Expression, cellular distribution, and prognostic relevance of TRAIL receptors in hepatocellular carcinoma.
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.
Kriegl
Lydia
L
Institute of Pathology, University of Munich, Munich, Germany.
Jung
Andreas
A
Engel
Jutta
J
Jackstadt
Rene
R
Gerbes
Alexander L
AL
Gallmeier
Eike
E
Reiche
Jana A
JA
Hermeking
Heiko
H
Rizzani
Antonia
A
Bruns
Christiane J
CJ
Kolligs
Frank T
FT
Kirchner
Thomas
T
Göke
Burkhard
B
De Toni
Enrico N
EN
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
D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand