Expression, Cellular Distribution, and Prognostic Relevance of TRAIL Receptors in Hepatocellular Carcinoma

Abstract

Purpose: 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 factorrelated 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.Experimental Design: 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.

Correlation Between Baseline Osteoprotegerin Serum Levels and Prognosis of Advanced-Stage Colorectal Cancer Patients

“…Our report is consistent with the proposed role of the TRAIL-system in carcinogenesis [3-5], with previous observations from different tumour entities [6-8], with the recent report on pre-therapeutic baseline levels of OPG in rectal carcinoma patients [12], and with data from a large prospective epidemiological Norwegian study showing that OPG in serum correlates with cancer-related mortality [14]. …”

“…In vivo investigation has shown that the TRAIL-system plays a role in the clearance of metastatic cells [2] and clinical data from human specimens have consistently shown a correlation between TRAIL-Receptor (TRAIL-R) loss and patients’ survival across different tumour entities [3-5]. Besides the downregulation of TRAIL-R1 and TRAIL-R2, apoptosis resistance can be caused by overexpression of decoy receptors for TRAIL (such as the membrane receptors TRAIL-R3 and TRAIL-R4 which competitively bind to TRAIL without inducing apoptotic signalling [1]) or by osteoprotegerin (OPG), a third, soluble form of the decoy receptor for TRAIL initially identified as a regulator of bone tissue modelling [1].…”

Expression of Apoptosis- and Vitamin D Pathway-Related Genes in Hepatocellular Carcinoma

“…Other groups also reported a M30 increase [15] and TRAIL upregulation [7] in HCC. TRAIL signaling in HCC is of particular interest and a loss of TRAIL receptors has recently been described to further decrease the survival of HCC patients [16]. In contrast, Jing et al [17] reported FasR to be downregulated in some HCC tumors emphasizing the heterogeneity of this cancer.…”

Apoptosis-Modulating Drugs for Improved Cancer Therapy

“…Overexpression of antiapoptotic molecules like Bcl-2, Bcl-xL, IAPs or survivin are therefore commonly detected in human cancer and linked to poor prognosis [79,80,81,82,83,84,85,86]. Consequently, also the loss of proapoptotic factors like death receptors, adapter molecules or caspases has been observed in this context [87,88,89,90,91,92,93]. Interestingly, also the commonly observed increased expression or activity of growth-factor signaling cascades (e.g.…”