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Tanti MJ, Nevitt S, Yeo M, Bolton W, Chumas P, Mathew R, Maguire MJ. Oedema as a prognostic factor for seizures in meningioma - a systematic review and meta-analysis. Neurosurg Rev 2025; 48:249. [PMID: 39969698 PMCID: PMC11839703 DOI: 10.1007/s10143-025-03416-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 02/02/2025] [Accepted: 02/10/2025] [Indexed: 02/20/2025]
Abstract
Meningiomas are benign intracranial tumours that commonly lead to seizures and oedema. An understanding of seizure risk factors is essential for the meningioma community. Many studies have differing conclusions on whether oedema is associated with seizure. Existing meta-analyses are limited by lack of focus on oedema. Our objective was to summarise all literature on oedema as a prognostic factor for seizures in meningioma patients. We searched OVID, Scopus, Pubmed, Web of Science, ClinicalTrials.gov and Google scholar up to April 2024 for reports with more than 10 human meningioma participants. Statistics were performed on R-Studio. Cochrane and Campbell guides for systematic reviews and meta-analysis were followed. Risk of bias was assessed with ROBINS-E. Our protocol was uploaded to INPLASY. We included 51 studies for meta-analysis and 21 for narrative review. Most studies were of surgically treated adults. Heterogeneity was low once outliers were removed. Preoperative oedema was associated with preoperative seizure (k = 28, n = 7,725, OR 3.5, 95% CI = 3.1-4.0, I2 = 0%, p < .001), early postoperative seizure (k = 9, n = 2,929, OR 1.5, CI = 1.1-1.9, I2 = 0%, p = .011) and late postoperative seizure (k = 9, n = 2,150, OR 1.9, CI = 1.5-2.2, I2 = 0%, p < .001). We performed an additional adjusted analysis for preoperative seizures which was also significant (k = 3, n = 2,241, OR 3.9, CI = 2.4-6.3, I2 = 0%, p = .007). There were few studies of post-radiosurgery oedema and seizure, and of postoperative oedema and seizure, with insignificant but positive associations. Preoperative oedema is a key factor for preoperative seizures. Oedema also increases risk of postoperative seizures. Further study in conservative, radiosurgery and paediatric populations, as well as study of oedema and seizure severity or subtype is warranted.
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Affiliation(s)
- Matthew J Tanti
- Faculty of Medicine and Health, University of Leeds, Leeds, LS2 9JT, UK.
- Department of Neurology, Leeds Teaching Hospitals NHS Foundation Trust, Leeds, LS1 3EX, UK.
| | - Sarah Nevitt
- Centre for Reviews and Dissemination, University of York, York, YO10 5DD, UK
| | - Molly Yeo
- Department of Neurology, Leeds Teaching Hospitals NHS Foundation Trust, Leeds, LS1 3EX, UK
| | - William Bolton
- Faculty of Medicine and Health, University of Leeds, Leeds, LS2 9JT, UK
- Department of Neurosurgery, Leeds Teaching Hospitals NHS Foundation Trust, Leeds, LS1 3EX, UK
| | - Paul Chumas
- Faculty of Medicine and Health, University of Leeds, Leeds, LS2 9JT, UK
- Department of Neurosurgery, Leeds Teaching Hospitals NHS Foundation Trust, Leeds, LS1 3EX, UK
| | - Ryan Mathew
- Faculty of Medicine and Health, University of Leeds, Leeds, LS2 9JT, UK
- Department of Neurosurgery, Leeds Teaching Hospitals NHS Foundation Trust, Leeds, LS1 3EX, UK
| | - Melissa J Maguire
- Faculty of Medicine and Health, University of Leeds, Leeds, LS2 9JT, UK
- Department of Neurology, Leeds Teaching Hospitals NHS Foundation Trust, Leeds, LS1 3EX, UK
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George Warren W, Osborn M, Yates A, O'Sullivan SE. The emerging role of fatty acid binding protein 7 (FABP7) in cancers. Drug Discov Today 2024; 29:103980. [PMID: 38614160 DOI: 10.1016/j.drudis.2024.103980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 03/27/2024] [Accepted: 04/05/2024] [Indexed: 04/15/2024]
Abstract
Fatty acid binding protein 7 (FABP7) is an intracellular protein involved in the uptake, transportation, metabolism, and storage of fatty acids (FAs). FABP7 is upregulated up to 20-fold in multiple cancers, usually correlated with poor prognosis. FABP7 silencing or pharmacological inhibition suggest FABP7 promotes cell growth, migration, invasion, colony and spheroid formation/increased size, lipid uptake, and lipid droplet formation. Xenograft studies show that suppression of FABP7 inhibits tumour formation and tumour growth, and improves host survival. The molecular mechanisms involve promotion of FA uptake, lipid droplets, signalling [focal adhesion kinase (FAK), proto-oncogene tyrosine-protein kinase Src (Src), mitogen-activated protein kinase kinase/p-extracellular signal-regulated kinase (MEK/ERK), and Wnt/β-catenin], hypoxia-inducible factor 1-alpha (Hif1α), vascular endothelial growth factor A/prolyl 4-hydroxylase subunit alpha-1 (VEGFA/P4HA1), snail family zinc finger 1 (Snail1), and twist-related protein 1 (Twist1). The oncogenic capacity of FABP7 makes it a promising pharmacological target for future cancer treatments.
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Affiliation(s)
| | - Myles Osborn
- Artelo Biosciences Limited, Alderley Park, Cheshire, UK
| | - Andrew Yates
- Artelo Biosciences Limited, Alderley Park, Cheshire, UK
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Abd Elhakeem AAE, Essa AA, Soliman RK, Hamdan ARK. Novel evaluation of the expression patterns CD44 and MMP9 proteins in intracranial meningiomas and their relationship to the overall survival. EGYPTIAN JOURNAL OF NEUROSURGERY 2022. [DOI: 10.1186/s41984-022-00173-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Abstract
Background
Meningiomas are common primary brain neoplasms. CD44 is a cell surface glycoprotein receptor that is involved in matrix-mediated cell signaling and cell–matrix adhesion. Matrix metalloproteinase-9 (MMP-9) plays important role in angiogenesis and tumor invasion. The expression of CD44 protein membranous and cytoplasmic (CD44M and CD44C) has been reported in several tumors (such as lobular carcinoma, renal cell carcinoma, sinonasal melanoma, and lymphoma) except CNS tumors.
Methods
This study addressed the expression of CD44M and CD44C and MMP9 proteins in intracranial meningiomas and their relationship to overall survival. The expression patterns of CD44M&C and MMP-9 proteins were examined in 32 cases of benign meningiomas, 12 cases of atypical meningiomas, and 6 cases of anaplastic meningiomas using immunohistochemical staining methods.
Results
There was more evidence of CD44M expression in atypical and anaplastic meningioma (p = < 0.001). Interestingly, Spearman correlation analyses revealed significant positive correlation between CD44M and MMP9 protein (r = 0.572, p = < 0.001) in spite of the negative correlation between MMP9 and CD44 score (r = − 0.035 p = 0.405). There was a significant association between Ki67 protein expression and the grade of meningiomas (p < 0.001) and gender (p = 0.026). There was a significant correlation between overall survival (OS) and age, gender, tumor grade, and Ki-67.
Conclusions
Extensive CD44M expression in high-grade meningioma may reflect a tendency toward more invasive power of meningioma cells into surrounding structures (dura, bone, and brain).CD44M/MMP-9 axis presented by this study is open for future investigations.
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von Spreckelsen N, Kesseler C, Brokinkel B, Goldbrunner R, Perry A, Mawrin C. Molecular neuropathology of brain-invasive meningiomas. Brain Pathol 2022; 32:e13048. [PMID: 35213084 PMCID: PMC8877755 DOI: 10.1111/bpa.13048] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/17/2021] [Accepted: 12/20/2021] [Indexed: 12/24/2022] Open
Abstract
Invasion of brain tissue by meningiomas has been identified as one key factor for meningioma recurrence. The identification of meningioma tumor tissue surrounded by brain tissue in neurosurgical samples has been touted as a criterion for atypical meningioma (CNS WHO grade 2), but is only rarely seen in the absence of other high-grade features, with brain-invasive otherwise benign (BIOB) meningiomas remaining controversial. While post-surgery irradiation therapy might be initiated in brain-invasive meningiomas to prevent recurrences, specific treatment approaches targeting key molecules involved in the invasive process are not established. Here we have compiled the current knowledge about mechanisms supporting brain tissue invasion by meningiomas and summarize preclinical models studying targeted therapies with potential inhibitory effects.
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Affiliation(s)
- Niklas von Spreckelsen
- Department of NeuropathologyUniversity Hospital MagdeburgMagdeburgGermany
- Department of General NeurosurgeryCenter for NeurosurgeryCologne University HospitalFaculty of Medicine and University HospitalUniversity of CologneGermany
| | - Christoph Kesseler
- Department of NeuropathologyUniversity Hospital MagdeburgMagdeburgGermany
| | | | - Roland Goldbrunner
- Department of General NeurosurgeryCenter for NeurosurgeryCologne University HospitalFaculty of Medicine and University HospitalUniversity of CologneGermany
| | - Arie Perry
- Department of PathologyUCSFSan FranciscoCaliforniaUSA
- Department of Neurological SurgeryUCSFSan FranciscoCaliforniaUSA
| | - Christian Mawrin
- Department of NeuropathologyUniversity Hospital MagdeburgMagdeburgGermany
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Bai X, Liu X, Wen J. Efficacy of Bevacizumab in High-Grade Meningiomas: A Retrospective Clinical Study. Neuropsychiatr Dis Treat 2022; 18:1619-1627. [PMID: 35968510 PMCID: PMC9364983 DOI: 10.2147/ndt.s368740] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 08/01/2022] [Indexed: 11/23/2022] Open
Abstract
OBJECTIVE We investigated the role of bevacizumab (BV) in high-grade meningiomas (HGMs) by retrospective analysis. METHODS We retrospectively analyzed the clinical data of 139 patients with HGMs. The chi-square test was used to compare progression-free survival (PFS) and overall survival (OS) between patients who received BV and those who did not. According to whether they received BV treatment, we divided the patients into the BV group and non-BV group, and the effect of BV on PFS and OS was compared. In addition, we compared Karnofsky performance status (KPS) and steroid doses between the BV and non-BV groups. RESULTS There were statistically differences in PFS and OS between the BV and non-BV groups at 12 and 36 months after surgery (P<0.05). However, there was no significant difference in PFS and OS between the two groups at 60 months postoperatively (P>0.05). Using survival curves drawn by the Kaplan Meier method, we found that the PFS and OS of the BV group were greater than those of the non-BV group, and the difference was statistically significant (P<0.05). CONCLUSION BV could improve PFS and OS at 12 and 36 months after surgery in patients with HGMs. In addition, BV was associated with lower preoperative steroid use.
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Affiliation(s)
- Xuexue Bai
- Neurosurgery, The First Affiliated Hospital, Jinan University, Guangzhou, People's Republic of China
| | - Xiaomin Liu
- Neurosurgery, Tianjin Huanhu Hospital, Tianjin, People's Republic of China
| | - Jun Wen
- Neurosurgery, The First Affiliated Hospital, Jinan University, Guangzhou, People's Republic of China
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Cyclooxygenase Inhibition Alters Proliferative, Migratory, and Invasive Properties of Human Glioblastoma Cells In Vitro. Int J Mol Sci 2021; 22:ijms22094297. [PMID: 33919029 PMCID: PMC8122446 DOI: 10.3390/ijms22094297] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 03/02/2021] [Accepted: 03/11/2021] [Indexed: 02/06/2023] Open
Abstract
Prostaglandin E2 (PGE2) is known to increase glioblastoma (GBM) cell proliferation and migration while cyclooxygenase (COX) inhibition decreases proliferation and migration. The present study investigated the effects of COX inhibitors and PGE2 receptor antagonists on GBM cell biology. Cells were grown with inhibitors and dose response, viable cell counting, flow cytometry, cell migration, gene expression, Western blotting, and gelatin zymography studies were performed. The stimulatory effects of PGE2 and the inhibitory effects of ibuprofen (IBP) were confirmed in GBM cells. The EP2 and EP4 receptors were identified as important mediators of the actions of PGE2 in GBM cells. The concomitant inhibition of EP2 and EP4 caused a significant decrease in cell migration which was not reverted by exogenous PGE2. In T98G cells exogenous PGE2 increased latent MMP2 gelatinolytic activity. The inhibition of COX1 or COX2 caused significant alterations in MMP2 expression and gelatinolytic activity in GBM cells. These findings provide further evidence for the importance of PGE2 signalling through the EP2 and the EP4 receptor in the control of GBM cell biology. They also support the hypothesis that a relationship exists between COX1 and MMP2 in GBM cells which merits further investigation as a novel therapeutic target for drug development.
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Dunn J, Lenis VP, Hilton DA, Warta R, Herold-Mende C, Hanemann CO, Futschik ME. Integration and Comparison of Transcriptomic and Proteomic Data for Meningioma. Cancers (Basel) 2020; 12:E3270. [PMID: 33167358 PMCID: PMC7694371 DOI: 10.3390/cancers12113270] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 11/03/2020] [Indexed: 12/17/2022] Open
Abstract
Meningioma are the most frequent primary intracranial tumour. Management of aggressive meningioma is complex, and development of effective biomarkers or pharmacological interventions is hampered by an incomplete knowledge of molecular landscape. Here, we present an integrated analysis of two complementary omics studies to investigate alterations in the "transcriptome-proteome" profile of high-grade (III) compared to low-grade (I) meningiomas. We identified 3598 common transcripts/proteins and revealed concordant up- and downregulation in grade III vs. grade I meningiomas. Concordantly upregulated genes included FABP7, a fatty acid binding protein and the monoamine oxidase MAOB, the latter of which we validated at the protein level and established an association with Food and Drug Administration (FDA)-approved drugs. Notably, we derived a plasma signature of 21 discordantly expressed genes showing positive changes in protein but negative in transcript levels of high-grade meningiomas, including the validated genes CST3, LAMP2, PACS1 and HTRA1, suggesting the acquisition of these proteins by tumour from plasma. Aggressive meningiomas were enriched in processes such as oxidative phosphorylation and RNA metabolism, whilst concordantly downregulated genes were related to reduced cellular adhesion. Overall, our study provides the first transcriptome-proteome characterisation of meningioma, identifying several novel and previously described transcripts/proteins with potential grade III biomarker and therapeutic significance.
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Affiliation(s)
- Jemma Dunn
- Faculty of Health: Medicine, Dentistry and Human Sciences, The Institute of Translational and Stratified Medicine, University of Plymouth, The John Bull Building, Plymouth Science Park, Research Way, Plymouth PL6 8BU, UK;
| | - Vasileios P. Lenis
- School of Health & Life Sciences, Centuria Building, Teesside University, Middlesbrough, Tees Valley TS1 3BX, UK;
| | - David A. Hilton
- Cellular and Anatomical Pathology, Plymouth Hospitals NHS Trust, Derriford Road, Plymouth PL6 8BU, UK;
| | - Rolf Warta
- Department of Neurosurgery, Division of Experimental Neurosurgery, Heidelberg University Hospital, 69120 Heidelberg, Germany; (R.W.); (C.H.-M.)
| | - Christel Herold-Mende
- Department of Neurosurgery, Division of Experimental Neurosurgery, Heidelberg University Hospital, 69120 Heidelberg, Germany; (R.W.); (C.H.-M.)
| | - C. Oliver Hanemann
- Faculty of Health: Medicine, Dentistry and Human Sciences, The Institute of Translational and Stratified Medicine, University of Plymouth, The John Bull Building, Plymouth Science Park, Research Way, Plymouth PL6 8BU, UK;
| | - Matthias E. Futschik
- Faculty of Medicine, School of Public Health, Imperial College London, Medical School, St Mary’s Hospital, Praed Street, London W2 1NY, UK
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Andreoli Miyake J, Nascimento Gomes R, Colquhoun A. Gamma-Linolenic acid alters migration, proliferation and apoptosis in human and rat glioblastoma cells. Prostaglandins Other Lipid Mediat 2020; 150:106452. [PMID: 32439412 DOI: 10.1016/j.prostaglandins.2020.106452] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 04/06/2020] [Accepted: 04/10/2020] [Indexed: 12/14/2022]
Abstract
Glioblastoma multiforme (GBM) is the most malignant astrocytoma, the main treatments consist of surgical resection followed by radiotherapy and chemotherapy. Patients, after diagnosed, have a survival rate of one year. GBM cells have an invasive, proliferative and migratory characteristic, also they do not respond properly for usual cancer treatment (radiotherapy, chemotherapy). Fatty acids have been studied as an adjuvant cancer treatment in breast, colorectal and GBM. The fatty acid can alter tumoural cell metabolism causing a modification of eicosanoids production. This study has observed some cellular aspects modified by fatty acid treatment in vitro, using GBM cells (human and rat). Modifications in cell behaviour were analyzed like cell proliferation, apoptosis, migration and invasion cell capacity after treatment with fatty acid (gamma-linolenic acid). The treatment suggested in this study showed an increased number of apoptotic cells and a decreased number of proliferative and migratory cells. These data recognize that gamma-linolenic acid could be used as an alternative treatment for glioblastoma.
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Affiliation(s)
- Juliano Andreoli Miyake
- Department of Morphological Sciences, Biological Sciences Centre, Federal University of Santa Catarina, Campus Trindade, Mailbox 476, 88040-900, Florianópolis, SC, Brazil.
| | - Renata Nascimento Gomes
- Department of Cell and Developmental Biology, Biomedical Sciences Institute, University of São Paulo, 1374, Prof. Lineu Prestes Av. 05508-900, São Paulo, SP, Brazil.
| | - Alison Colquhoun
- Department of Cell and Developmental Biology, Biomedical Sciences Institute, University of São Paulo, 1374, Prof. Lineu Prestes Av. 05508-900, São Paulo, SP, Brazil.
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Abstract
The tumor microenvironment consists of noncancerous cells, such as immune cells and fibroblasts, and the proteins produced by these cells as well as the extracellular matrix components in the environment around a tumor. Tumor influences the behavior of the cells present in the surrounding environment, while the cells in the tumor microenvironment modulate the evolution of the tumor. Little is known about the microenvironment of meningioma, the most common benign intracranial tumor. Here, we review the current knowledge of the tumor microenvironment of meningioma and discusses its importance in meningioma tumorigenesis as well as in the designation of novel therapeutic approaches.
