TRAIL is a stimulator of apoptosis in transformed cells and can induce cell death in tumor cells while not affecting normal, surrounding cells. Five TRAIL receptors have been identified in humans. This study determined the expression pattern of TRAIL receptors; death receptors DR4 and DR5, decoy receptors DcR1 and DcR2, and the apoptosis inhibiting protein FLIPL in 200 prostate cancer specimens. The prognostic implications of expression were correlated with recurrence-free survival.
The epithelial and stromal protein expression of TRAIL and its receptors were assessed by immunohistochemistry in array panels of malignant and benign prostate tissue. In normal prostate tissue, there was greater TRAIL expression in stromal cells (60.3%) compared with prostate epithelium (50.8%). However, in prostate cancer specimens TRAIL expression was significantly lower in stroma (28.6%) compared with epithelium (86.9%). TRIAL epithelial expression was greater in tumors and PIN compared to benign tissue. Stromal TRAIL was higher in benign tissues compared to prostate cancer and PIN. They found that death receptor expression was increased in tumor tissue when compared with benign tissue. PIN had an intermediate expression pattern for all TRAIL receptors except for decoy receptors, which were similar in the tumor and PIN tissues. The relationship between TRAIL death receptors and FLIPL expression was studied, as tumor cells can escape TRAIL-induced apoptosis by either downregulating death receptors or overexpressing FLIPL. What they found was a positive correlation between death receptors and FLIPL, suggesting that CaP cells may evade TRAIL-induced apoptosis by increasing the intracellular levels of the apoptotic pathway in tumors with elevated levels of FLIPL. FLIPL was also increased in tumors expressing high epithelial TRAIL levels, which was not the case for stromal TRAIL expression. High epithelial TRAIL expression was associated with increased death receptor expression. Virtually all the samples in the array had elevated FLIPL expression (26.6%), low expression of death receptors (10.6%), or both (62.8%).
Tumors with Gleason scores of 7 or higher had a significant reduction in DR4 expression. After adjusting for Gleason score, no significant correlation between FLIPL expression and risk of recurrence was found. Death receptor and decoy receptor expression also did not correlate with CaP survival. Finally, they found that TRAIL expression in the prostate tumor microenvironment correlated with better recurrence-free survival.
Anees M, Horak P, El-Gazzar A, Susani M, Heinze G, Perco P, Loda M, Lis R, Krainer M, Oh WK
Cancer. 2010 Nov 8. [Epub ahead of print]
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