Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA.
Gynecol Oncol. 2014 Jun;133(3):607-15. doi: 10.1016/j.ygyno.2014.03.560. Epub 2014 Mar 22.
Uterine serous carcinoma (USC) represents an aggressive subtype of endometrial cancer. We sought to understand Notch pathway activity in USC and determine if pathway inhibition has anti-tumor activity.
Patient USC tissue blocks were obtained and used to correlate clinical outcomes with Notch1 expression. Three established USC cell lines were treated with gamma-secretase inhibitor (GSI) in vitro. Mice harboring cell line derived or patient derived USC xenografts (PDXs) were treated with vehicle, GSI, paclitaxel and carboplatin (P/C), or combination GSI and P/C. Levels of cleaved Notch1 protein and Hes1 mRNA were determined in GSI treated samples. Statistical analysis was performed using the Wilcoxon rank sum and Kaplan-Meier methods.
High nuclear Notch1 protein expression was observed in 58% of USC samples with no correlation with overall survival. GSI induced dose-dependent reductions in cell number and decreased levels of cleaved Notch1 protein and Hes1 mRNA in vitro. Treatment of mice with GSI led to decreased Hes1 mRNA expression in USC xenografts. In addition, GSI impeded tumor growth of cell line xenografts as well as UT1 USC PDXs. When GSI and P/C were combined, synergistic anti-tumor activity was observed in UT1 xenografts.
Notch1 is expressed in a large subset of USC. GSI-mediated Notch pathway inhibition led to both reduced cell numbers in vitro and decreased tumor growth of USC some xenograft models. When combined with conventional chemotherapy, GSI augmented anti-tumor activity in one USC PDX line suggesting that targeting of the Notch signaling pathway is a potential therapeutic strategy for future investigation.
子宫浆液性癌（USC）是子宫内膜癌的一种侵袭性亚型。我们旨在了解 Notch 通路在 USC 中的活性，并确定该通路抑制是否具有抗肿瘤活性。
获取患者 USC 组织块，将 Notch1 表达与临床结果相关联。体外用γ-分泌酶抑制剂（GSI）处理三种已建立的 USC 细胞系。携带细胞系衍生或患者衍生 USC 异种移植（PDX）的小鼠用载体、GSI、紫杉醇和卡铂（P/C）或 GSI 和 P/C 联合治疗。在 GSI 处理的样品中测定裂解的 Notch1 蛋白和 Hes1 mRNA 的水平。使用 Wilcoxon 秩和和 Kaplan-Meier 方法进行统计分析。
在 58%的 USC 样本中观察到高核 Notch1 蛋白表达，但与总生存期无相关性。GSI 诱导体外细胞数量呈剂量依赖性减少，并降低裂解的 Notch1 蛋白和 Hes1 mRNA 的水平。GSI 处理小鼠导致 USC 异种移植中 Hes1 mRNA 表达减少。此外，GSI 阻碍了细胞系异种移植和 UT1 USC PDX 的肿瘤生长。当 GSI 和 P/C 联合使用时，在 UT1 异种移植中观察到协同的抗肿瘤活性。
Notch1 在很大一部分 USC 中表达。GSI 介导的 Notch 通路抑制导致体外细胞数量减少和 USC 某些异种移植模型肿瘤生长减少。当与常规化疗联合使用时，GSI 增强了一种 USC PDX 系的抗肿瘤活性，表明靶向 Notch 信号通路是未来研究的一种潜在治疗策略。