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Dasanu CA, Alvarez-Argote J, Limonadi FM, Codreanu I. Bevacizumab in refractory higher-grade and atypical meningioma: the current state of affairs. Expert Opin Biol Ther 2018; 19:99-104. [PMID: 30556741 DOI: 10.1080/14712598.2019.1559292] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Historically, systemic agents had shown limited efficacy in meningioma, at the expense of significant pharmacologic and/or financial toxicity. As meningiomas are highly vascularized, they might derive benefit from antiangiogenic therapy. AREAS COVERED This review summarizes the literature regarding bevacizumab pharmacology, safety and efficacy in patients with refractory meningioma. We have searched PubMed/Medline database for pertinent articles published from inception to 1 September 2018. EXPERT COMMENTARY Results of two prospective phase II trials, supported by several retrospective cohorts, suggest a clinical benefit for the vascular endothelial growth factor inhibitor bevacizumab in meningiomas refractory to surgery and radiation therapy. This agent has a tolerable toxicity profile and seems more effective in higher-grade histologies and atypical meningioma, although responses in low-grade meningiomas have also been documented. Our conclusions are restricted due to a small size and lack of control in the prospective trials as well as the retrospective design of other studies. Further study of bevacizumab in refractory higher-grade meningiomas seems warranted.
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Affiliation(s)
- Constantin A Dasanu
- a Lucy Curci Cancer Center, Eisenhower Medical Center , Rancho Mirage , CA , USA.,b Department of Oncology , University of California San Diego Health System , La Jolla , CA , USA
| | | | - Farhad M Limonadi
- d Department of Neurosurgery , Eisenhower Medical Center , Rancho Mirage , CA , USA
| | - Ion Codreanu
- e Department of Radiology and Imaging , State University of Medicine and Pharmacy "Nicolae Testemitanu" , Chisinau , Moldova
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Dasanu CA, Samara Y, Codreanu I, Limonadi FM, Hamid O, Alvarez-Argote J. Systemic therapy for relapsed/refractory meningioma: Is there potential for antiangiogenic agents? J Oncol Pharm Pract 2018; 25:638-647. [PMID: 30253729 DOI: 10.1177/1078155218799850] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Effective therapies for relapsed/refractory meningioma after surgery and radiation therapy represent an unmet need. Most meningiomas are highly vascularized tumors and, therefore, potentially amenable to antiangiogenic therapy. Herein, we review comprehensively the scientific literature on systemic therapy options for relapsed, persistent or metastatic meningioma, not amenable to local therapy. Also, this review offers insights into the function of vascular endothelial growth factor/receptor pathway both in health and disease. Further, we address the current status of the preclinical and clinical studies targeting vascular endothelial growth factor/receptor signaling in meningioma. Most relevant publications were identified through searching the PubMed/Medline database for articles published from inception to 1 February 2018. Vascular endothelial growth factor pathway activation might represent the primary driver of angiogenesis in meningioma. Positive findings of two prospective phase II trials, supported by the results of several retrospective cohorts, suggest a clinical benefit for the vascular endothelial growth factor inhibitor bevacizumab in refractory meningioma. Bevacizumab causes both peritumoral brain edema reduction and true meningioma shrinkage. Patients with WHO grades II-III meningioma appear to benefit more than patients with grade I disease. Similarly, responses have been documented with certain oral targeted anti-vascular endothelial growth factor/receptor agents. Further exploration of the role of vascular endothelial growth factor/receptor inhibitors in refractory meningioma seems warranted.
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Affiliation(s)
- Constantin A Dasanu
- 1 Lucy Curci Cancer Center, Eisenhower Medical Center, Rancho Mirage, CA, USA.,2 University of California San Diego Health System, La Jolla, CA, USA
| | - Yazeed Samara
- 3 Department of Medicine, Eisenhower Medical Center, Rancho Mirage, CA, USA
| | - Ion Codreanu
- 4 Department of Radiology and Imaging, State University of Medicine and Pharmacy "Nicolae Testemitanu", Chisinau, Moldova
| | - Farhad M Limonadi
- 5 Department of Neurosurgery, Eisenhower Medical Center, Rancho Mirage, CA, USA
| | - Omid Hamid
- 6 Department of Translational Research and Immunotherapy, The Angeles Clinic and Research Institute, Los Angeles, CA, USA
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Dijkstra BM, Motekallemi A, den Dunnen WFA, Jeltema JR, van Dam GM, Kruyt FAE, Groen RJM. SSTR-2 as a potential tumour-specific marker for fluorescence-guided meningioma surgery. Acta Neurochir (Wien) 2018; 160:1539-1546. [PMID: 29858948 PMCID: PMC6060877 DOI: 10.1007/s00701-018-3575-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 05/23/2018] [Indexed: 12/25/2022]
Abstract
BACKGROUND Meningiomas are the most frequently occurring primary intracranial tumours in adults. Surgical removal can only be curative by complete resection; however surgical access can be challenging due to anatomical localization and local invasion of bone and soft tissues. Several intraoperative techniques have been tried to improve surgical resection, including intraoperative fluorescence guided imaging; however, no meningioma-specific (fluorescent) targeting has been developed yet. Here, we aimed to identify the most promising biomarkers for targeted intra-operative fluorescence guided meningioma surgery. METHODS One hundred forty-eight meningioma specimens representing all meningioma grades were analysed using immunohistochemistry (IHC) on tissue microarrays (TMAs) to determine expression patterns of meningioma biomarkers epithelial membrane antigen (EMA), platelet-derived growth factor β (PDGF-β), vascular endothelial growth factor α (VEGF-α), and somatostatin receptor type 2 (SSTR-2). Subsequently, the most promising biomarker was selected based on TArget Selection Criteria (TASC). Marker expression was examined by IHC in 3D cell culture models generated from freshly resected tumour material. RESULTS TMA-IHC showed strongest staining for SSTR-2. All cases were positive, with 51.4% strong/diffuse, 30.4% moderate/diffuse and only 18.2% focal/weak staining patterns. All tested biomarkers showed at least weak positivity in all meningiomas, regardless of WHO grade. TASC analysis showed that SSTR-2 was the most promising target for fluorescence guided imaging, with a total score of 21 (out of 22). SSTR-2 expression was determined on original patient tumours and 3D cultures of three established cultures. CONCLUSIONS SSTR-2 expression was highly sensitive and specific in all 148 meningiomas, regardless of WHO grade. According to TASC analysis, SSTR-2 is the most promising receptor for meningioma targeting. After establishing in vitro meningioma models, SSTR-2 cell membrane expression was confirmed in two of three meningioma cultures as well. This indicates that specific fluorescence in an experimental setting can be performed for the further development of targeted fluorescence guided meningioma surgery and near-infrared fluorescent tracers targeting SSTR-2.
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Affiliation(s)
- B M Dijkstra
- Department of Neurosurgery, University Medical Center Groningen, University of Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands
| | - A Motekallemi
- Department of Neurosurgery, University Medical Center Münster, Münster, Germany
| | - W F A den Dunnen
- Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - J R Jeltema
- Department of Neurosurgery, University Medical Center Groningen, University of Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands
| | - G M van Dam
- Department of Surgery, Nuclear Medicine and Molecular Imaging and Intensive Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - F A E Kruyt
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - R J M Groen
- Department of Neurosurgery, University Medical Center Groningen, University of Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands.
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Ozek E, Ozcan D, Celik SE, Iplikcioglu AC. Matrix metalloprotease-9 expresssion in meningioma: Correlation with growth fraction and role of gender. A pilot immunohistochemical study. Clin Neurol Neurosurg 2018; 172:169-173. [PMID: 30021149 DOI: 10.1016/j.clineuro.2018.07.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Revised: 06/28/2018] [Accepted: 07/01/2018] [Indexed: 10/28/2022]
Abstract
OBJECTIVE Matrix metalloproteases (MMPs), particularly MMP2 and MMP9 increase tumor invasion and edema in meningiomas. Although lesser recognized, MMPs may also enhance cell growth via liberating growth factors or via cleaving inactive growth factors into active isoforms. However, there exist very few studies, which investigated correlation of MMPs with growth fraction in meningiomas. Meningiomas are seen more frequently in women and their growth accelarate during pregnancy. However, no study examined whether MMP-expressions in meningioma differ with gender. PATIENTS AND METHODS In a pilot immunohistochemical study, we analyzed the correlation of MMP9 expression with Ki67 index and whether gender influences MMP9 expression. We retrospectively selected 24 meningioma cases including 10 cases with WHO Grade-1 tumors and 7 cases each with WHO Grade-2 and 3 tumors, respectively. RESULTS We separately determined the intensity and area of MMP9 staining and also calculated an expression index by multiplying these two parameters. Spearman correlation analyses revealed that MMP9 staining intensity, staining area and expression index significantly correlated with Ki67 proliferation index. MMP9 staining indices were significantly higher in women specimens. CONCLUSION If these findings will be confirmed in larger series, MMP-inhibitors and female hormone receptor-antagonists may be combined to augment chemotherapy efficacy and to attenuate invasion in high-grade meningiomas.
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Affiliation(s)
- Erdinc Ozek
- Neurosurgery Department, Bezmialem Vakif University, Fatih, Istanbul, Turkey.
| | - Deniz Ozcan
- Pathology Department, Okmeydani Training and Research Hospital, Sisli, Istanbul, Turkey
| | - Suat Erol Celik
- Neurosurgery Department, Okmeydani Training and Research Hospital, Sisli, Istanbul, Turkey
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The prostanoid pathway contains potential prognostic markers for glioblastoma. Prostaglandins Other Lipid Mediat 2018; 137:52-62. [PMID: 29966699 DOI: 10.1016/j.prostaglandins.2018.06.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 06/27/2018] [Accepted: 06/28/2018] [Indexed: 02/01/2023]
Abstract
Prostanoids derived from the activity of cyclooxygenases and their respective synthases contribute to both active inflammation and immune response in the tumor microenvironment. Their synthesis, deactivation and role in glioma biology have not yet been fully explored and require further study. Using quantitative real time PCR, gas chromatography/ electron impact mass spectrometry and liquid chromatography/ electrospray ionization tandem mass spectrometry, we have further characterized the prostanoid pathway in grade IV glioblastoma (GBM). We observed significant correlations between high mRNA expression levels and poor patient survival for microsomal PGE synthase 1 (mPGES1) and prostaglandin reductase 1 (PTGR1). Conversely, high mRNA expression levels for 15-hydroxyprostaglandin dehydrogenase (15-HPGD) were correlated with better patient survival. GBMs had a higher quantity of the prostanoid precursor, arachidonic acid, versus grade II/III tumors and in GBMs a significant positive correlation was found between arachidonic acid and PGE2 content. GBMs also had higher concentrations of TXB2, PGD2, PGE2 and PGF2α versus grade II/III tumors. A significant decrease in survival was detected for high versus low PGE2, PGE2 + PGE2 deactivation products (PGEMs) and PGF2α in GBM patients. Our data show the potential importance of prostanoid metabolism in the progression towards GBM and provide evidence that higher PGE2 and PGF2α concentrations in the tumor are correlated with poorer patient survival. Our findings highlight the potential importance of the enzymes 15-HPGD and PTGR1 as prognostic biomarkers which could be used to predict survival outcome of patients with GBM.
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Mostafa RR, Khairy RA. CD44 Expression in Meningioma and its Correlation with Proliferation Indices. J Clin Diagn Res 2017; 11:EC12-EC15. [PMID: 28969134 PMCID: PMC5620774 DOI: 10.7860/jcdr/2017/28438.10379] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 05/15/2017] [Indexed: 02/02/2023]
Abstract
INTRODUCTION CD44 is a cell adhesion molecule assumed to be related to tumour invasion and metastatic ability and is expressed in variety of tumours including meningiomas. AIM To evaluate the immunohistochemical expression of CD44 in variable grades and variants of eningioma and to correlate the results with Ki-67 proliferation index and available clinicopathologic variables. MATERIALS AND METHODS A total of 40 meningioma cases were studied for immunohistochemical expression of CD44 and Ki-67 and correlated with different clinicopathologic variables. A p-value less than 0.05 was considered statistically significant. RESULTS CD44 was markedly expressed in high grade (II and III) meningioma (81.8%) compared to grade I (18.2%) and that was statistically significant (p<0.001). Ki-67 proliferation activity was significantly correlated with meningioma grade (p<0.001) and brain invasiveness (p=0.033). Moreover, statistically positive correlation (p=0.01) was reported between CD44 and Ki-67 proliferative activity. No statistically significant correlation was detected between CD44 or Ki-67 expression and patients' age, sex, and tumour recurrence rate (p>0.05). CONCLUSION We concluded that CD44 is a marker of aggressiveness in meningioma as it was significantly highly expressed in grade II and III meningioma and was, positively correlated with higher Ki-67 proliferation indices. Therefore, researches should be carried out to identify the role of CD44 targeted therapy in atypical and anaplastic meningiomas as done in other tumours e.g., breast cancer.
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Affiliation(s)
| | - Rasha Ahmed Khairy
- Lecturer, Department of Pathology, Faculty of Medicine, Cairo University, Egypt
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Colquhoun A. Cell biology-metabolic crosstalk in glioma. Int J Biochem Cell Biol 2017; 89:171-181. [PMID: 28549626 DOI: 10.1016/j.biocel.2017.05.022] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 05/15/2017] [Accepted: 05/17/2017] [Indexed: 12/19/2022]
Abstract
The renewed interest in cancer metabolism in recent years has been fuelled by the identification of the involvement of key oncogenes and tumour suppressor genes in the control of metabolic pathways. Many of these alterations lead to dramatic changes in bioenergetics, biosynthesis and redox balance within tumour cells. The complex relationship between tumour cell metabolism and the tumour microenvironment has turned this field of biochemistry and cell biology into a challenging and exciting area for study. In the case of gliomas the involvement of altered metabolic pathways including glycolysis, oxidative phosphorylation and glutaminolysis are pointing the way to new possibilities for treatment. The tumour-promoting effects of inflammation are an emerging hallmark of cancer and the role of the eicosanoids in gliomas is an area of active research to elucidate the importance of individual eicosanoids in glioma cell proliferation, migration and immune escape. In this review, the different aspects of metabolic reprogramming which occur in gliomas are highlighted and their relationship to glioma cell biology and the wider tumour microenvironment is described.
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Affiliation(s)
- Alison Colquhoun
- Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
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Elmaci İ, Altinoz MA, Sav A, Yazici Z, Ozpinar A. Giving another chance to mifepristone in pharmacotherapy for aggressive meningiomas—A likely synergism with hydroxyurea? Curr Probl Cancer 2016; 40:229-243. [DOI: 10.1016/j.currproblcancer.2016.05.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Revised: 04/10/2016] [Accepted: 05/02/2016] [Indexed: 12/31/2022]
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Casas Parera I, Báez A, Banfi N, Blumenkrantz Y, Halfon MJ, Barros M, Campero Á, Larrarte G, De Robles P, Rostagno R, Gonzalez Roffo A, Campanucci V, Igirio Gamero JL, Figueroa Intriago WL, Díaz Granados S, Martínez Tamborini N, Kuchkaryan VB, Lozano C. Meningiomas en neurooncología. ACTA ACUST UNITED AC 2016. [DOI: 10.1016/j.neuarg.2016.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Barresi V, Tuccari G. Increased ratio of vascular endothelial growth factor to semaphorin3A is a negative prognostic factor in human meningiomas. Neuropathology 2016; 30:537-46. [PMID: 20337947 DOI: 10.1111/j.1440-1789.2010.01105.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Semaphorin3A (SEMA3A) is an anti-angiogenic factor which is expressed in human meningiomas in association with low microvessel density (MVD). It competes with vascular endothelial growth factor (VEGF) for receptor neuropilin-1 (NRP-1). The ratio between VEGF and SEMA3A has been recently demonstrated to regulate neo-angiogenesis, proliferation and progression of tumors. To clarify the involvement of these proteins in the above-mentioned phenomena, we analyzed the immunohistochemical expression of SEMA3A, VEGF and NRP-1 and their correlation with MVD in a series of 48 cases of meningioma with different histotype and histological grade. SEMA3A and VEGF expression was encountered in about half the cases, although at different levels. NRP-1 staining was evidenced in the vessels within all but two tumors and in the neoplastic cells of 18/48 meningiomas. A negative significant correlation emerged between SEMA3A amount and MVD; on the other hand, high VEGF levels appeared to be significantly associated with high MVD. A high VEGF/SEMA3A was significantly associated with high histological grade, proliferation index and MVD as well as with a higher recurrence rate of the meningiomas. Present data suggest that the balance between the expression of the pro-angiogenic factor VEGF and the anti-angiogenic SEMA3A may be involved in the regulation of neo-angiogenesis and proliferation in meningiomas, representing also a predictor of recurrences in these tumors. Further validation of our results may open the way for the use of drugs targeting not only VEGF, but also NRP-1 and SEMA3A to prevent recurrences of meningiomas.
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Affiliation(s)
- Valeria Barresi
- Department of Human Pathology, University of Messina, Messina, Italy
| | - Giovanni Tuccari
- Department of Human Pathology, University of Messina, Messina, Italy
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Hilton DA, Shivane A, Kirk L, Bassiri K, Enki DG, Hanemann CO. Activation of multiple growth factor signalling pathways is frequent in meningiomas. Neuropathology 2015; 36:250-61. [DOI: 10.1111/neup.12266] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 09/25/2015] [Accepted: 09/26/2015] [Indexed: 01/14/2023]
Affiliation(s)
- David A Hilton
- Department of Cellular and Anatomical Pathology; Derriford Hospital; Plymouth UK
| | - Aditya Shivane
- Department of Cellular and Anatomical Pathology; Derriford Hospital; Plymouth UK
| | - Leanne Kirk
- Department of Cellular and Anatomical Pathology; Derriford Hospital; Plymouth UK
| | - Kayleigh Bassiri
- Institute of Translational and Stratified Medicine; Plymouth University Peninsula Schools of Medicine & Dentistry; Plymouth UK
| | - Doyo G Enki
- Plymouth University Peninsula Schools of Medicine & Dentistry; Plymouth UK
| | - C Oliver Hanemann
- Institute of Translational and Stratified Medicine; Plymouth University Peninsula Schools of Medicine & Dentistry; Plymouth UK
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CD41 and CD45 expression marks the angioformative initiation of neovascularisation in human haemangioblastoma. Tumour Biol 2015; 37:3765-74. [DOI: 10.1007/s13277-015-4200-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 10/05/2015] [Indexed: 12/17/2022] Open
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Furuse M, Nonoguchi N, Kawabata S, Miyata T, Toho T, Kuroiwa T, Miyatake SI. Intratumoral and peritumoral post-irradiation changes, but not viable tumor tissue, may respond to bevacizumab in previously irradiated meningiomas. Radiat Oncol 2015. [PMID: 26223253 PMCID: PMC4520201 DOI: 10.1186/s13014-015-0446-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
The efficacy of bevacizumab has not been determined for treatment-refractory meningiomas. We treated meningiomas with low-dose bevacizumab and compared the radiological responses of non-irradiated meningiomas with previously irradiated meningiomas. In addition, we assessed intraparenchymal radiation necrosis following bevacizumab treatment. Six patients with meningiomas (three anaplastic, one atypical, and two grade I) who were previously treated with multiple sessions of radiotherapy and subsequently developed perilesional edema were treated with bevacizumab. Of six patients, two patients with anaplastic meningiomas developed three tumors following radiotherapy, which were defined as non-irradiated tumors. There were 12 pre-existing extra-axial tumors that were previously irradiated. Some of these tumors demonstrated adjacent intraparenchymal contrast enhancement. These tumors were defined as post-irradiated tumors. Four patients had intraparenchymal radiation necrosis. Low-dose bevacizumab was administered biweekly over 3–6 cycles to all patients. Four tumors decreased in contrast-enhanced volume, nine tumors were unchanged, and two tumors progressed. Of the three non-irradiated tumors, two tumors increased in volume (126 % and 198 %) and one tumor was stable (−5 %). The median reduction rates determined by contrast volume were −31 % and −71 % in post-irradiated tumors and radiation necrosis, respectively. Non-irradiated tumors had a significantly poorer response to bevacizumab than post-irradiated tumors and radiation necrosis (p = 0.0013 and p = 0.0005, respectively, Tukey-Kramer test). Low-dose bevacizumab did not demonstrate efficacy in the treatment of non-irradiated meningiomas. Responses to low-dose bevacizumab could be related to its effect on post-irradiation changes, rather than its effect on biologically active tumor tissue in post-irradiated meningiomas. Radiological responses to low-dose bevacizumab may distinguish biologically active tumors from post-irradiation changes in progressive meningiomas following radiotherapy.
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Affiliation(s)
- Motomasa Furuse
- Department of Neurosurgery, Osaka Medical College, 2-7, Daigakumachi, Takatsuki, Osaka, 569-8686, Japan.
| | - Naosuke Nonoguchi
- Department of Neurosurgery, Osaka Medical College, 2-7, Daigakumachi, Takatsuki, Osaka, 569-8686, Japan.
| | - Shinji Kawabata
- Department of Neurosurgery, Osaka Medical College, 2-7, Daigakumachi, Takatsuki, Osaka, 569-8686, Japan.
| | - Tomo Miyata
- Department of Neurosurgery, Osaka Medical College, 2-7, Daigakumachi, Takatsuki, Osaka, 569-8686, Japan.
| | - Taichiro Toho
- Department of Neurosurgery, Osaka Medical College, 2-7, Daigakumachi, Takatsuki, Osaka, 569-8686, Japan.
| | - Toshihiko Kuroiwa
- Department of Neurosurgery, Osaka Medical College, 2-7, Daigakumachi, Takatsuki, Osaka, 569-8686, Japan.
| | - Shin-Ichi Miyatake
- Department of Neurosurgery, Osaka Medical College, 2-7, Daigakumachi, Takatsuki, Osaka, 569-8686, Japan.
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Mandara MT, Reginato A, Foiani G, Baroni M, Poli F, Gasparinetti N, Bernardini M. Papillary meningioma in the dog: A clinicopathological case series study. Res Vet Sci 2015; 100:213-9. [DOI: 10.1016/j.rvsc.2015.03.029] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2015] [Revised: 03/13/2015] [Accepted: 03/22/2015] [Indexed: 01/19/2023]
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Hicks J, Platt S, Kent M, Haley A. Canine brain tumours: a model for the human disease? Vet Comp Oncol 2015; 15:252-272. [PMID: 25988678 DOI: 10.1111/vco.12152] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Revised: 04/04/2015] [Accepted: 04/06/2015] [Indexed: 01/10/2023]
Abstract
Canine brain tumours are becoming established as naturally occurring models of disease to advance diagnostic and therapeutic understanding successfully. The size and structure of the dog's brain, histopathology and molecular characteristics of canine brain tumours, as well as the presence of an intact immune system, all support the potential success of this model. The limited success of current therapeutic regimens such as surgery and radiation for dogs with intracranial tumours means that there can be tremendous mutual benefit from collaboration with our human counterparts resulting in the development of new treatments. The similarities and differences between the canine and human diseases are described in this article, emphasizing both the importance and limitations of canines in brain tumour research. Recent clinical veterinary therapeutic trials are also described to demonstrate the areas of research in which canines have already been utilized and to highlight the important potential benefits of translational research to companion dogs.
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Affiliation(s)
- J Hicks
- Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
| | - S Platt
- Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
| | - M Kent
- Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
| | - A Haley
- Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
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Kang HC, Kim IH, Park CI, Park SH. Immunohistochemical analysis of cyclooxygenase-2 and brain fatty acid binding protein expression in grades I-II meningiomas: correlation with tumor grade and clinical outcome after radiotherapy. Neuropathology 2014; 34:446-54. [PMID: 24779988 DOI: 10.1111/neup.12128] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Revised: 04/04/2014] [Accepted: 04/06/2014] [Indexed: 11/27/2022]
Abstract
This study was done to evaluate the association of cyclooxygenase 2 (COX-2) and brain fatty acid binding protein (BFABP) with tumor grade and outcome of grades I-II meningiomas treated with radiotherapy. From 1996 to 2008, 40 patients with intracranial grades I-II meningiomas were treated with radiotherapy. Immunohistochemical staining for COX-2 and BFABP were performed on formalin-fixed paraffin-embedded tissues. COX-2 expression was significantly associated with BFABP status and both COX-2 (P < 0.01) and BFABP (P = 0.01) expression were stronger in the grade II meningiomas than in grade I tumors. Among the clinicopathologic factors, age and COX-2 status were prognostic in progression-free survival. Patients with moderate or strong COX-2 expression had worse outcome than those with negative or weak COX-2 expression (P = 0.03) after controlling for potential confounders. Our results suggest that the molecular biomarker COX-2 has prognostic significance in intracranial grades I-II meningiomas following radiotherapy.
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Affiliation(s)
- Hyun-Cheol Kang
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea; Department of Radiation Oncology, Dongnam Institute of Radiological and Medical Sciences, Busan, Korea
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Jiang J, Lin C, Liu N, Zhang Z, Sun Y, Fang X, Qi J. The expression of fatty acid metabolism-associated proteins is correlated with the prognosis of meningiomas. APMIS 2013; 121:997-1003. [PMID: 23879478 DOI: 10.1111/apm.12135] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2012] [Accepted: 05/10/2013] [Indexed: 11/30/2022]
Abstract
The expression of fatty acid metabolism-associated proteins is correlated with the prognosis of meningiomas. Meningioma is a common tumor of the nervous system; however, reliable prognostic markers for meningioma are currently insufficient. High fatty acid synthase (FAS) expression occurs in many tumors, and is associated with tumor progression and grade. Few studies have previously investigated fatty acid metabolism in meningioma; thus, in this study, we investigated the expression of FAS and brain fatty acid-binding protein (BFABP) proteins in all grades of meningioma and determined the association to meningioma grade, invasiveness, recurrence, and progression. We determined expression levels of FAS and BFABP in all grade meningiomas by immunohistochemical analysis in 314 patients diagnosed with meningioma. The expression levels of FAS and BFABP increased significantly in correlation with meningioma grade (p < 0.01). Compared with benign meningioma, the expression levels of FAS and BFABP were significantly higher in brain invasive meningioma (p < 0.01). Compared with nonrecurrent meningioma (benign meningioma), the expression of FAS was also increased in recurrent meningioma (p < 0.01). The expression of fatty acid metabolism-associated proteins potentially correlates with meningioma grade, invasiveness, aggressiveness, and recurrent status and provides evidence for a novel therapeutic target for meningioma.
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Affiliation(s)
- Jie Jiang
- Department of Pathology, First Affiliated Hospital of Harbin Medical University, Harbin, China
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Proteins involved in regulating bone invasion in skull base meningiomas. Acta Neurochir (Wien) 2013; 155:421-7. [PMID: 23238945 PMCID: PMC3569595 DOI: 10.1007/s00701-012-1577-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2012] [Accepted: 10/18/2012] [Indexed: 12/31/2022]
Abstract
Background Bone invasive skull base meningiomas are a subset of meningiomas that present a unique clinical challenge due to brain and neural structure involvement and limitations in complete surgical resection, resulting in higher recurrence and need for repeat surgery. To date, the pathogenesis of meningioma bone invasion has not been investigated. We investigated immunoexpression of proteins implicated in bone invasion in other tumor types to establish their involvement in meningioma bone invasion. Methods Retrospective review of our database identified bone invasive meningiomas operated on at our institution over the past 20 years. Using high-throughput tissue microarray (TMA), we established the expression profile of osteopontin (OPN), matrix metalloproteinase-2 (MMP2), and integrin beta-1 (ITGB1). Differential expression in tumor cell and vasculature was evaluated and comparisons were made between meningioma anatomical locations. Results MMP2, OPN, and ITGB1 immunoreactivity was cytoplasmic in tumor and/or endothelial cells. Noninvasive transbasal meningiomas exhibited higher vascular endothelial cell MMP2 immunoexpression compared to invasive meningiomas. We found higher expression levels of OPN and ITGB1 in bone invasive transbasal compared to noninvasive meningiomas. Strong vascular ITGB1 expression extending from the endothelium through the media and into the adventitia was found in a subset of meningiomas. Conclusions We have demonstrated that key proteins are differentially expressed in bone invasive meningiomas and that the anatomical location of bone invasion is a key determinant of expression pattern of MMP1, OPN, and ITGB1. This data provides initial insights into the pathophysiology of bone invasion in meningiomas and identifies factors that can be pursued as potential therapeutic targets.
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Yamada S, Taoka T, Nakagawa I, Nishimura F, Motoyama Y, Park YS, Nakase H, Kichikawa K. A magnetic resonance imaging technique to evaluate tumor-brain adhesion in meningioma: brain-surface motion imaging. World Neurosurg 2013; 83:102-7. [PMID: 23403345 DOI: 10.1016/j.wneu.2013.02.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2012] [Revised: 12/12/2012] [Accepted: 02/02/2013] [Indexed: 11/27/2022]
Abstract
OBJECTIVE We examined the effectiveness of a newly developed magnetic resonance imaging (MRI) technique, brain surface motion imaging (BSMI), in the preoperative evaluation of tumor-brain adhesion in meningioma surgery. METHODS Cine phase-contrast MRI was used to measure cerebrospinal fluid (CSF) pulsations and heart rates at 2 different time points to create a subtraction image in meningioma patients who underwent BSMI. With no tumor-brain adhesion, a gap was observed in the tumor-brain movements, resulting in an outline of the tumor in BSMI. If adhesion was evident, no outline was observed. Cases were evaluated as exact if the presence or absence of edema in T2-weighted MRI, BSMI findings, and intraoperative findings all matched; as effected when only BSMI findings and intraoperative images matched; and as false when BSMI findings and intraoperative findings did not match. RESULTS BSMI judged 27 patients as adhesion (+) and 33 as adhesion (-), whereas surgical findings evaluated 22 as adhesion (+) and 38 as adhesion (-). The sensitivity and specificity were both high, at 95.5% and 84.2%, respectively. Forty-one of 60 patients were evaluated as exact, 12 as effected, and 7 as false. World Health Organization tumor grade assessment of effected subjects included 16.7% in grade 1 and 36.4% in grade 2. CONCLUSIONS BSMI was shown to be effective in evaluating adhesion between the meningioma and the brain, allowing safe and effective removal planning to be carried out preoperatively.
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Affiliation(s)
- Shuichi Yamada
- Department of Neurosurgery, Nara Medical University, Nara, Japan.
| | - Toshiaki Taoka
- Department of Radiology, Nara Medical University, Nara, Japan
| | - Ichiro Nakagawa
- Department of Neurosurgery, Nara Medical University, Nara, Japan
| | | | - Yasushi Motoyama
- Department of Neurosurgery, Nara Medical University, Nara, Japan
| | - Young S Park
- Department of Neurosurgery, Nara Medical University, Nara, Japan
| | - Hiroyuki Nakase
- Department of Neurosurgery, Nara Medical University, Nara, Japan
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Huang Q, Zhao SL, Tian XY, Li B, Li Z. Increased co-expression of macrophage migration inhibitory factor and matrix metalloproteinase 9 is associated with tumor recurrence of meningioma. Int J Med Sci 2013; 10:276-85. [PMID: 23372434 PMCID: PMC3558716 DOI: 10.7150/ijms.5185] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2012] [Accepted: 12/27/2012] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND AND OBJECTIVE We detected the expression of MIF and matrix metalloproteinase 9 (MMP9) in meningiomas to determine whether they are valuable recurrence predictor for meningioma. METHODS 67 cases of meningiomas, including 57 benign tumors (WHO grade I) and 10 non-benign tumors (WHO grade II and III), were collected, and expression of MIF and MMP9 in tissue microarray was evaluated immunohistochemically. The correlations between immunostainings and clinicopathological parameters, as well as the follow-up data of patients, were analyzed statistically. RESULTS Increased expressions of both MIF (58.2%, 39/67) and MMP9 (55.2%, 37/67) were significantly associated with microvessel density (MVD) of tumor, but only dual high-expression of MIF and MMP9 was in relation to tumor invasion (P=0.016) and tumor recurrence (P=0.001). Based on univariate analysis, histological grade, tumor invasion and co-expression of MIF and MMP9 were significant predictors for recurrence. However, only histological grade and co-expression of MIF and MMP9 in tumor were independent recurrence factors with a hazard ratio of 49.033 (P=0.002) and 37.766 (P=0.002) in multivariate analysis. CONCLUSIONS Together with histological grade, increased co-expression of MIF and MMP9 in tumor might be a valuable predictor for recurrence, especially for benign meningiomas.
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Affiliation(s)
- Quan Huang
- Department of Neurosurgery, The First Affiliated Hospital, Sun Yat-sen University. 58 Zhongshan Road II, Guangzhou 510080, China
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Kwon MJ, Sung CO, Kang SY, Do IG, Suh YL. Differential expression of extracellular matrix-related genes in rare variants of meningioma. Hum Pathol 2012; 44:260-8. [PMID: 22995327 DOI: 10.1016/j.humpath.2012.05.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Revised: 05/22/2012] [Accepted: 05/23/2012] [Indexed: 11/16/2022]
Abstract
Secretory, clear cell, and rhabdoid meningiomas are rare variants of meningiomas characterized by unique histologies and behaviors. Extracellular matrix proteins provide a morphologic structure and influence the biologic behavior of tumors. However, the effects of extracellular matrix proteins on morphologies and biologic behaviors of secretory meningioma, clear cell meningioma, and rhabdoid meningioma have not been established. We evaluated the expression of matrix metalloproteinase 2, matrix metalloproteinase 9, galectin-3, fibronectin, and collagen IV in a series of those rare variants of meningioma and verified their clinicopathologic significance. A total 51 cases included 12 secretory meningiomas, 9 clear cell meningiomas, and 30 rhabdoid meningiomas. Extracellular matrix proteins showed different expression patterns according to the histologic subtypes, and messenger RNA levels were well correlated with immunoexpressions. Secretory meningiomas showed high expressions of fibronectin and galectin-3. Clear cell meningiomas showed high expression of matrix metalloproteinase 2, matrix metalloproteinase 9, and collagen IV. Rhabdoid meningiomas showed high expressions of matrix metalloproteinase 9, galectin-3, and fibronectin. Clinically, high expression of matrix metalloproteinase 9 was associated with tumor recurrence (P < .001) and local invasion at the time of diagnosis (P = .018) among the extracellular matrix-related proteins, and was also associated with shorter recurrence-free survival (P = .025) in the patients with rhabdoid meningioma. In conclusion, the differential expressions of extracellular matrix-related genes according to the histologic subtypes appear to be involved in biologic behavior and clinical outcome, and high matrix metalloproteinase 9 expression is associated with recurrences in rhabdoid meningiomas.
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Affiliation(s)
- Mi Jung Kwon
- Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Gyeonggi-do 431-070, South Korea
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Domingues PH, Teodósio C, Ortiz J, Sousa P, Otero A, Maillo A, Bárcena P, García-Macias MC, Lopes MC, de Oliveira C, Orfao A, Tabernero MD. Immunophenotypic identification and characterization of tumor cells and infiltrating cell populations in meningiomas. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 181:1749-61. [PMID: 22982440 DOI: 10.1016/j.ajpath.2012.07.033] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2012] [Revised: 06/12/2012] [Accepted: 07/06/2012] [Indexed: 11/27/2022]
Abstract
Meningiomas are primary tumors of the central nervous system composed of both neoplastic and other infiltrating cells. We determined the cellular composition of 51 meningioma samples by multiparameter flow cytometric (MFC) immunophenotyping and investigated the potential relationship between mRNA and protein expression levels of neoplastic cells. For immunophenotypic, morphologic, and cytogenetic characterization of individual cell populations, a large panel of markers was used together with phagocytic/endocytic functional assays and MFC sorting. Overall, our results revealed coexistence of CD45(-) neoplastic cells and CD45(+) immune infiltrating cells in all meningiomas. Infiltrating cells included tissue macrophages, with an HLA-DR(+)CD14(+)CD45(+)CD68(+)CD16(-/+)CD33(-/+) phenotype and high phagocytic/endocytic activity, and a small proportion of cytotoxic lymphocytes (mostly T CD8(+) and natural killer cells). Tumor cells expressed multiple cell adhesion proteins, tetraspanins, HLA-I/HLA-DR molecules, complement regulatory proteins, cell surface ectoenzymes, and growth factor receptors. Noteworthy, the relationship between mRNA and protein levels was variable, depending on the proteins evaluated and the level of infiltration by immune cells. In summary, our results indicate that MFC immunophenotyping provides a reliable tool for the characterization of the patterns of protein expression of different cell populations coexisting in meningioma samples, with a more accurate measure of gene expression profiles of tumor cells at the functional/protein level than conventional mRNA microarray, independently of the degree of infiltration of the tumor by immune cells.
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Affiliation(s)
- Patrícia H Domingues
- Centre for Neurosciences and Cell Biology, Faculty of Pharmacy, University of Coimbra, Portugal
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Fatty acid synthase is a predictive marker for aggressiveness in meningiomas. J Neurooncol 2012; 109:399-404. [PMID: 22744755 DOI: 10.1007/s11060-012-0907-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Accepted: 05/29/2012] [Indexed: 10/28/2022]
Abstract
Meningiomas are the most frequent intracranial tumors. Although most are benign WHO grade I tumors, grade II and III tumors are aggressive and survival is poor. Treatment options for grade II and III meningiomas are limited, and molecular targets are few. The re-programming of metabolic pathways including glycolysis, lipogenesis, and nucleotide synthesis is a hallmark of the physiological changes in cancer cells. Because fatty acid synthase (FAS), the enzyme responsible for the de-novo synthesis of fatty acids, has emerged as a potential therapeutic target for several cancers, we investigated its involvement in meningiomas. We subjected 92 paraffin-embedded samples from 57 patients with grade I, 18 with grade II and III, and six with radiation-induced tumors to immunohistochemical study of FAS. Whereas its expression was increased in grade II and III meningiomas (62.9 %) compared with grade I tumors (29.8 %) (chi-squared test: p < 0.001), FAS was expressed in grade I tumors with a high MIB-1 index and infiltration into surrounded tissues. All radiation-induced meningiomas expressed FAS and its expression was positively correlated with the MIB-1 index (p < 0.005). Our findings suggest that increased FAS expression reflects the aggressiveness of meningiomas and that it may be a novel therapeutic target for treatment of unresectable or malignant tumors.
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33
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Motta L, Mandara MT, Skerritt GC. Canine and feline intracranial meningiomas: An updated review. Vet J 2012; 192:153-65. [DOI: 10.1016/j.tvjl.2011.10.008] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2011] [Revised: 10/10/2011] [Accepted: 10/11/2011] [Indexed: 12/24/2022]
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Barresi V, Alafaci C, Caffo M, Barresi G, Tuccari G. Clinicopathological characteristics, hormone receptor status and matrix metallo-proteinase-9 (MMP-9) immunohistochemical expression in spinal meningiomas. Pathol Res Pract 2012; 208:350-5. [PMID: 22494536 DOI: 10.1016/j.prp.2012.02.013] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2011] [Revised: 02/21/2012] [Accepted: 02/29/2012] [Indexed: 11/17/2022]
Abstract
Meningiomas involving the spinal meninges show a reduced tendency to recur compared to those of the intracranial compartment. Nonetheless, due to the few reports with a significant number of patients, their biological characteristics largely remain to be investigated. With the aim of clarifying the biology of these tumors, we examined in the present paper the clinicopathological features, the estrogen receptor (ER) and progesterone receptor (PR) status, as well as the Ki-67 labeling index (LI) and matrix metallo-proteinase-9 (MMP-9) expression of 58 spinal meningiomas. Ki-67 LI ranged between 1% and 5% (median: 1%); no expression of ER was found in all the cases, whereas PR immunoexpression was found in 86% of the tumors. High MMP-9 expression was encountered in 46% of meningiomas, and it was significantly correlated with the percentage of PR expression. The recurrence rate was 1.7%. The only recurred case showed high MMP-9 expression, absence of PR and low Ki-67 LI. Our findings confirm that spinal meningiomas are indolent tumors with low growth fraction and recurrence rate. In these neoplasms, high MMP-9 expression seems to be associated with the development of recurrences only in the absence of PR expression. Thus, the evaluation of both MMP-9 and PR expression might be of use in the identification of spinal meningiomas at higher risk of relapse.
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Affiliation(s)
- Valeria Barresi
- Department of Human Pathology, University of Messina, Messina, Italy.
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35
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Wilson TJ, Heth JA. Regression of a meningioma during paclitaxel and bevacizumab therapy for breast cancer. J Clin Neurosci 2012; 19:468-9. [DOI: 10.1016/j.jocn.2011.07.024] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2011] [Accepted: 07/17/2011] [Indexed: 12/13/2022]
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36
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Goutagny S, Raymond E, Sterkers O, Colombani J, Kalamarides M. Radiographic regression of cranial meningioma in a NF2 patient treated by bevacizumab. Ann Oncol 2011; 22:990-991. [DOI: 10.1093/annonc/mdr012] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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37
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Barresi V. Angiogenesis in meningiomas. Brain Tumor Pathol 2011; 28:99-106. [PMID: 21290262 DOI: 10.1007/s10014-010-0012-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2010] [Accepted: 11/14/2010] [Indexed: 12/25/2022]
Abstract
Neoangiogenesis has been correlated to biological aggressiveness and an adverse clinical course of several neoplasias. Its prognostic role in meningiomas appears to be controversial. Nonetheless, if adequately quantified with specific markers and appropriate scoring methods, angiogenesis seems to be significantly associated with a high growth fraction, development of recurrences and shorter overall survival of meningiomas. As a consequence, neoangiogenesis may represent a target for therapies aimed at reducing the growth of inoperable meningiomas or recurrence risk of totally resected tumors. Even more significantly, the identification of the factors that mediate angiogenesis in meningiomas could help us to determine appropriate novel anti-angiogenic therapies for these tumors. Herein the methods for quantification of angiogenesis as well as its regulating factors in meningiomas are reviewed.
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Affiliation(s)
- Valeria Barresi
- Department of Human Pathology, University of Messina, Messina, Italy.
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Ide T, Uchida K, Suzuki K, Kagawa Y, Nakayama H. Expression of cell adhesion molecules and doublecortin in canine anaplastic meningiomas. Vet Pathol 2010; 48:292-301. [PMID: 21123860 DOI: 10.1177/0300985810389312] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Tumor cell invasion into the surrounding nervous tissue is one of the histologic hallmarks of anaplastic meningiomas. To identify other possible markers for aggression in canine meningiomas, the relationship between histologic features and the expression of molecules involved in cell adhesion, cell proliferation, and invasion was examined. Immunohistochemistry for epithelial cadherin (E-cadherin), neural cadherin (N-cadherin), β-catenin, doublecortin (DCX), and Ki-67 was performed for 55 cases of canine meningioma. DCX was preferentially expressed in tumor cells invading the brain parenchyma (12 of 14 cases), suggesting its involvement in the invasion process. Regardless of the histologic type, E-cadherin and N-cadherin expression was observed in 31 of 55 and 44 of 55 cases, respectively. There was a significant positive correlation between DCX and N-cadherin expression and a significant negative correlation between E-cadherin and N-cadherin expression, suggesting that decreased E-cadherin and increased N-cadherin expression induce DCX expression. Typical membranous β-catenin expression was observed in 10 of 55 cases, whereas nuclear translocation was observed in 33 cases. Nuclear β-catenin expression was frequently found in anaplastic meningiomas (12 of 14 cases). The Ki-67 labeling indices were significantly higher in anaplastic meningiomas than in other types. These findings indicate that the expression of N-cadherin and DCX and the nuclear translocation of β-catenin are closely associated with the presence of invasion and anaplasia in canine meningiomas. Notably, granular cell meningiomas were negative for almost all the molecules examined, suggesting that they have a different tumor biology than other meningiomas.
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Affiliation(s)
- T Ide
- Department of Veterinary Pathology, Graduate School of Agricultural and Life Science, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
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Barresi V, Vitarelli E, Tuccari G, Barresi G. MMP-9 expression in meningiomas: a prognostic marker for recurrence risk? J Neurooncol 2010; 102:189-96. [PMID: 20652360 DOI: 10.1007/s11060-010-0312-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2010] [Accepted: 07/08/2010] [Indexed: 10/19/2022]
Abstract
Despite total macroscopic resection of meningiomas relapses do occur in these tumours, possibly because of microscopic clusters of neoplastic cells left in the dura mater or in the arachnoid membrane. The invasiveness of the neoplastic cells of human meningiomas has been related to expression of matrix-metalloproteinase-9 (MMP-9), a peptidase actively implicated in the degradation of the extracellular matrix; nonetheless, the prognostic value of MMP-9 in the risk of recurrence of meningiomas has not been sufficiently investigated. Herein, we analysed MMP-9 expression in a series of meningiomas of different histotype and histological grade and assessed its correlation with various clinico-pathological indicators and with the clinical outcome of these tumours. We also tested the eventual pro-angiogenic role of MMP-9 expression in meningiomas through its correlation with vascular endothelial growth factor (VEGF) and microvessel density (MVD) revealed in the same cases. MMP-9 expression was observed in 64% of cases; high expression of this protein was significantly associated with high histological grade and proliferation index, but not with high MVD, of the tumours. A trend towards correlation between MMP-9 and VEGF expression was found, although statistical significance was not reached. In addition, high MMP-9 expression was a negative independent prognostic factor associated with higher recurrence risk in totally resected meningiomas. In conclusion, we demonstrated for the first time the potential prognostic value of MMP-9 expression in meningiomas. Inhibition of MMP-9 may be a new therapeutic strategy to prevent recurrences of meningiomas, particularly the high-grade type.
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Affiliation(s)
- V Barresi
- Department of Human Pathology, University of Messina, Messina, Italy.
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40
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Pećina-Slaus N, Nikuseva Martić T, Deak AJ, Zeljko M, Hrasćan R, Tomas D, Musani V. Genetic and protein changes of E-cadherin in meningiomas. J Cancer Res Clin Oncol 2010; 136:695-702. [PMID: 19908067 DOI: 10.1007/s00432-009-0708-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2009] [Accepted: 10/19/2009] [Indexed: 10/20/2022]
Abstract
PURPOSE The molecular mechanisms and candidate genes involved in development of meningiomas still needs investigation and elucidation. METHODS In the present study 60 meningiomas were analyzed regarding changes of tumor suppressor gene E-cadherin (CDH1), a component of adherens junction and an indirect modulator of the wnt signaling. Gene instability was tested by polymerase chain reaction/loss of heterozygosity (LOH) method. Protein expression was analyzed by immunohistochemistry. RESULTS The results of our analysis showed altogether 32% of samples with LOH of the CDH1 gene. Interestingly, another type of genomic instability was detected; replication error-positive samples (RER+). Three out of 28 heterozygous samples were RER+ (11%). The instability is the result of impaired cellular mismatch repair. Fibrous and angiomatous cases showed higher percent of genetic changes, 67 and 75%, respectively. Immunostaining showed that overall 73% of samples had downregulation of E-cadherin expression. Intense downregulation of E-cadherin was noticed in tumors with grades II and III. Five out of nine samples with LOH were accompanied with the downregulation of E-cadherin protein expression (56%). One RER+ sample had lower expression of E-cadherin. We noticed that 36.4% of samples with lower E-cadherin expression had beta-catenin located in the nucleus. Also, 75% of samples with genomic instabilities had beta-catenin in the nucleus. Our findings demonstrated that there is significant association between the genetic changes of CDH1 and the nuclear localization of beta-catenin protein (chi(2) = 5.25, df = 1, P < 0.022). Beta-catenin was progressively upregulated from meningothelial to atypical, while 60% of anaplastic showed upregulation and nuclear localization of the protein. CONCLUSIONS Our results suggest that genetic instabilities of the E-cadherin gene have a role in meningioma development and progression. Detected microsatellite instability indicates that mismatch repair may also be targeted in meningioma.
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Affiliation(s)
- Nives Pećina-Slaus
- Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Croatia.
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41
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Castells X, García-Gómez JM, Navarro A, Acebes JJ, Godino O, Boluda S, Barceló A, Robles M, Ariño J, Arús C. Automated brain tumor biopsy prediction using single-labeling cDNA microarrays-based gene expression profiling. ACTA ACUST UNITED AC 2010; 18:206-18. [PMID: 19861896 DOI: 10.1097/pdm.0b013e31818f071b] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
AIMS Gene signatures obtained from microarray experiments may be of use to improve the prediction of brain tumor diagnosis. Nevertheless, automated and objective prediction with accuracy comparable to or better than the gold standard should be convincingly demonstrated for possible clinician uptake of the new methodology. Herewith, we demonstrate that primary brain tumor types can be discriminated using microarray data in an automated and objective way. METHODS Postsurgical biopsies from 35 patients [17 glioblastoma multiforme (Gbm) and 18 meningothelial meningioma (Mm)] were stored in liquid nitrogen, total RNA was extracted, and cDNA was labeled with Cy3 fluorochrome and hybridized onto a cDNA-based microarray containing 11,500 cDNA clones representing 9300 loci. Scanned data were preprocessed, normalized, and used for predictor development. The predictive functions were fitted to a subset of samples and their performance evaluated with an independent subset. Expression results were validated by means of real time-polymerase chain reaction. RESULTS Some gene expression-based predictors achieved 100% accuracy both in training resampling validation and independent testing. One of them, composed of GFAP, PTPRZ1, GPM6B and PRELP, produced a 100% prediction accuracy for both training and independent test datasets. Furthermore, the gene signatures obtained, increased cell detoxification, motility and intracellular transport in Gbm, and increased cell adhesion and cytochrome-family genes in Mm, agree well with the expected biologic and pathologic characteristics of the studied tumors. CONCLUSIONS The ability of gene signatures to automate prediction of brain tumors through a fully objective approach has been demonstrated. A comparison of gene expression profiles between Gbm and Mm may provide additional clues about patterns associated with each tumor type.
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Affiliation(s)
- Xavier Castells
- Grup d'aplicacions Biomèdiques de la RMN, Departament de Bioquímica i Biologia Molecular, Facultat de Biociències, Universitat Autònoma de Barcelona, Spain
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Angiogenesis and expression of estrogen and progesterone receptors as predictive factors for recurrence of meningioma. J Neurooncol 2009; 98:379-84. [DOI: 10.1007/s11060-009-0086-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2009] [Accepted: 11/30/2009] [Indexed: 12/18/2022]
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43
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Pećina-Slaus N, Nikuseva Martić T, Deak AJ, Zeljko M, Hrasćan R, Tomas D, Musani V. Genetic and protein changes of E-cadherin in meningiomas. J Cancer Res Clin Oncol 2009. [PMID: 19908067 DOI: 10.1007/s00432-009- 0708-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
PURPOSE The molecular mechanisms and candidate genes involved in development of meningiomas still needs investigation and elucidation. METHODS In the present study 60 meningiomas were analyzed regarding changes of tumor suppressor gene E-cadherin (CDH1), a component of adherens junction and an indirect modulator of the wnt signaling. Gene instability was tested by polymerase chain reaction/loss of heterozygosity (LOH) method. Protein expression was analyzed by immunohistochemistry. RESULTS The results of our analysis showed altogether 32% of samples with LOH of the CDH1 gene. Interestingly, another type of genomic instability was detected; replication error-positive samples (RER+). Three out of 28 heterozygous samples were RER+ (11%). The instability is the result of impaired cellular mismatch repair. Fibrous and angiomatous cases showed higher percent of genetic changes, 67 and 75%, respectively. Immunostaining showed that overall 73% of samples had downregulation of E-cadherin expression. Intense downregulation of E-cadherin was noticed in tumors with grades II and III. Five out of nine samples with LOH were accompanied with the downregulation of E-cadherin protein expression (56%). One RER+ sample had lower expression of E-cadherin. We noticed that 36.4% of samples with lower E-cadherin expression had beta-catenin located in the nucleus. Also, 75% of samples with genomic instabilities had beta-catenin in the nucleus. Our findings demonstrated that there is significant association between the genetic changes of CDH1 and the nuclear localization of beta-catenin protein (chi(2) = 5.25, df = 1, P < 0.022). Beta-catenin was progressively upregulated from meningothelial to atypical, while 60% of anaplastic showed upregulation and nuclear localization of the protein. CONCLUSIONS Our results suggest that genetic instabilities of the E-cadherin gene have a role in meningioma development and progression. Detected microsatellite instability indicates that mismatch repair may also be targeted in meningioma.
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Affiliation(s)
- Nives Pećina-Slaus
- Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Croatia.
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Rossmeisl JH, Robertson JL, Zimmerman KL, Higgins MA, Geiger DA. Cyclooxygenase-2 (COX-2) expression in canine intracranial meningiomas. Vet Comp Oncol 2009; 7:173-80. [DOI: 10.1111/j.1476-5829.2009.00188.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Mandara MT, Pavone S, Mandrioli L, Bettini G, Falzone C, Baroni M. Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 Expression in Canine and Feline Meningioma. Vet Pathol 2009; 46:836-45. [DOI: 10.1354/vp.08-vp-0185-m-fl] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Fifty-one meningiomas obtained from 28 dogs and 23 cats were selected for this study to investigate the immunohistochemical expression of matrix metalloproteinase (MMP)-2 and MMP-9 and to compare it to the reverse transcriptase subunit of human-telomerase, progesterone receptor expression, and the proliferative index of the tumors, expressed by Ki67 and proliferating cellular nuclear antigen. Paraffin-embedded tumor tissue was obtained from biopsy samples (28 cases) and at necropsy (23 cases). The most common histotype was malignant in dogs (12/28) and transitional in cats (12/23). Slides immunolabelled for MMPs showed a diffuse cytoplasmic pattern. Twenty-one cases (19 dogs and 2 cats) did not express MMP-2, while only 2 cases were completely negative for MMP-9. The highest values of MMP-2 and MMP-9 were observed in a psammomatous and meningothelial tumor, respectively. On statistical analysis, MMP-2 expression did not show a significant correlation with MMP-9. Moreover, both MMP expressions failed to show significant variance among histologic patterns of the tumor and correlation with the proliferative index. MMP immunolabeling showed an inconstant correlation with progesterone receptor expression. No significant correlation was found between MMP and reverse transcriptase subunit of human-telomerase expression. In feline meningiomas, the MMP-2 value was significantly higher than in canine tumors and the MMP-9 value tended to be low for meningiomas with a follow-up duration from the 23rdmonth to the 44thmonth. In cats, the longer the time from surgery, the lower the proliferative index seemed to be. In dogs, we failed to find a correlation between MMP expression and the follow-up duration.
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Affiliation(s)
- M. T. Mandara
- Department of Biopathological Science and Hygiene of Animal and Food Productions, Faculty of Veterinary Medicine, University of Perugia, Perugia, Italy
| | - S. Pavone
- Department of Biopathological Science and Hygiene of Animal and Food Productions, Faculty of Veterinary Medicine, University of Perugia, Perugia, Italy
| | - L. Mandrioli
- Department of Veterinary Public Health and Animal Pathology, Faculty of Veterinary Medicine, Bologna, Italy
| | - G. Bettini
- Department of Veterinary Public Health and Animal Pathology, Faculty of Veterinary Medicine, Bologna, Italy
| | - C. Falzone
- Clinica Veterinaria Valdinievole, Monsummano Terme, Pistoia, Italy
| | - M. Baroni
- Clinica Veterinaria Valdinievole, Monsummano Terme, Pistoia, Italy
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