BAFF, APRIL, TWEAK, BCMA, TACI and Fn14 Proteins Are Related to Human Glioma Tumor Grade: Immunohistochemistry and Public Microarray Data Meta-Analysis Vassiliki Pelekanou 1,2 *, George Notas 1 , Marilena Kampa 1 , Eleftheria Tsentelierou 2 , Efstathios N. Stathopoulos 2 , Andreas Tsapis 1,3 , Elias Castanas 1 * 1 Laboratories of Experimental Endocrinology, University of Crete, School of Medicine, Heraklion, Greece, 2 Laboratories of Pathology, University of Crete, School of Medicine, Heraklion, Greece, 3 INSERM U976, Ho ˆ pital Saint Louis, Paris, France; (4) Universite ´ Paris Diderot, Paris, France Abstract Gliomas are common and lethal tumors of the central nervous system (CNS). Genetic alterations, inflammatory and angiogenic processes have been identified throughout tumor progression; however, treatment still remains palliative for most cases. Biological research on parameters influencing cell survival, invasion and tumor heterogeneity identified several cytokines interfering in CNS inflammation, oxidative stress and malignant transformation, including TNF-superfamily (TNFSF) members. In this report we performed a meta-analysis of public gene-array data on the expression of a group of TNFSF ligands (BAFF, APRIL, TWEAK) and their receptors (BAFF-R, TACI, BCMA, Fn14) in gliomas. In addition, we investigated by immunohistochemistry (IHC) the tumor cells’ expression of these ligands and receptors in a series of 56 gliomas of different grade. We show that in IHC, BAFF and APRIL as well as their cognate receptors (BCMA, TACI) and Fn14 expression correlate with tumor grade. This result was not evidenced in micro-arrays meta-analysis. Finally, we detected for the first time Fn14, BAFF, BCMA and TACI in glioma-related vascular endothelium. Our data, combined with our previous report in glioma cell lines, suggest a role for these receptors and ligands in glioma biology and advance these molecules as potential markers for the classification of these tumors to the proliferative, angiogenic or stem-like molecular subtype. Citation: Pelekanou V, Notas G, Kampa M, Tsentelierou E, Stathopoulos EN, et al. (2013) BAFF, APRIL, TWEAK, BCMA, TACI and Fn14 Proteins Are Related to Human Glioma Tumor Grade: Immunohistochemistry and Public Microarray Data Meta-Analysis. PLoS ONE 8(12): e83250. doi:10.1371/journal.pone.0083250 Editor: Jeffrey K. Harrison, University of Florida, United States of America Received May 31, 2013; Accepted November 1, 2013; Published December 20, 2013 Copyright: ß 2013 Pelekanou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was partially supported by the European Union-FP7 Marie Curie Actions-Career Reintegration Grants PCIG-GA-2011-303723 (to VP) and the University of Crete Research Committee funds to EC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: pelekanou@med.uoc.gr (VP); castanas@med.uoc.gr (EC) Introduction Gliomas are brain neoplasms that arise from glial cells and represent the most common primary tumors of the central nervous system (,30%), with high lethality, approaching 80% in the first year of diagnosis. Despite their limited metastatic potential, gliomas are characterized by increased mortality, mainly attrib- uted to high rates of local invasion and angiogenesis, accompanied by immunosuppression. Moreover, late diagnosis results in advanced stage/grade tumors and contributes to impaired prognosis, as high-grade gliomas are usually accompanied by broad vascular infiltration, with extensive hypoxic areas and necro-inflammatory features [1]. Gliomas are classified histolog- ically as astrocytic, oligodendrocytic and oligoastrocytic tumors. In addition to this histological classification, a four-tiered grading system has been introduced in 2002 by the World Health Organization (WHO), proposing four grades of ascending malignancy: low grade (WHO grade I–II), anaplastic (grade III) and glioblastoma multiform (grade IV) [2]. The last WHO Classification of Tumors of the Central Nervous System was introduced in 2007, integrating morphological features, growth pattern and molecular profile of neoplastic cells [3]. It defined malignancy grade with an adequate prognostic relevance, providing important information for the clinical setting and the choice of therapeutic regimen [4]. Our knowledge on glioma behavior has been recently enriched by gene microarray analysis which has revealed specific subtypes, with distinct gene signatures, as well as predictive and prognostic relevance [5–8]. This transcriptome investigation revealed previously undescribed sub- classes, with neural stem cell, proliferative, angiogenetic or mesenchymal traits, strengthening the hypothesis of multiple cellular origins in the genesis of gliomas and eventual transition from one type to another, throughout disease progression. Inflammation can be a pluripotent promoter of tumor initiation, promotion and progression (see[9], for a review). During this process, an array of soluble mediators, produced by tumor cells or supplied by the tumor microenvironment/infiltrating cells, accounts for complex interactions influencing differentiation, activation, function and survival/apoptosis of multiple cell types. Among these mediators, members of the Tumor Necrosis Factor Superfamily (TNFSF, 19 ligands and 29 receptors) hold a prominent place, orchestrating a wide range of biological functions PLOS ONE | www.plosone.org 1 December 2013 | Volume 8 | Issue 12 | e83250