Trop-2 在低分化子宫内膜样腺癌中的过表达：人源化抗 Trop-2 单克隆抗体 hRS7 免疫治疗的意义。
Trop-2 overexpression in poorly differentiated endometrial endometrioid carcinoma: implications for immunotherapy with hRS7, a humanized anti-trop-2 monoclonal antibody.
机构信息
Angelo Nocivelli Institute of Molecular Medicine, Division of Gynecologic Oncology.
出版信息
Int J Gynecol Cancer. 2011 Dec;21(9):1613-21. doi: 10.1097/IGC.0b013e318228f6da.
OBJECTIVE
We evaluated the expression of human trophoblast cell surface marker (Trop-2) in endometrial endometrioid carcinoma (EEC) and the potential application of hRS7, a humanized monoclonal anti-Trop-2 antibody, as a therapeutic agent against poorly differentiated EEC.
METHODS
Trop-2 expression was evaluated by immunohistochemistry in 131 EEC with different degrees of differentiation and 32 normal endometrial controls (NEC). Trop-2 expression was also evaluated by quantitative real-time polymerase chain reaction and flow cytometry in 3 primary EEC cell lines derived from patients harboring poorly differentiated EEC. Finally, the sensitivity of grade 3 EEC cell lines to hRS7 antibody-dependent cellular cytotoxicity was tested in standard 5-hour Cr release assays.
RESULTS
Trop-2 expression was detected in 126 (96.2%) of 131 EEC samples. Tumor tissues showed markedly increased Trop-2 positivity compared with NEC (P = 0.001). Trop-2 expression was significantly higher in all grades of EEC versus NEC. Grade 3 tumors displayed significantly stronger Trop-2 immunostaining compared with grade 1 EEC (P = 0.01). High Trop-2 expression by quantitative real-time polymerase chain reaction and flow cytometry was found in 1 grade 3 EEC primary cell line (EEC-ARK-1). Unlike Trop-2-negative EEC cell lines, EEC-ARK-1 was found highly sensitive to hRS7-mediated antibody-dependent cellular cytotoxicity in vitro (range of killing, 33.9%-50.6%; P = 0.004). Human serum did not significantly inhibit hRS7-mediated cytotoxicity against EEC-ARK-1 (P = 0.773).
CONCLUSIONS
Trop-2 is highly expressed in EEC, and its expression is significantly higher in poorly differentiated EEC when compared with well-differentiated EEC. Primary grade 3 EECs overexpressing Trop-2 are highly sensitive to hRS7-mediated cytotoxicity in vitro. hRS7 may represent a novel therapeutic agent for the treatment of high-grade EEC refractory to standard treatment modalities.
目的
我们评估了人滋养层细胞表面标志物（Trop-2）在子宫内膜样癌（EEC）中的表达，以及 hRS7（一种人源化单克隆抗 Trop-2 抗体）作为治疗低分化 EEC 的潜在应用。
方法
通过免疫组织化学法检测 131 例不同分化程度的 EEC 和 32 例正常子宫内膜对照（NEC）中 Trop-2 的表达。还通过定量实时聚合酶链反应和流式细胞术检测了源自患有低分化 EEC 的 3 种原发性 EEC 细胞系中 Trop-2 的表达。最后，在标准 5 小时 Cr 释放测定中测试了 hRS7 抗体依赖性细胞毒性对 3 级 EEC 细胞系的敏感性。
结果
在 131 例 EEC 样本中的 126 例（96.2%）中检测到 Trop-2 表达。与 NEC 相比，肿瘤组织中 Trop-2 阳性率明显增加（P = 0.001）。所有分级的 EEC 中 Trop-2 的表达均明显高于 NEC。与 1 级 EEC 相比，3 级肿瘤的 Trop-2 免疫染色明显更强（P = 0.01）。通过定量实时聚合酶链反应和流式细胞术发现，在 1 种 3 级 EEC 原代细胞系（EEC-ARK-1）中 Trop-2 表达较高。与 Trop-2 阴性的 EEC 细胞系不同，EEC-ARK-1 在体外对 hRS7 介导的抗体依赖性细胞毒性高度敏感（杀伤范围为 33.9%-50.6%；P = 0.004）。人血清对 hRS7 介导的对 EEC-ARK-1 的细胞毒性没有显著抑制作用（P = 0.773）。
结论
Trop-2 在 EEC 中高度表达，在低分化 EEC 中与高分化 EEC 相比表达显著更高。过度表达 Trop-2 的原发性 3 级 EEC 对 hRS7 介导的细胞毒性在体外高度敏感。hRS7 可能代表一种治疗对标准治疗方案有抗性的高级别 EEC 的新型治疗剂。
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