Institute of Pathology, University of Munich, Munich, Germany.
PLoS One. 2012;7(12):e51654. doi: 10.1371/journal.pone.0051654. Epub 2012 Dec 20.
The fact that the receptors for the TNF-related apoptosis inducing ligand (TRAIL) are almost invariably expressed in colorectal cancer (CRC) represents the rationale for the employment of TRAIL-receptors targeting compounds for the therapy of patients affected by this tumor. Yet, first reports on the use of these bioactive agents provided disappointing results. We therefore hypothesized that loss of membrane-bound TRAIL-R might be a feature of some CRC and that the evaluation of membrane staining rather than that of the overall expression of TRAIL-R might predict the response to TRAIL-R targeting compounds in this tumor.
Thus, we evaluated the immunofluorescence pattern of TRAIL-receptors and E-cadherin to assess the fraction of membrane-bound TRAIL-receptors in 231 selected patients with early-stage CRC undergoing surgical treatment only. Moreover, we investigated whether membrane staining for TRAIL-receptors as well as the presence of KRAS mutations or of microsatellite instability (MSI) had an effect on survival and thus a prognostic effect.
As expected, almost all CRC samples stained positive for TRAIL-R1 and 2. Instead, membrane staining for these receptors was positive in only 71% and 16% of samples respectively. No correlation between KRAS mutation status or MSI-phenotype and prognosis could be detected. TRAIL-R1 staining intensity correlated with survival in univariate analysis, but only membranous staining of TRAIL-R1 and TRAIL-R2 on cell membranes was an independent predictor of survival (cox multivariate analysis: TRAIL-R1: p = 0.019, RR 2.06[1.12-3.77]; TRAIL-R2: p = 0.033, RR 3.63[1.11-11.84]).
In contrast to the current assumptions, loss of membrane staining for TRAIL-receptors is a common feature of early stage CRC which supersedes the prognostic significance of their staining intensity. Failure to achieve therapeutic effects in recent clinical trials using TRAIL-receptors targeting compounds might be due to insufficient selection of patients bearing tumors with membrane-bound TRAIL-receptors.
TNF 相关凋亡诱导配体（TRAIL）受体几乎在所有结直肠癌（CRC）中都有表达，这为使用靶向 TRAIL 受体的化合物治疗患有这种肿瘤的患者提供了依据。然而，这些生物活性药物的首次应用报告结果令人失望。因此，我们假设细胞膜 TRAIL-R 的丢失可能是某些 CRC 的特征，评估细胞膜染色而非 TRAIL-R 的总表达可能预测这种肿瘤对 TRAIL-R 靶向化合物的反应。
因此，我们评估了 231 例接受手术治疗的早期 CRC 患者的 TRAIL 受体和 E-钙黏蛋白的免疫荧光模式，以评估细胞膜 TRAIL 受体的比例。此外，我们还研究了细胞膜 TRAIL-R 染色以及 KRAS 突变或微卫星不稳定性（MSI）的存在是否对生存产生影响，从而具有预后作用。
与预期一致，几乎所有 CRC 样本均对 TRAIL-R1 和 2 呈阳性染色。相反，这些受体的细胞膜染色仅分别在 71%和 16%的样本中呈阳性。未发现 KRAS 突变状态或 MSI 表型与预后之间的相关性。TRAIL-R1 染色强度在单变量分析中与生存相关，但只有 TRAIL-R1 和 TRAIL-R2 的细胞膜染色是生存的独立预测因子（cox 多变量分析：TRAIL-R1：p = 0.019，RR 2.06[1.12-3.77]；TRAIL-R2：p = 0.033，RR 3.63[1.11-11.84]）。
与当前的假设相反，细胞膜 TRAIL-R 染色缺失是早期 CRC 的常见特征，超过了其染色强度的预后意义。最近使用 TRAIL 受体靶向化合物进行的临床试验中未能取得治疗效果，可能是由于选择了携带细胞膜 TRAIL-R 的肿瘤患者不足。
Zotero 插件