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Prognostic significance of TRAIL signaling molecules in stage II and III colorectal cancer.


ABSTRACT: PURPOSE:We previously found that cellular FLICE-inhibitory protein (c-FLIP), caspase 8, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 2 (DR5) are major regulators of cell viability and chemotherapy-induced apoptosis in colorectal cancer. In this study, we determined the prognostic significance of c-FLIP, caspase 8, TRAIL and DR5 expression in tissues from patients with stage II and III colorectal cancer. EXPERIMENTAL DESIGN:Tissue microarrays were constructed from matched normal and tumor tissue derived from patients (n = 253) enrolled in a phase III trial of adjuvant 5-fluorouracil-based chemotherapy versus postoperative observation alone. TRAIL, DR5, caspase 8, and c-FLIP expression levels were determined by immunohistochemistry. RESULTS:Colorectal tumors displayed significantly higher expression levels of c-FLIP (P < 0.001), caspase 8 (P = 0.01), and DR5 (P < 0.001), but lower levels of TRAIL (P < 0.001) compared with matched normal tissue. In univariate analysis, higher TRAIL expression in the tumor was associated with worse overall survival (P = 0.026), with a trend to decreased relapse-free survival (RFS; P = 0.06), and higher tumor c-FLIP expression was associated with a significantly decreased RFS (P = 0.015). Using multivariate predictive modeling for RFS in all patients and including all biomarkers, age, treatment, and stage, we found that the model was significant when the mean tumor c-FLIP expression score and disease stage were included (P < 0.001). As regards overall survival, the overall model was predictive when both TRAIL expression and disease stage were included (P < 0.001). CONCLUSIONS:High c-FLIP and TRAIL expression may be independent adverse prognostic markers in stage II and III colorectal cancer and might identify patients most at risk of relapse.

SUBMITTER: McLornan DP 

PROVIDER: S-EPMC2896551 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Prognostic significance of TRAIL signaling molecules in stage II and III colorectal cancer.

McLornan Donal P DP   Barrett Helen L HL   Cummins Robert R   McDermott Ultan U   McDowell Cliona C   Conlon Susie J SJ   Coyle Victoria M VM   Van Schaeybroeck Sandra S   Wilson Richard R   Kay Elaine W EW   Longley Daniel B DB   Johnston Patrick G PG  

Clinical cancer research : an official journal of the American Association for Cancer Research 20100622 13


<h4>Purpose</h4>We previously found that cellular FLICE-inhibitory protein (c-FLIP), caspase 8, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 2 (DR5) are major regulators of cell viability and chemotherapy-induced apoptosis in colorectal cancer. In this study, we determined the prognostic significance of c-FLIP, caspase 8, TRAIL and DR5 expression in tissues from patients with stage II and III colorectal cancer.<h4>Experimental design</h4>Tissue microarrays were co  ...[more]

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