title: Expression, cellular distribution, and prognostic relevance of TRAIL receptors in hepatocellular carcinoma.
abstract: OBJECTIVE
  After the advent of targeted therapies for hepatocellular carcinoma (HCC), much work is being done to provide a comprehensive description of the different signaling pathways contributing to cell survival and proliferation in this tumor. Apoptotic signaling mediated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents an important mechanism of tumor surveillance, but its importance in the development of HCC is not known. We thus investigated the cellular distribution and the prognostic importance of TRAIL receptors in HCC.
  
  
  METHODS
  Immunohistochemical staining for TRAIL receptors was evaluated in HCC tissues and in matched surrounding nontumor tissues of 157 HCC patients treated with liver transplantation or partial hepatectomy. Survival was analyzed in 93 patients who underwent partial hepatectomy.
  
  
  RESULTS
  The fraction of HCC samples with positive membrane staining for TRAIL receptor 1 (TRAIL-R1) and 2 (TRAIL-R2) was 1.4- and 2.7-fold lower compared with that of hepatocytes from surrounding tissues (P = 0.01). Loss of either TRAIL-R1 or TRAIL-R2, as confirmed by a multivariate analysis, significantly worsened 5-year survival of HCC patients {survival, 27% versus 52% and 15% versus 43%; hazard ratio (HR), 2.3 [95% confidence interval (CI), 1.1-4.4] and 2.4 (95% CI, 1.1-5.2), respectively}. Loss of both TRAIL receptors further decreased survival of patients [HR, 5.72 (95% CI, 2.1-15.5) versus double-negative staining; P = 0.001], indicating an additive effect on survival of TRAIL-R1 and TRAIL-R2.
  
  
  CONCLUSIONS
  This pilot study suggests that loss of TRAIL receptors is a frequent feature of HCCs and an independent predictor of survival in patients undergoing partial hepatectomy. Future therapeutic protocols are likely to profit from the characterization of their expression and cellular distribution. Clin Cancer Res; 16(22); 5529-38. ©2010 AACR.
authors.affiliation: Institute of Pathology, University of Munich, Munich, Germany.
authors.forename: Lydia
authors.initials: L
authors.lastname: Kriegl
authors.forename: Andreas
authors.initials: A
authors.lastname: Jung
authors.forename: Jutta
authors.initials: J
authors.lastname: Engel
authors.forename: Rene
authors.initials: R
authors.lastname: Jackstadt
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Gerbes
authors.forename: Eike
authors.initials: E
authors.lastname: Gallmeier
authors.forename: Jana A
authors.initials: JA
authors.lastname: Reiche
authors.forename: Heiko
authors.initials: H
authors.lastname: Hermeking
authors.forename: Antonia
authors.initials: A
authors.lastname: Rizzani
authors.forename: Christiane J
authors.initials: CJ
authors.lastname: Bruns
authors.forename: Frank T
authors.initials: FT
authors.lastname: Kolligs
authors.forename: Thomas
authors.initials: T
authors.lastname: Kirchner
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Enrico N
authors.initials: EN
authors.lastname: De Toni
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000175:diagnosis* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis*; D016019:Survival Analysis; D014018:Tissue Distribution
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand