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Comparative Proteomic Profiles of Meningioma Subtypes

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Comparative Proteomic Profiles of Meningioma Subtypes Research Article Comparative Proteomic Profiles of Meningioma Subtypes Hiroaki Okamoto,1,3 Jie Li,1 Alexander O. Vortmeyer,1 Howard Jaffe,2 Youn-Soo Lee,4 Sven Gla¨sker,1 Tae-Sung Sohn,1 Weifen Zeng,5 Barbara Ikejiri,1 Martin A. Proescholdt,6 Christina Mayer,6 Robert J. Weil,1,5 Edward H. Oldfield,1 and Zhengping Zhuang1 1Surgical Neurology Branch and 2Protein/Peptide Sequencing Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland; 3Department of Neurosurgery, Faculty of Medicine, Saga University, Saga, Japan; 4Department of Clinical Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea; 5Brain Tumor Institute, Cleveland Clinic Foundation, Cleveland, Ohio; and 6Department of Neurosurgery, Regensburg University Medical Center, Regensburg, Germany Abstract WHO grade 1 tumors (4.7-7.2% of meningiomas; refs. 1–3). Meningiomas are classified into three groups (benign, However, sampling issues and imperfect histopathologic features atypical, and anaplastic) based on morphologic character- of these tumors can make exact grading difficult. Some markers, istics. Atypical meningiomas, which are WHO grade 2 tumors, such as vimentin, are frequently present in meningiomas (1, 4) but and anaplastic meningiomas, which are WHO grade 3tumors, do not correlate specifically with grade. exhibit an increased risk of recurrence and premature death The origins of atypical and anaplastic meningiomas are still compared with benign WHO grade 1 tumors. Although unclear. It is well known that some high-grade tumors arise atypical and anaplastic meningiomas account for <10% of from low-grade tumors. For instance, Vogelstein et al. showed all of meningiomas, it can be difficult to distinguish them accumulating molecular alterations that paralleled clinical pro- from benign meningiomas by morphologic criteria alone. We gression in colorectal tumors (5). It has also been reported that glioblastomas consist of two different types of tumors with used selective tissue microdissection to examine 24 human de novo meningiomas and did two-dimensional gel electrophoresis to different pathogenesis ( and secondary tumors) in which determine protein expression patterns. Proteins expressed low-grade gliomas develop through a multistep process (6, 7). differentially by meningiomas of each WHO grade were Generally, meningiomas are also thought to have the potential to identified and sequenced. Proteomic analysis revealed protein progress from low grade to high grade, as colorectal carcinomas expression patterns unique to WHO grade 1, 2, and 3 or secondary glioblastomas (1, 8, 9). Weber et al. documented a meningiomas and identified 24 proteins that distinguish each genetic model of progression in meningiomas by accumulated subtype. Fifteen proteins showed significant changes in alterations (8). However, it is still unclear whether high-grade meningiomas progress from benign meningiomas, or arise expression level between benign and atypical meningiomas, de novo whereas nine distinguished atypical from anaplastic meningi- primarily as more aggressive tumors (9). Thus, specific omas. Differential protein expression was confirmed by markers that would reliably coincide with meningiomas of a Western blotting and immunohistochemistry. We established particular grade and clinical behavior, and with pathogenetic differential proteomic profiles that characterize and distin- mechanisms, would be useful. Proteomics is a broad protein profile screening approach that guish meningiomas of increasing grades. The proteins and proteomic profiles enhance understanding of the pathogene- permits a direct analysis of proteins differentially or uniquely sis of meningiomas and have implications for diagnosis, expressed by a cell or a tissue type. Proteomic research has been developed recently in the post-genome era. Using a combination of prognosis, and treatment. (Cancer Res 2006; 66(20): 10199-204) two-dimensional gel electrophoresis, mass spectrometry, and bioinformatics, one can now readily scan a particular cell type Introduction and establish protein expression patterns. Recent studies have Meningiomas are common central nervous system (CNS) tumors shown that specific proteomic patterns and proteins can distin- that arise from the coverings of the brain and the spinal cord, with guish subtypes or grades of human brain tumors (10, 11). We set out an incidence of between 13% and 26% of all primary intracranial to use selective tissue microdissection to obtain a pure population tumors (1). Most meningiomas (>90%) are slowly growing benign of meningioma tumor cells to determine whether we could identify tumors and correspond histologically to grade 1 according to the proteins and protein patterns that distinguish WHO grade 1, 2, WHO classification of tumors of the CNS (1). Anaplastic and 3 meningiomas. meningiomas are WHO grade 3 neoplasms and are associated with a high risk for recurrence and a less favorable prognosis; Materials and Methods fortunately, they are rare (1-2.8% of all meningiomas; refs. 1–3). An intermediate group, the atypical meningiomas (WHO grade 2), also Patients and clinical data. Twenty-four meningiomas were collected at exhibit an increased risk of recurrence and death compared with surgery, immediately snap-frozen in liquid nitrogen, and stored at À80jC until analyzed. Tumors were classified according to the 2000 WHO Histologic Classification (1): 10 benign meningiomas (grade 1), 9 atypical meningiomas (grade 2), and 5 anaplastic meningiomas (grade 3). Tissues Note: H. Okamoto and J. Li contributed equally to this study. and clinical information were obtained as part of an Institutional Review Requests for reprints: Zhengping Zhuang, Surgical Neurology Branch, National Board–approved study at the Cleveland Clinic Foundation, Cleveland, OH Institute of Neurological Disorders and Stroke, NIH, Building 10, Room 5D 37, 10 and the University of Regensburg, Regensburg, Germany. Additional Center Drive, Bethesda, MD 20892-1414. Phone: 301-534-8445; Fax: 301-402-0380; independent 30 paraffin slides were obtained from the Cleveland Clinic E-mail: [email protected]. n I2006 American Association for Cancer Research. Foundation for immunohistochemical studies, including benign ( = 10), doi:10.1158/0008-5472.CAN-06-0955 atypical (n = 10), and anaplastic (n = 10) tumors. www.aacrjournals.org 10199 Cancer Res 2006; 66: (20). October 15, 2006 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2006 American Association for Cancer Research. Cancer Research Tissue and sample preparation. Selective tissue microdissection was Results done, as previously described, to avoid normal brain or areas of necrosis, hemorrhage, and inflammation (10). Microdissected tissues were dissolved Two-dimensional gel electrophoresis. Two-dimensional gel in extraction buffer II containing 8 mol/L urea, 4% (w/v) Bio-Lyte 4/7, and electrophoresis of the 10 benign, nine atypical, and five anaplastic 2 mmol/L tributyl phosphine (Bio-Rad, Hercules, CA); vigorously vortexed; meningiomas was done over a pH range of 4 to 7 (Fig. 1). We and centrifuged in a microcentrifuge. The supernatant was combined with compared proteomic patterns between the benign and atypical a rehydration buffer containing rehydration buffer [8 mol/L urea, 2% meningiomas and between the atypical and anaplastic meningi- CHAPS, 50 mmol/L DTT, and 0.2% (w/v) Bio-Lyte 4/7 ampholytes; Bio- omas. Consistently expressed protein patterns and individual Rad], IPG buffer (Amersham Biosciences, Piscataway, NJ), and bromophe- proteins on two-dimensional gels within each group were selected nol blue and subsequently rehydrated overnight with Immobiline Drystrips with statistically significant values by t-test (P < 0.05) using two- (pH 4/7, 11 cm; Amersham Biosciences) on a Reswelling Tray (Amersham dimensional gel analysis software (Proteomweaver, Definiens, Biosciences). Munich). Twenty-four proteins that were differentially expressed Two-dimensional gel electrophoresis. Isometric focusing for the first dimensional electrophoresis was done with a Multiphore II Electrophoresis in all members of each tumor grade were isolated and identified System (Amersham Biosciences). The strips were subjected to high voltages by LC-MS/MS. at 300 to 3,500 V. Immobilized pH gradient (IPG) strips were equilibrated Comparison between benign and atypical meningiomas. with equilibration buffer I containing 6 mol/L urea, 2% SDS, 375 mmol/L First, we compared proteomic patterns and identified proteins Tris-HCL (pH 8.8), 20% glycerol, and 2% (w/v) DTT and buffer II containing that differentiated the 10 benign and 9 atypical meningiomas 6 mol/L urea, 2% SDS, 375 mmol/L Tris-HCL (pH 8.8), 20% glycerol, and (Table 1A and B). Fifteen distinguishing proteins that were highly 2.5% (w/v) iodoacetamide (Bio-Rad). Precast gels (ExcelGel SDS gradient gel; expressed in either the benign or atypical group were identified. Â Â pH 4-7 12-14%, 245 180 0.5 mm; Amersham Biosciences) were used for Six of the 15 distinguishing proteins were differentially overex- the second dimension of protein separation by a Multiphor II Flated System pressed in benign meningiomas (Table 1A). Meanwhile, 9 of the 15 (Amersham Biosciences) under a constant voltage of 700 V. A silver staining identified proteins were differentially up-regulated in atypical menin- kit (Amersham Biosciences) was used to detect protein spots according to the manufacturer’s instructions. All samples were run in duplicate. giomas (Table 1B). These
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