Department of Human Cancer Genomic Research, MBC 98-16,Research Centre at KFNCCC, King Faisal Specialist Hospital and Research Centre,PO Box 3354, Riyadh 11211,Kingdom of Saudi Arabia.
Mol Cancer. 2010 Jul 30;9:203. doi: 10.1186/1476-4598-9-203.
Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumour necrosis factor cytokine family that induces apoptosis upon binding to its death domain containing receptors, TRAIL receptor 1 (DR4) and TRAIL receptor 2 (DR5). Expression of TRAIL receptors is higher in colorectal carcinoma (CRC) as compared to normal colorectal mucosa and targeted therapy with TRAIL leads to preferential killing of tumor cells sparing normal cells.
We investigated the expression of TRAIL and its receptors in a tissue microarray cohort of 448 Middle Eastern CRC. We also studied the correlation between TRAIL receptors and various clinico-pathological features including key molecular alterations and overall survival.
CRC subset with TRAIL-R1 expression was associated with a less aggressive phenotype characterized by early stage (p = 0.0251) and a histology subtype of adenocarcinomas (p = 0.0355). Similarly CRC subset with TRAIL-R2 expression was associated with a well-differentiated tumors (p < 0.0001), histology subtype of adenocarcinomas (p = 0.0010) and tumors in left colon (p = 0.0009). Over expression of pro apoptotic markers: p27KIP1 and KRAS4A isoforms was significantly higher in CRC subset with TRAIL-R1 and TRAIL-R2 expression; TRAIL-R1 expression was also associated with cleaved caspase-3(p = 0.0011). Interestingly, TRAIL-R2 expression was associated with a microsatellite stable (MS--S/L) phenotype (p = 0.0003) and with absence of KRAS mutations (p = 0.0481).
TRAIL-R1 expression was an independent prognostic marker for better survival in all CRC samples and even in the CRC group that received adjuvant therapy. The biological effects of TRAIL in CRC models, its enhancement of chemosensitivity towards standard chemotherapeutic agents and the effect of endogenous TRAIL receptor levels on survival make TRAIL an extremely attractive therapeutic target.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）是肿瘤坏死因子细胞因子家族的一员，在与包含其死亡结构域的受体，即 TRAIL 受体 1（DR4）和 TRAIL 受体 2（DR5）结合后，诱导细胞凋亡。与正常结直肠黏膜相比，结直肠癌（CRC）中 TRAIL 受体的表达更高，TRAIL 靶向治疗导致肿瘤细胞优先死亡，而正常细胞不受影响。
我们在一个包含 448 例中东 CRC 的组织微阵列队列中研究了 TRAIL 和其受体的表达。我们还研究了 TRAIL 受体与各种临床病理特征之间的相关性，包括关键的分子改变和总生存。
具有 TRAIL-R1 表达的 CRC 亚组表现出侵袭性较低的表型，其特征为早期（p = 0.0251）和腺癌组织学亚型（p = 0.0355）。同样，具有 TRAIL-R2 表达的 CRC 亚组与分化较好的肿瘤（p < 0.0001）、腺癌组织学亚型（p = 0.0010）和左半结肠癌（p = 0.0009）相关。促凋亡标志物 p27KIP1 和 KRAS4A 异构体的过度表达在具有 TRAIL-R1 和 TRAIL-R2 表达的 CRC 亚组中显著更高；TRAIL-R1 表达也与 cleaved caspase-3（p = 0.0011）相关。有趣的是，TRAIL-R2 表达与微卫星稳定（MS--S/L）表型相关（p = 0.0003），与 KRAS 突变缺失相关（p = 0.0481）。
在所有 CRC 样本中，包括接受辅助治疗的 CRC 组中，TRAIL-R1 表达是生存的独立预后标志物。TRAIL 在 CRC 模型中的生物学效应、其增强对标准化疗药物的敏感性以及内源性 TRAIL 受体水平对生存的影响，使 TRAIL 成为极具吸引力的治疗靶点。
