Gene expression profiling of meningiomas: current status after a decade of microarray-based transcriptomic studies

Purpose This article provides a review of the transcriptomic expression profiling studies that have been performed on meningiomas so far. We discuss some future prospects and challenges ahead in the field of gene expression profiling. Methods We performed a systematic search in the PubMed and EMBASE databases in May 2010 using the following search terms alone or in combination: “meningioma”, “microarray analysis”, “oligonucleotide array sequence analysis”, or “gene expression profiling”. Only original research articles in English that had used RNA hybridized to high-resolution microarray chips to generate gene expression profiles were included. Results We identified 13 articles matching the inclusion criteria. All studies had been performed during the last decade. Conclusions The main results of the studies can be grouped in three categories: (1) several groups have identified meningioma-specific genes and genes associated with the three WHO grades, and the main histological subtypes of grade I meningiomas; (2) one publication has shown that the general transcription profile of samples of all WHO grades differs in vivo and in vitro; (3) one report provides evidence that microarray technology can be used in an automated fashion to classify tumors. Due to lack of consensus on how microarray data are presented, possible general trends found across the studies are difficult to extract. This could obstruct the discovery of important genes and pathways universally involved in meningioma biology

Global Proteome and Phospho-proteome Analysis of Merlin-deficient Meningioma and Schwannoma Identifies PDLIM2 as a Novel Therapeutic Target

Loss or mutation of the tumour suppressor Merlin predisposes individuals to develop multiple nervous system tumours, including schwannomas and meningiomas, sporadically or as part of the autosomal dominant inherited condition Neurofibromatosis 2 (NF2). These tumours display largely low grade features but their presence can lead to significant morbidity. Surgery and radiotherapy remain the only treatment options despite years of research, therefore an effective therapeutic is required. Unbiased omics studies have become pivotal in the identification of differentially expressed genes and proteins that may act as drug targets or biomarkers. Here we analysed the proteome and phospho-proteome of these genetically defined tumours using primary human tumour cells to identify upregulated/activated proteins and/or pathways. We identified over 2000 proteins in comparative experiments between Merlin-deficient schwannoma and meningioma compared to human Schwann and meningeal cells respectively. Using functional enrichment analysis we highlighted several dysregulated pathways and Gene Ontology terms. We identified several proteins and phospho-proteins that are more highly expressed in tumours compared to controls. Among proteins jointly dysregulated in both tumours we focused in particular on PDZ and LIM domain protein 2 (PDLIM2) and validated its overexpression in several tumour samples, while not detecting it in normal cells. We showed that shRNA mediated knockdown of PDLIM2 in both primary meningioma and schwannoma leads to significant reductions in cellular proliferation. To our knowledge, this is the first comprehensive assessment of the NF2-related meningioma and schwannoma proteome and phospho-proteome. Taken together, our data highlight several commonly deregulated factors, and indicate that PDLIM2 may represent a novel, common target for meningioma and schwannoma

Co-localization and regulation of basic fibroblast growth factor and arginine vasopressin in neuroendocrine cells of the rat and human brain

<p>Abstract</p> <p>Background</p> <p>Adult rat hypothalamo-pituitary axis and choroid plexus are rich in basic fibroblast growth factor (FGF2) which likely has a role in fluid homeostasis. Towards this end, we characterized the distribution and modulation of FGF2 in the human and rat central nervous system. To ascertain a functional link between arginine vasopressin (AVP) and FGF2, a rat model of chronic dehydration was used to test the hypothesis that FGF2 expression, like that of AVP, is altered by perturbed fluid balance.</p> <p>Methods</p> <p>Immunohistochemistry and confocal microscopy were used to examine the distribution of FGF2 and AVP neuropeptides in the normal human brain. In order to assess effects of chronic dehydration, Sprague-Dawley rats were water deprived for 3 days. AVP neuropeptide expression and changes in FGF2 distribution in the brain, neural lobe of the pituitary and kidney were assessed by immunohistochemistry, and western blotting (FGF2 isoforms).</p> <p>Results</p> <p>In human hypothalamus, FGF2 and AVP were co-localized in the cytoplasm of supraoptic and paraventricular magnocellular neurons and axonal processes. Immunoreactive FGF2 was associated with small granular structures distributed throughout neuronal cytoplasm. Neurohypophysial FGF2 immunostaining was found in axonal processes, pituicytes and Herring bodies. Following chronic dehydration in rats, there was substantially-enhanced FGF2 staining in basement membranes underlying blood vessels, pituicytes and other glia. This accompanied remodeling of extracellular matrix. Western blot data revealed that dehydration increased expression of the hypothalamic FGF2 isoforms of ca. 18, 23 and 24 kDa. In lateral ventricle choroid plexus of dehydrated rats, FGF2 expression was augmented in the epithelium (Ab773 as immunomarker) but reduced interstitially (Ab106 immunostaining).</p> <p>Conclusions</p> <p>Dehydration altered FGF2 expression patterns in AVP-containing magnocellular neurons and neurohypophysis, as well as in choroid plexus epithelium. This supports the involvement of centrally-synthesized FGF2, putatively coupled to that of AVP, in homeostatic mechanisms that regulate fluid balance.</p

Expression des récepteurs à la somatostatine dans les médulloblastomes et les épendymomes

Nous recherchons l'expression des cinq sous-types de récepteurs à la somatostatine dans une série de médulloblastomes et d'épendymomes. Vingt deux médulloblastomes et vingt huit épendymomes sont étudiés. Les données cliniques et l'évolution sont précisées. Les tumeurs sont caractérisées par une étude en microscopie optique et immunohistochimique. L'expression de l'ARNm des cinq sous-types de récepteurs à la somatostatine est recherchée par RT-PCR et celle de la protéine de sst1, sst2A, sst2B par immunohistochimie sur certains médulloblastomes et épendymomes. L'effet anti-prolifératif de la somatostatine est évalué in vitro par l'incorporation de thymidine tritiée sur une lignée de médulloblastome et sur des cellules tumorales de médulloblastome. Des corrélations entre l'expression des différents transcrits et des données histologiques et cliniques sont recherchées : grade, différenciation cellulaire, âge, métastase, récidive, survie. La fiabilité de la scintigraphie à l'octréotide marqué pour le diagnostic et le suivi est étudiée sur huit médulloblastomes et dix épendymomes. Les résultats sont comparés avec ceux obtenus par l'imagerie par résonance magnétique. Tous les récepteurs sont présents à des niveaux variables dans les différentes tumeurs. Dans les deux types histologiques l'ARNm du sst2 est le plus exprimé. La quantité de transcrits codant ce récepteur est deux fois plus importante dans les médulloblastomes que dans les épendymomes. Dans ce dernier type de tumeur, l'ARNm de sst1 est également fortement exprimé. En immunohistochimie, le marquage de sst1 et surtout de sst2A est plus intense dans les médulloblastomes que dans les épendymomes. La localisation observée pour le récepteur sst1 est identique pour les deux types de tumeur et est essentiellement cytoplasmique. En revanche, la localisation de sst2 est essentiellement membranaire pour les médulloblastomes et exclusivement cytoplasmique pour les épendymomes. Aucune corrélation n'est constatée entre l'évolution clinique, l'histologie et l'expression des transcrits des différents récepteurs. In vitro, la somatostatine exerce un effet anti-prolifératif significatif sur la lignée et les cellules tumorales de médulloblastome. La scintigraphie à l'octréotide marqué s'est révélée fiable sur 17 des 23 examens réalisés. Ces résultats ouvrent des perspectives pour le suivi des patients opérés de médulloblastomes et d'épendymomes.LYON1-BU Santé (693882101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF