in RBC glutathione reductase (GRx) and superoxide dismutase (SOD) activity in most types of brain tumor cases. Patients with acoustic neurinoma showed a significant reduction in selenium-dependent glutathione peroxidase (Se-GPx) activity. A decrease in catalase (CT) activity was seen in most of the brain tumor patients but remained statistically insignificant when compared to controls. A significant increase in plasma ceruloplasmin concentration was observed in patients with glioma. These enzymes were also studied in 27 post-treatment cases. GRx activity returned to normal levels in these patients. RBC SOD and plasma ceruloplasmin levels showed a tendency to return to normal. Hence, a marked decrease in the antioxidant enzymes may have a role in the genesis of considerable oxidative stress in patients with brain tumors.

Characterization of molecular forms of acetyl- and butyrylcholinesterase in human acoustic neurinomas.

Acoustic neurinomas were sequentially extracted with saline and saline-Triton X-100 buffers. Detergent was required to detach the bulk of acetylcholinesterase (AChE), but butyrylcholinesterase (BuChE) was mostly released with saline buffer. Sedimentation analysis and hydrophobic chromatography revealed that neurinomas contain principally amphiphilic AChE tetramers, dimers and monomers, and hydrophilic BuChE tetramers. The AChE dimers and monomers remained amphiphilic after incubation with phosphatidylinositol-specific phospholipase C (PIPLC), after or without prior treatment with alkaline hydroxylamine, which shows that, in contrast to the meningioma AChE dimers and monomers, the neurinoma isoforms are devoid of glycolipid. Neurinoma AChE reacted with the antibodies HR2 and AE1 raised against AChE from human brain or erythrocyte, whereas BuChE bound to a sheep antiserum.

Plasminogen activator activity and molecular weight patterns in human brain tumors.

Fresh human brain-tumor samples were assayed for their plasminogen activator (PA) content. Specific molecular weight patterns were identified for each of five common brain tumors and for normal brain, suggesting a cell-specific origin of the various PA forms. Malignant tumors contained higher PA activity and a larger number of molecular weight patterns than benign tumors, with the exception of acoustic neurinomas. Irradiated tumors contained lower PA activity than nonirradiated tumors. Finally, a slight but definite correlation between brain edema and PA activity was detected. The future role of brain-tumor PA's for diagnostic and therapeutic purposes is discussed.

Human acoustic neurinomas: nervous system specific biochemical parameters.

A series of 24 human acoustic neurinomas from 24 patients has been assayed for several biochemical parameters characteristic of the nervous system. S 100 protein, 2', 3'-cyclic nucleotide 3'-phosphohydrolase activity, and the myelin lipids galactosylceramide and sulfogalactosylceramide (sulfatide). Myelin basic protein was not detected. These finding further support the neuroectodermal origin of the human acoustic neurinoma, and provide additional biochemical markers for further study.