Spierings Diana C J, de Vries Elisabeth G E, Timens Wim, Groen Harry J M, Boezen H Marike, de Jong Steven
Departments of Medical Oncology, University Hospital Groningen, Groningen 9713 GZ, the Netherlands.
Clin Cancer Res. 2003 Aug 15;9(9):3397-405.
Several in vitro studies have shown that non-small cell lung cancer (NSCLC) cell lines are sensitive to apoptosis induction by the recombinant human (rh) tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death ligand, indicating that rhTRAIL might become an attractive molecule for treatment of NSCLCs. To investigate the therapeutic potential of rhTRAIL, the expression of TRAIL and its apoptosis-inducing receptors DR4 and DR5 was evaluated in tumors of stage III NSCLC patients.
Before treatment, tumor biopsies from locally advanced NSCLC patients were obtained by bronchoscopy. DR4, DR5, and TRAIL expression were determined immunohistochemically in 87 tumors. Patients were randomized for treatment with 60 Gy radiotherapy with or without carboplatin as radiosensitizer.
DR4, DR5, and TRAIL were expressed in 99%, 82%, and 91% of the tumors, respectively. Seventeen percent of the samples expressed only DR4 and no DR5. In NSCLCs with squamous cell differentiation, a typical staining pattern for DR4 and DR5 was observed. Cells from the basal layer were strongly positive, and the more mature cells were less positive or negative. An inverse staining pattern was observed for TRAIL. Poorly differentiated areas showed strong staining intensity for DR4, DR5, and TRAIL. DR5-positive staining was associated with increased risk of death (odds ratio, 5.76; 95% confidence interval, 1.04-31.93; P = 0.045).
The majority of the locally irresectable stage III NSCLCs expressed at least one of the two death receptors for TRAIL. Therefore, these death receptors may provide a target for the use of rhTRAIL as a new adjunct in the treatment of stage III NSCLC.
多项体外研究表明，非小细胞肺癌（NSCLC）细胞系对重组人（rh）肿瘤坏死因子相关凋亡诱导配体（TRAIL）死亡配体诱导的凋亡敏感，这表明rhTRAIL可能成为治疗NSCLC的有吸引力的分子。为了研究rhTRAIL的治疗潜力，对III期NSCLC患者肿瘤中TRAIL及其凋亡诱导受体DR4和DR5的表达进行了评估。
在治疗前，通过支气管镜获取局部晚期NSCLC患者的肿瘤活检组织。采用免疫组织化学方法检测87例肿瘤中DR4、DR5和TRAIL的表达。患者被随机分为接受60 Gy放疗联合或不联合卡铂作为放射增敏剂的治疗组。
DR4、DR5和TRAIL分别在99%、82%和91%的肿瘤中表达。17%的样本仅表达DR4而不表达DR5。在具有鳞状细胞分化的NSCLC中，观察到DR4和DR5典型的染色模式。基底层细胞呈强阳性，而较成熟的细胞阳性较弱或为阴性。TRAIL的染色模式相反。低分化区域DR4、DR5和TRAIL染色强度较强。DR5阳性染色与死亡风险增加相关（比值比，5.76；95%置信区间，1.04 - 31.93；P = 0.045）。
大多数局部不可切除的III期NSCLC表达TRAIL的两种死亡受体中的至少一种。因此，这些死亡受体可能为rhTRAIL作为III期NSCLC治疗新辅助手段的应用提供靶点。
