环氧化酶-2 及COX-2mRNA 在脑膜瘤中的表达及意义

  目的 观察环氧化酶-2(COX-2)蛋白及COX-2mRNA在人脑膜瘤组织中的表达，探讨COX-2基因表达与脑膜瘤病理分型的相关性。方法 收集1995年3月～2003年4月在我院住院的56例脑膜瘤病人经手术治疗切除的肿瘤标本，另选颅脑损伤内减压手术切除的脑组织标本8例作为正常对照标本。石蜡包埋切片后，用免疫组化的方法检测COX-2蛋白在脑膜瘤中的表达，用原位杂交的方法检测COX-2mRNA在脑膜瘤中的表达。结果 脑膜瘤的COX-2蛋白和COX-2mRNA的阳性表达率分别为53．57％和58．93％；正常对照组不表达。恶性脑膜瘤的COX-2蛋白和COX-2mRNA表达率明显高于良性脑膜瘤(P<0．01)。结论 COX-2和COX-2mRNA在脑膜瘤中高度表达，且与脑膜瘤的病理分型有关；从蛋白水平和基因分子水平阐明COX-2可能在脑膜瘤的发生、发展过程中起重要作用。     

Clinicopathological evaluation of cyclooxygenase-2 expression in meningioma: immunohistochemical analysis of 76 cases of low and high-grade meningioma

Tumorigenic activity of cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the production of prostaglandins (PGs), has been proved for some types of cancer, including brain tumors. We evaluated expression of COX-2 in meningioma, one of the most common intracranial tumors in adults which accounts for 24–30 % of intracranial tumors. We performed immunostaining for COX-2 in 76 cases of meningioma consisting of 44 cases of low-grade (WHO Grade I) and 32 cases of high-grade (29 cases of Grade II and 3 cases of Grade III) meningioma, and evaluated COX-2 expression levels on the basis of staining intensity and proportion in tumor cells. The expression level of COX-2 in meningioma cells was significantly correlated with WHO grade (P = 0.0153). In addition, COX-2 expression was significantly correlated with MIB-1 labeling index for all 76 cases of meningioma (P = 0.0075), suggesting tumor promotion by COX-2 in meningioma progression. Our results may indicate the therapeutic value of non-steroidal anti-inflammatory drugs against meningioma, especially for patients with elevated proliferation, to regulate the tumorigenic activity of COX-2 in meningioma cells.     

Transforming Growth Factor-β Effects on Meningioma Cell Proliferation and Signal Transduction Pathways

The role of transforming growth factor-beta (TGF-beta) in regulation of meningioma growth and intracellular events transducing its signals are not established. In this study, we evaluated the effects of TGF-beta1 on basal meningioma cell proliferation in 10 primary human meningioma cell cultures and whether TGF-beta's signals are transduced by the Smad 2/3, MAPK/Erk kinase-1 (MEK-1)-mitogen-activated protein kinase (MAPK), Akt-p70(S6K) or p38-JUNK pathways in 5. We also tested whether neutralizing antibodies to TGF-beta alter CSF stimulation of meningioma cell proliferation. On average, TGF-beta reduced meningioma cell [3H]-thymidine incorporation to 58% of controls at 24% and to 61% of controls at 36 h. TGF-beta inhibition of meningioma cell proliferation was associated with a suggestion increased phosphorylation of Smad 2/3 in 2 cases and high basal phosphorylation in 3 but no change in activation of the MEK-1-MAPK, Akt-p70(S6K) or p38-JUNK pathways. As shown previously, CSF stimulated meningioma cell proliferation in the 3 cultures tested. Neutralizing antibody against TGF-beta augmented this stimulation in 2 of 3 cultures. These findings suggest that TGF-beta exerts a largely inhibitory effect on basal meningioma proliferation, perhaps in part through Smad 2/3.     

