Women's Cancer Research Centre, Royal Women's Hospital , Parkville, VIC , Australia ; Department of Surgery, St Vincent Hospital, University of Melbourne , Melbourne, VIC , Australia.
Department of Surgery, Royal Melbourne Hospital, University of Melbourne , Melbourne, VIC , Australia.
Front Oncol. 2014 Apr 9;4:75. doi: 10.3389/fonc.2014.00075. eCollection 2014.
Chemotherapy resistance associated with recurrent disease is the major cause of poor survival of ovarian cancer patients. We have recently demonstrated activation of the JAK2/STAT3 pathway and the enhancement of a cancer stem cell (CSC)-like phenotype in ovarian cancer cells treated in vitro with chemotherapeutic agents. To elucidate further these mechanisms in vivo, we used a two-tiered paclitaxel treatment approach in nude mice inoculated with ovarian cancer cells. In the first approach, we demonstrate that a single intraperitoneal administration of paclitaxel in mice 7 days after subcutaneous transplantation of the HEY ovarian cancer cell line resulted in a significant increase in the expression of CA125, Oct4, and CD117 in mice xenografts compared to control mice xenografts which did not receive paclitaxel. In the second approach, mice were administered once weekly with paclitaxel and/or a daily dose of the JAK2-specific inhibitor, CYT387, over 4 weeks. Mice receiving paclitaxel only demonstrated a significant decrease in tumor volume compared to control mice. At the molecular level, mouse tumors remaining after paclitaxel administration showed a significant increase in the expression of Oct4 and CD117 coinciding with a significant activation of the JAK2/STAT3 pathway compared to control tumors. The addition of CYT387 with paclitaxel resulted in the suppression of JAK2/STAT3 activation and abrogation of Oct4 and CD117 expression in mouse xenografts. This coincided with significantly smaller tumors in mice administered CYT387 in addition to paclitaxel, compared to the control group and the group of mice receiving paclitaxel only. These data suggest that the systemic administration of paclitaxel enhances Oct4- and CD117-associated CSC-like marker expression in surviving cancer cells in vivo, which can be suppressed by the addition of the JAK2-specific inhibitor CYT387, leading to a significantly smaller tumor burden. These novel findings have the potential for the development of CSC-targeted therapy to improve the treatment outcomes of ovarian cancer patients.
化疗耐药与复发性疾病有关，是卵巢癌患者生存不良的主要原因。我们最近在体外研究中发现，用化疗药物处理卵巢癌细胞会激活 JAK2/STAT3 通路并增强癌症干细胞（CSC）样表型。为了在体内进一步阐明这些机制，我们使用了在接种卵巢癌细胞的裸鼠中进行的两阶段紫杉醇治疗方法。在第一种方法中，我们证明了在皮下移植 HEY 卵巢癌细胞系 7 天后，单次腹腔内给予紫杉醇会导致小鼠异种移植物中 CA125、Oct4 和 CD117 的表达显著增加，而未接受紫杉醇的对照小鼠异种移植物则没有。在第二种方法中，每周一次给予紫杉醇和/或 JAK2 特异性抑制剂 CYT387 治疗 4 周。仅接受紫杉醇治疗的小鼠与对照小鼠相比，肿瘤体积显著减小。在分子水平上，与对照肿瘤相比，紫杉醇给药后残留的小鼠肿瘤中 Oct4 和 CD117 的表达显著增加，同时 JAK2/STAT3 通路的激活显著增加。紫杉醇联合 CYT387 可抑制 JAK2/STAT3 激活，并阻断小鼠异种移植物中 Oct4 和 CD117 的表达。与仅接受紫杉醇治疗的对照组和对照组相比，同时接受 CYT387 和紫杉醇治疗的小鼠的肿瘤明显更小。这些数据表明，紫杉醇的全身给药会增强体内存活癌细胞中与 Oct4 和 CD117 相关的 CSC 样标记物的表达，而添加 JAK2 特异性抑制剂 CYT387 可抑制其表达，从而显著减少肿瘤负担。这些新发现有可能开发针对 CSC 的治疗方法，以改善卵巢癌患者的治疗效果。
