Prognostic significance of TRAIL signaling molecules in stage II and III colorectal cancer.
Prognostic significance of TRAIL signaling molecules in stage II and III colorectal cancer.
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DOI：
10.1158/1078-0432.ccr-10-0052
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发表时间：
2010-07-01
期刊：
影响因子：
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通讯作者：
Johnston PG
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文献类型：
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作者：
McLornan DP;Barrett HL;Cummins R;McDermott U;McDowell C;Conlon SJ;Coyle VM;Van Schaeybroeck S;Wilson R;Kay EW;Longley DB;Johnston PG
我们之前发现 c-FLIP、caspase 8 和 TRAIL 受体 2 (DR5) 是结直肠癌 (CRC) 细胞活力和化疗诱导的细胞凋亡的主要调节因子。在这项研究中，我们确定了 II 期和 III 期 CRC 患者组织中 c-FLIP、caspase 8、TRAIL 和 DR5 表达的预后意义。组织微阵列 (TMA) 是由参加基于 5-FU 辅助化疗与单独术后观察的 III 期试验的患者 (n=253) 匹配的正常组织和肿瘤组织构建的。通过免疫组织化学 (IHC) 测定 TRAIL、DR5、caspase 8 和 c-FLIP 表达水平。与匹配的正常组织相比，结直肠肿瘤的 c-FLIP (p<0.001)、caspase 8 (p=0.01) 和 DR5 (p<0.001) 表达水平显着较高，但 TRAIL 水平较低 (p<0.001)。在单变量分析中，肿瘤中较高的 TRAIL 表达与较差的总生存期 (OS) (p=0.026) 相关，并且有无复发生存期 (RFS) 降低的趋势 (p=0.06)，较高的肿瘤 c-FLIP 表达与显着降低的 RFS 相关 (p=0.015)。对所有患者使用 RFS 多变量预测模型，包括所有生物标志物、年龄、治疗和分期，我们发现，当包括平均肿瘤 c-FLIP 表达评分和疾病分期时，该模型具有显着性 (p<0.001)。至于 OS，当同时包含 TRAIL 表达和疾病阶段时，整体模型具有预测性 (p<0.001)。高 c-FLIP 和 TRAIL 表达可能是 II 期和 III 期 CRC 的独立不良预后标志物，并且可以识别最有复发风险的患者。
We previously found that c-FLIP, caspase 8 and TRAIL receptor 2 (DR5) are major regulators of cell viability and chemotherapy-induced apoptosis in colorectal cancer (CRC). 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 CRC. Tissue Microarrays (TMAs) were constructed from matched normal and tumor tissue derived from patients (n=253) enrolled in a phase III trial of adjuvant 5-FU-based chemotherapy versus post-operative observation alone. TRAIL, DR5, caspase 8 and c-FLIP expression levels were determined by immunohistochemistry (IHC). 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 (OS) (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 modelling 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 OS, the overall model was predictive when both TRAIL expression and disease stage were included (p<0.001). High c-FLIP and TRAIL expression may be independent adverse prognostic markers in stage II and III CRC and may identify patients most at risk of relapse.