Correlation between 99mTc-HYNIC-octreotide SPECT/CT somatostatin receptor scintigraphy and pathological grading of meningioma

The aim of this study was to explore the association of ^99mTc-HYNIC-octreotide SPECT/CT somatostatin receptor scintigraphy (SRS) with the pathological grading and expression of somatostatin receptor 2 (SSTR2) for meningioma, and to define possible roles of SRS in the pathological grading of meningioma. Thirty patients with meningiomas diagnosed by MRI and treated with ^99mTc-HYNIC-octreotide SPECT/CT SRS. Meningioma tissues were obtained from analyzing pathological grading and measuring the expression of SSTR2 with immunohistochemical staining. The meningioma side (T) to the contralateral side (NT) ratios (T/TN) of radioactive counts were calculated to investigate their association with the pathological grading of meningioma and the expression of SSTR2. All 30 cases showed high meningioma radioactivity accumulation using SRS with a sensitivity of 100 %, while CT scans only detected 25 cases with a sensitivity of 83 %. Twenty cases with grade I meningioma had a T/NT ratio of 3.80 ± 1.67, which was significantly lower than the other 10 cases (9.57 ± 3.78) with a grade II meningioma (P < 0.01). All meningiomas expressed SSTR2 as detected by immunohistochemical staining, and the T/NT ratio was positively associated with the pathological grading of meningioma and the expression of SSTR2 (with r of 0.784 and 0.805, respectively). ^99mTc-HYNIC-octreotide SPECT/CT SRS is a sensitive technique for detecting meningioma, and the T/NT ratio of the SRS data closely correlates with the pathological grade of meningioma and the expression of SSTR2.     

Genotyping of patients with sporadic and radiation-associated meningiomas.

Ionizing radiation is the most established risk factor for meningioma formation. Our aim was to evaluate the main effect of selected candidate genes on the development of meningioma and their possible interaction with ionizing radiation in the causation of this tumor. The total study population included 440 cases and controls: 150 meningioma patients who were irradiated for tinea capitis in childhood, 129 individuals who were similarly irradiated but did not develop meningioma, 69 meningioma patients with no previous history of irradiation, and 92 asymptomatic population controls. DNA from peripheral blood samples was genotyped for single nucleotide polymorphisms (SNP) in 12 genes: NF2, XRCC1, XRCC3, XRCC5, ERCC2, Ki-ras, p16, cyclin D1, PTEN, E-cadherin, TGFB1, and TGFBR2. SNP analysis was done using the MassArray system (Sequenom, San Diego, CA) and computerized analysis by SpectroTYPER. Logistic regressions were applied to evaluate main effect of each gene on meningioma formation and interaction between gene and radiation. Intragenic SNPs in the Ki-ras and ERCC2 genes were associated with meningioma risk (odds ratio, 1.76; 95% confidence interval, 1.07-2.92 and odds ratio, 1.68; 95% confidence interval, 1.00-2.84, respectively). A significant interaction was found between radiation and cyclin D1 and p16 SNPs (P for interaction = 0.005 and 0.057, respectively). Our findings suggest that Ki-ras and ERCC2 SNPs are possible markers for meningioma formation, whereas cyclin D1 and p16 SNPs may be markers of genes that have an inverse effect on the risk to develop meningioma in irradiated and nonirradiated populations.     

Identification of a progenitor cell of origin capable of generating diverse meningioma histological subtypes

Meningiomas are among the most common primary central nervous system tumours in adults. Studies focused on the molecular basis for meningioma development are hampered by a lack of information with regard to the cell of origin for these brain tumours. Herein, we identify a prostaglandin D synthase-positive meningeal precursor as the cell of origin for murine meningioma, and show that neurofibromatosis type 2 (Nf2) inactivation in prostaglandin D2 synthase (PGDS) (+) primordial meningeal cells, before the formation of the three meningeal layers, accounts for the heterogeneity of meningioma histological subtypes. Using a unique PGDSCre strain, we define a critical embryonic and early postnatal developmental window in which biallelic Nf2 inactivation in PGDS (+) progenitor cells results in meningioma formation. Moreover, we identify differentially expressed markers that characterize the two major histological meningioma subtypes both in human and mouse tumours. Collectively, these findings establish the cell of origin for these common brain tumours as well as a susceptible developmental period in which signature genetic mutations culminate in meningioma formation.     

