Targeted Disruption of the JAK2/STAT3 Pathway in Combination with Systemic Administration of Paclitaxel Inhibits the Priming of Ovarian Cancer Stem Cells Leading to a Reduced Tumor Burden.
Targeted Disruption of the JAK2/STAT3 Pathway in Combination with Systemic Administration of Paclitaxel Inhibits the Priming of Ovarian Cancer Stem Cells Leading to a Reduced Tumor Burden.
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DOI：
10.3389/fonc.2014.00075
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发表时间：
2014
影响因子：
4.7
通讯作者：
Ahmed N
中科院分区：
文献类型：
--
作者：
Abubaker K;Luwor RB;Escalona R;McNally O;Quinn MA;Thompson EW;Findlay JK;Ahmed N
与复发性疾病相关的化疗耐药性是卵巢癌患者生存率低的主要原因。我们最近证明了用化疗药物体外治疗的卵巢癌细胞中 JAK2/STAT3 通路的激活和癌症干细胞 (CSC) 样表型的增强。为了进一步阐明这些体内机制，我们在接种卵巢癌细胞的裸鼠中使用了两级紫杉醇治疗方法。在第一种方法中，我们证明，与未接受紫杉醇的对照小鼠异种移植物相比，HEY卵巢癌细胞系皮下移植7天后，对小鼠进行单次腹腔内注射紫杉醇导致小鼠异种移植物中CA125、Oct4和CD117的表达显着增加。在第二种方法中，小鼠每周接受一次紫杉醇和/或每日剂量的 JAK2 特异性抑制剂 CYT387，持续 4 周。与对照小鼠相比，接受紫杉醇的小鼠仅表现出肿瘤体积显着减小。在分子水平上，与对照肿瘤相比，给予紫杉醇后剩余的小鼠肿瘤显示 Oct4 和 CD117 表达显着增加，同时 JAK2/STAT3 通路显着激活。添加 CYT387 和紫杉醇可抑制小鼠异种移植物中 JAK2/STAT3 的激活并消除 Oct4 和 CD117 的表达。这与对照组和仅接受紫杉醇的小鼠组相比，同时施用CYT387和紫杉醇的小鼠的肿瘤显着较小相一致。这些数据表明，紫杉醇的全身给药可增强体内存活癌细胞中与 Oct4 和 CD117 相关的 CSC 样标志物的表达，而这种表达可通过添加 JAK2 特异性抑制剂 CYT387 来抑制，从而显着减轻肿瘤负荷。这些新发现有可能开发 CSC 靶向治疗，以改善卵巢癌患者的治疗结果。
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.