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


METHODS
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.
McLornan
Donal P
DP
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.
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
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D017326:Clinical Trials, Phase III as Topic; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000378:metabolism*; D039621:Eukaryotic Initiation Factor-3 / Q000032:analysis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C105988:EIF3A protein, human; D039621:Eukaryotic Initiation Factor-3; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D053181:Caspase 8