Different distribution of c-myc and MIB-1 positive cells in malignant meningiomas with reference to TGFs, PDGF, and PgR expression

We investigated the expression of transforming growth factors (TGFs), platelet-derived growth factor (PDGF), progesterone receptor (PgR), and c-myc in 20 cases of meningioma of various grades: 17 benign, 2 atypical, and 1 anaplastic. All cases of atypical and anaplastic meningioma were positive for c-myc, whereas all 17 benign meningiomas were negative for c-myc immunostaining. Expression of TGF-α, TGF-β, and PDGF-BB proteins was seen in more than 80% of the meningioma cases and was not restricted to their histological grade of meningioma. PgR was expressed mainly in benign meningiomas. Moreover, the cells expressing c-myc protein were not usually stained by MIB-1. These results indicate that c-myc does not directly work on the proliferation of meningioma cells, and even in homogeneous meningioma cells, there may be many functional variations that lead the meningioma cells to their growth.     

Thioredoxin-Interact ing-Pro t e in [TXNIP] and Transglutaminase 2 [TGM2] Expression in Meningiomas of Different Grades and the Role of Their Expression in Meningioma Recurrence and Prognosis

Background: Meningiomas are common central nervous system (CNS) tumors that account for thirty percent of primary intracranial tumors.. The accuracy of predicting meningioma recurrence and progression is not enough. So, there is a real need for discovering recent factors for identification of the relapse risk, progression rates, which patients will need aggressive treatment and predicting and improving patients’ survival. Thioredoxin-interacting-protein [TXNIP] is an alpha-arrestin-protein family member that is mapped on chromosome 1-q21–22 and is found to participate in cellular redox reactions regulations and control. Transglutaminase 2 (TGM2) is a transglutaminase enzyme family member that is found in many human cells, it may act as an enzyme, a structural protein and also has multiple roles in many cellular activities. Aim of our study: It was to explore the expression of TXNIP, TGM2 and Ki-67 using immunohistochemistry in different pathological grades of meningiomas, and to investigate the relevance between their expressions, clinicopathological criteria, disease recurrence and prognosis of meningioma patients. Methods: we included 50 cases of meningioma of different pathological grades; all patients were managed according to their grade by surgery alone, with radiotherapy or combined modalities. Sections from paraffin blocks prepared from samples of all patients stained by TXNIP, TGM2 and Ki-67 using immunohistochemistry. Results: high expression of TXNIP in 28 out of 50 (56%) cases of meningioma of different pathological grades and was positively correlated with meningioma lower grade, low KI labeling index (p=0.000), adequacy of resection, negatively correlated with high incidence of recurrence after surgery and it was negatively correlated with meningioma higher pathological grades (p=0.000). We detected high expression of TGM2 in 21 out of 50 (42%) cases of meningioma and it was positively correlated with meningioma higher grade (p= 0.002), high KI labeling index (p=0.000), high incidence of recurrence after surgery, progression to higher pathological grades and was negatively correlated with adequacy of resection of meningioma (p=0.000). Conclusion: There is inverse relation between both [TXNIP and TGM2 expression in meningiomas and the combination of decreased expression of TXNIP and increased expression of TGM2 could predict risk of meningioma recurrence and progression in to higher pathological grades.     

AR42, a novel histone deacetylase inhibitor, as a potential therapy for vestibular schwannomas and meningiomas

Neurofibromatosis type 2 (NF2) is an autosomal-dominant disease that results in the formation of bilateral vestibular schwannomas (VSs) and multiple meningiomas. Treatment options for NF2-associated tumors are limited, and to date, no medical therapies are FDA approved. The ideal chemotherapeutic agent would inhibit both VS and meningiomas simultaneously. The objectives of this study are (1) to test the efficacy of AR42, a novel histone deacetylase inhibitor, to inhibit VS and meningioma growth and (2) to investigate this drug's mechanisms of action. Primary cultures of human VS and meningioma cells were established. Nf2-deficient mouse schwannoma and benign human meningioma Ben-Men-1 cells were also cultured. Cells were treated with AR42, and the drug's effects on proliferation and the cell cycle were analyzed using a methanethiosulfonate assay and flow cytometry, respectively. Human phospho-kinase arrays and Western blots were used to evaluate the effects of AR42 on intracellular signaling. The in vivo efficacy of AR42 was investigated using schwannoma xenografts. Tumor volumes were quantified using high-field, volumetric MRI, and molecular target analysis was performed using immunohistochemistry. AR42 inhibited the growth of primary human VS and Nf2-deficient mouse schwannoma cells with a half maximal inhibitory concentration (IC(50)) of 500 nM and 250-350 nM, respectively. AR42 also inhibited primary meningioma cells and the benign meningioma cell line, Ben-Men-1, with IC(50) values of 1.5 μM and 1.0 μM, respectively. AR42 treatment induced cell-cycle arrest at G(2) and apoptosis in both VS and meningioma cells. Also, AR42 exposure decreased phosphorylated Akt in schwannoma and meningioma cells. In vivo treatment with AR42 inhibited the growth of schwannoma xenografts, induced apoptosis, and decreased Akt activation. The potent growth inhibitory activity of AR42 in schwannoma and meningioma cells suggests that AR42 should be further evaluated as a potential treatment for NF2-associated tumors.     

MGEA6 is tumor-specific overexpressed and frequently recognized by patient-serum antibodies.

Tumorigenesis of meningioma has been associated with chromosome 22, most notably the NF2 gene, but additional genes have also been implicated in meningioma development. Previously, we have cloned the cDNAs for the meningioma expressed antigen 6 (MGEA6) and its splice variant MGEA11. Here, we show that antibodies against recombinantly expressed MGEA6/11 are found in 41.7% (10/24) of the sera from meningioma patients and in 2/8 sera of glioblastoma patients, whereas no response was seen in 12 sera from healthy persons. Western-blot analyses using generated polyclonal antibodies, revealed overexpression in meningioma and glioma tumor samples compared to normal brain. Immunohistochemical staining of tissue sections confirms reactivity in meningioma tumor cells and tumor cells of glial origin. We found no reactivity to normal astrocytes and only faint reactivity to normal leptomeninges. Sequence analysis predicted membranic localization of MGEA6/11, that was confirmed by cell fractionation. The immune response to MGEA6/11 is frequent in both meningioma and glioma patients and may likely be attributed to overexpression of the MGEA6/11 protein in the tumor cells.     

脑膜瘤的MRI表现和诊断--附126例分析

背景与目的：在脑膜瘤的MRI研究中,尚缺乏大组病例评价呐膜瘤MRI定性诊断指标,对脑膜瘤瘤周水肿等问题亦缺乏共识。本研究拟分析126例呐膜瘤的MRI表现,总结、归纳出诊断脑膜瘤的主要依据。方法：126例脑膜瘤的病理组织亚型分别为合体细胞型32例,纤维母细胞型35例,砂粒体型24例、血管母细胞型9例,过渡型18例,乳头型3例,恶性5例。全部病例均行T1、T2加权和T1加权增强扫描。结果：本组脑膜瘤以大脑凸面最多,约占35．5％;大小在1．4～9．9cm之问,圆形或类圆形占81％;T2加权信号以等或稍高为多,占70．6％。脑膜尾征出现率为62．7％,假包膜出现率为49．2％,脑实质挤压征在肿瘤大于4cm时出现率达83．8％,增强扫描呈明显的均匀强化的达82．5％。瘤周水肿出现率达45．2％,且与肿瘤的大小有一定关系。其它少见的征象包括囊变、出血、钙化、邻近骨改变和瘤内血管征。本组诊断准确率为95．2％。结论：脑膜瘤的MRI表现多样,其中脑实质外肿瘤的判定、T2加权典型信号、脑膜尾征和明显均匀强化形式是诊断脑膜瘤的关键。     

Novel tankyrase-related gene detected with meningioma-specific sera.

In many meningiomas, alterations of chromosome 22 can be found, and the NF2 (neurofibromatosis type 2) gene, in particular, is of great interest as a putative gene involved in meningioma. Because the NF2 gene is not mutated in all meningiomas, additional genes may be involved. Instead of looking for alterations directly at the DNA level, we used the immune response of meningioma patients to identify immunogenic antigens that may be associated with the disease. We screened a fetal brain cDNA expression library with sera pools from different patients bearing meningioma classified according to the three WHO grades, using the serological identification of antigens by recombinant expression cloning immunological screening method. Here, we report the finding of a new tankyrase-related protein. We found 16 overlapping clones with homologies to tankyrase when we screened the library with the common-type meningioma sera pool and 2 such clones when we screened the library with the atypical meningioma sera. The anaplastic meningioma sera did not identify any tankyrase-related clones. We tested some of the newly identified clones with 13 single sera, 6 of which (37.5%) reacted positively with the tankyrase-related clones. In addition, we screened the tankyrase-related clone with six sera pools from individuals without obvious disease. Although 1 of 24 (4.2%) normal sera reacted with the tankyrase-related clone, we found a striking difference in the frequency of reactivity to this clone by sera from patients bearing tumors corresponding to the three WHO meningioma grades; common-type sera was the most frequently reactive. Northern blot analysis demonstrates expression of the novel tankyrase gene in two common-type meningiomas from patients with immune response.     

Presence of the proteinase-activated receptor-2 (PAR-2) in human brain tumor cells--trypsin- and SLIGRL-induced calcium response in primary cultured meningiomas.

This study focused on proteinase-activated receptor-2 (PAR-2) in primary cultured human meningioma cells. Stimulation of these cells with the serine proteinase trypsin resulted in a dose-dependent transient calcium response. Since the specific PAR-2 agonist peptide SLIGRL also induced [Ca2+]i mobilization in human meningioma cells and successive application of SLIGRL and trypsin elicited no new calcium signal we conclude that trypsin-induced calcium signaling is mediated by PAR-2 in human meningioma cells. To our knowledge, this is the first report describing functional PAR-2-type receptors in human brain tumor cells.     

IL-1α、EphA2蛋白在脑膜瘤及瘤周水肿组织中的表达及临床意义

目的 探究IL-1α、EphA2在脑膜瘤及瘤周水肿组织中的表达及临床意义.方法 选取脑膜瘤患者120例,采用免疫组化方法检测IL-1α和EphA2在脑肿瘤以及瘤周水肿组织中的表达情况.结果 脑膜瘤组织中的IL-1α、EphA2阳性表达率明显高于瘤周水肿组织(P<0.05).在不同程度瘤周水肿组织中IL-1α、EphA2...     

Different responses of benign and atypical meningiomas to gamma-knife radiosurgery: report of two cases with immunohistochemical analysis

Recent reports have shown that gamma-knife radiosurgery provides a safe and effective strategy for the management of brain tumors. To evaluate the role of stereotactic radiosurgery in the management of meningiomas, we investigated the histopathology of two patients. The patients, a 37-year-old man and a 54-year-old woman, presented with visual field disturbance or headache. Imaging studies demonstrated intracranial meningiomas-tentorial and sphenoid ridge, respectively. Each patient undewent subtotal surgical resection (more than 90% in both patients), followed by gamma-knife radiosurgery of the remnant tumor marginal doses of 15 Gy. Pathological examination of the original tumors revealed a meningothelial meningioma and an atypical meningioma, respectively. Enlargement of the remnant tumors 4 months after radiosurgery resulted in total surgical resection in both patients. Thirteen months later, the patient with the atypical meningioma underwent a third operation for early recurrence of the tumor. Histopathology was investigated, and MIB-1, p53, and bcl-2 labeling indexes (LI) were analyzed immunohistochemically. Histopathologically, the specimens showed necrosis and intratumoral vessel obliteration after radiosurgery in both cases. However, more remnant tumor cells survived in the atypical meningioma. Immunohistochemically, increased wild-type p53, decreased bcl-2 expression, and decreased MIB-1 LI were observed in the benign meningioma. In the atypical meningioma, on the contrary, MIB-1 LI was decreased and mutant-type p53 and bcl-2 expression were unchanged. The specimen from the third operation revealed an anaplastic meningioma, and MIB-1 LI was markedly increased. These findings suggest that the efficacy of radiosurgery may differ between benign and atypical meningiomas.     

Valproic acid promotes radiosensitization in meningioma stem-like cells

Although meningioma stem-like cells have been isolated and characterized, their therapeutic targeting remains a challenge. Meningioma sphere cells (MgSCs) with cancer stem cells properties show chemo- and radioresistance in comparison with meningioma adherent cells (MgACs). We tested the effect of valproic acid (VPA), a commonly used anti-epileptic drug, which passes the blood brain barrier, on cultured MgSCs. VPA reduced the viability of MgSCs and MgACs. In MgSCs, treatment with VPA increased radio-sensitivity, expression of p-cdc2, p-H2AX and cleaved caspase-3 and PARP. Anchorage-independent growth (AIG) was reduced by VPA. AIG was further reduced by combined treatment with irradiation. Expression of a stem cell marker, Oct4, was reduced by VPA. Oct4 was further decreased by combined treatment with irradiation. These results suggest that VPA may be a potential treatment for meningioma through targeting meningioma stem-like cells.     

脑膜瘤CT、MR 表现与病理-超微结构和免疫组化对照研究

 目的　提高 CT、MR对脑膜瘤的诊断水平。方法　 5 2 9例经 CT检查 5 1 5例 ,MR检查78例 ,均经手术病理证实。按 1 990年 WHO脑膜瘤新分类进行光镜分类 ,配合 JEM- 1 0 0透射电镜观察超微结构 ,作 6种肿瘤的免疫组织化学检测波形蛋白 ( Vimentin) ,胶质纤维酸性蛋白( GFAP) ,角蛋白 ( Keratin) ,S- 1 0 0蛋白 ,上皮膜抗原 ( EMA) ,黑色素瘤抗原 ( HMB45 )。结果　对CT显示混合密度、囊性低密度区 ;MR呈长 T1、长 T2等信号与电镜所见瘤细胞空泡状 ,突起交织形成囊状超微结构的微囊型脑膜瘤为密切关系。其它良、恶性脑膜瘤的 CT、MR表现与电镜显示肿瘤超微结构均为密切关系。对病理分类的 1 2种良、恶性脑膜瘤检测显示 Vimentin和 EMA均为阳性。结论　对 CT、MR可疑脑膜瘤和电镜较难确诊者 ,应配合电镜进行肿瘤超微结构观察和肿瘤免疫组化检测确诊.     

Phase II study of subcutaneous octreotide in adults with recurrent or progressive meningioma and meningeal hemangiopericytoma

The objective of this phase II study was to evaluate the efficacy and safety of subcutaneous octreotide therapy for the treatment of recurrent meningioma and meningeal hemangiopericytoma. Octreotide is an agonist of somatostatin receptors, which are frequently expressed in meningioma, and reports have suggested that treatment with somatostatin agonists may lead to objective response in meningioma. Patients with recurrent/progressive meningioma or meningeal hemangiopericytoma were eligible for enrollment; those with atypical/anaplastic meningioma or hemangiopericytoma must have experienced disease progression despite radiotherapy or have had a contraindication to radiation. Patients received subcutaneous octreotide with a goal dose of 500 μg 3 times per day, as tolerated. Imaging was performed every 3 months during therapy. The primary outcome measure was radiographic response rate. Eleven patients with meningioma and 1 with meningeal hemangiopericytoma were enrolled during the period 1992-1998. Side effects included diarrhea (grade 1 in 4 patients and grade 2 in 2), nausea or anorexia (grade 1 in 4 patients), and transaminitis (grade 1 in 1 patient). One patient developed extra hepatic cholangiocarcinoma, which was likely unrelated to octreotide therapy. No radiographic responses were observed. Eleven of the 12 patients experienced progression, with a median time to progression of 17 weeks. Two patients experienced long progression-free intervals (30 months and ≥18 years). Eleven patients have died. Median duration of survival was 2.7 years. Immunohistochemical staining of somatostatin receptor Sstr2a expression in a subset of patients did not reveal a correlation between level of expression and length of progression-free survival. Octreotide was well-tolerated but failed to produce objective tumor response, although 2 patients experienced prolonged stability of previously progressive tumors.