title: Perturbation of the tumor necrosis factor--related apoptosis-inducing ligand cascade in ovarian cancer: overexpression of FLIPL and deregulation of the functional receptors DR4 and DR5.
abstract: OBJECTIVE
  Epithelial ovarian cancer is the most common cause of mortality from gynecologic malignancies. Due to advanced stage at diagnosis, most patients need systemic treatment in addition to surgery. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family with a promising toxicity profile and synergistic activity with chemotherapeutic agents.
  
  
  METHODS
  We used an arrayed panel of epithelial ovarian cancer tissue to assess the protein expression of TRAIL and the clinically most relevant members of its pathway death receptors 4 and 5 (DR4 and DR5) and the long form of FLICE inhibitory protein (FLIPL).
  
  
  RESULTS
  We could show that a majority (66.2%) of the tumor tissues displayed either reduced DR4/DR5 expression (20.6%), increased FLIPL expression (39.7%), or both (5.9%) as determined by immunohistochemistry. Furthermore, higher TRAIL expression in the surrounding connective tissue but not in the tumor cells is significantly (P<0.05) linked with favorable overall survival in advanced-stage patients.
  
  
  CONCLUSIONS
  Mechanisms to escape the immune surveillance mediated by TRAIL are developed by ovarian cancer cells in a high percentage. TRAIL expression in the ovarian cancer microenvironment has an effect on overall survival. These findings enhance our understanding of ovarian cancer pathology and might be helpful in guiding TRAIL-based therapy in future.
authors.affiliation: Clinical Division of Oncology, Department of Medicine I, University of Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Horak
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pils
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kaider
authors.forename: Alexander
authors.initials: A
authors.lastname: Pinter
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Elandt
authors.forename: Cornelia
authors.initials: C
authors.lastname: Sax
authors.forename: Christoph C
authors.initials: CC
authors.lastname: Zielinski
authors.forename: Reinhard
authors.initials: R
authors.lastname: Horvat
authors.forename: Robert
authors.initials: R
authors.lastname: Zeillinger
authors.forename: Alexander
authors.initials: A
authors.lastname: Reinthaller
authors.forename: Michael
authors.initials: M
authors.lastname: Krainer
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000378:metabolism*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002277:Carcinoma / Q000737:chemistry / Q000378:metabolism* / Q000401:mortality; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007120:Immunochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000032:analysis / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000401:mortality; D040081:Protein Array Analysis; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis / Q000378:metabolism*; D017154:Stromal Cells / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha