title: WHO grade related expression of TRAIL-receptors and apoptosis regulators in meningioma.
abstract: OBJECTIVE
  The expression of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors and key regulators of the extrinsic apoptosis pathway correlate with clinical features and the WHO grade of malignancy in some tumor entities. Expression of pro-apoptotic TRAIL receptors and executioners of apoptosis are a prerequisite for TRAIL-based therapies as a promising future targeted therapy.
  
  
  METHODS
  Human meningioma tissues (n=24 WHO grade I, n=7 WHO grade II, n=6 WHO grade III) were immunohistochemically analyzed for the expression of TRAIL-R1, TRAIL-R2, TRAIL-R3, TRAIL-R4, caspase-8, cFLIP, Bcl-2, Bcl-XL, Mcl-1, Bax, and Bak. Staining intensities were quantified by an automated software-based algorithm.
  
  
  RESULTS
  While TRAIL-R1 and TRAIL-R3 were nearly absent in meningiomas, TRAIL-R2 and TRAIL-R4 were abundantly expressed. However, only TRAIL-R4 expression correlated with the WHO grade of malignancy. Bcl-2 showed a non-significant upregulation in WHO grade III meningiomas. Bcl-XL and Mcl-1 expression was significantly higher in WHO grade II compared to grade I. Bcl-XL and TRAIL-R4 expression correlated with the mitotic activity (Ki67) of the tumor. Furthermore, TRAIL-R2 expression correlated with TRAIL-R4. Bak expression correlated with both, Bcl-XL and Mcl-1 expression. The expression patterns did neither correlate with the progression-free nor with the overall survival of the meningioma patients.
  
  
  CONCLUSIONS
  Apoptosis-inducing TRAIL-R2 and all key executioners of the extrinsic apoptosis pathway are abundantly expressed in meningioma. For some regulators of apoptosis with opposite functions, the expression of the pro-apoptotic protein significantly correlated with the expression level of the respective anti-apoptotic binding partner, possibly resulting in a steady-state of apoptosis. TRAIL-R2 might serve as a novel therapeutic target in meningioma.
authors.affiliation: Dept. of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany. Electronic address: ronald.koschny@med.uni-heidelberg.de.
authors.forename: Ronald
authors.initials: R
authors.lastname: Koschny
authors.affiliation: Dept. of Neurosurgery, University of Leipzig, Leipzig, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Krupp
authors.affiliation: Dept. of Neurosurgery, University of Leipzig, Leipzig, Germany; Translational Centre for Regenerative Medicine (TRM) Leipzig and Faculty of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Li-Xin
authors.initials: LX
authors.lastname: Xu
authors.affiliation: Dept. of Neuropathology, University of Leipzig, Leipzig, Germany.
authors.forename: Wolf C
authors.initials: WC
authors.lastname: Mueller
authors.affiliation: Dept. of Neuropathology, University of Leipzig, Leipzig, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Bauer
authors.affiliation: Dept. of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Sinn
authors.affiliation: Dept. of Cardiology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Keller
authors.affiliation: Ames Laboratory - US DOE, and Department of Physics and Astronomy, Iowa State University, Ames, Iowa, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Koschny
authors.affiliation: Centre for Cell Death, Cancer and Inflammation (CCCI), UCL Cancer Institute, London, United Kingdom.
authors.forename: Henning
authors.initials: H
authors.lastname: Walczak
authors.affiliation: Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bruckner
authors.affiliation: Dept. of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Tom M
authors.initials: TM
authors.lastname: Ganten
authors.affiliation: Translational Centre for Regenerative Medicine (TRM) Leipzig and Faculty of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Holland
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000502:physiology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008577:Meningeal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008579:Meningioma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D060787:Neoplasm Grading; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand
keywords: Apoptosis regulators; Immunohistochemistry; Meningioma; TRAIL-receptor