Department of Pathology, The University of Michigan Medical School, Ann Arbor, USA.
Clin Cancer Res. 2011 Dec 1;17(23):7359-72. doi: 10.1158/1078-0432.CCR-11-1388. Epub 2011 Sep 8.
Genetically engineered mouse (GEM) models of ovarian cancer that closely recapitulate their human tumor counterparts may be invaluable tools for preclinical testing of novel therapeutics. We studied murine ovarian endometrioid adenocarcinomas (OEA) arising from conditional dysregulation of canonical WNT and PI3K/AKT/mTOR pathway signaling to investigate their response to conventional chemotherapeutic drugs and mTOR or AKT inhibitors.
OEAs were induced by injection of adenovirus expressing Cre recombinase (AdCre) into the ovarian bursae of Apc(flox/flox); Pten(flox/flox) mice. Tumor-bearing mice or murine OEA-derived cell lines were treated with cisplatin and paclitaxel, mTOR inhibitor rapamycin, or AKT inhibitors API-2 or perifosine. Treatment effects were monitored in vivo by tumor volume and bioluminescence imaging, in vitro by WST-1 proliferation assays, and in OEA tissues and cells by immunoblotting and immunostaining for levels and phosphorylation status of PI3K/AKT/mTOR signaling pathway components.
Murine OEAs developed within 3 weeks of AdCre injection and were not preceded by endometriosis. OEAs responded to cisplatin + paclitaxel, rapamycin, and AKT inhibitors in vivo. In vitro studies showed that response to mTOR and AKT inhibitors, but not conventional cytotoxic drugs, was dependent on the status of PI3K/AKT/mTOR signaling. AKT inhibition in APC(-)/Pten(-) tumor cells resulted in compensatory upregulation of ERK signaling.
The studies show the utility of this GEM model of ovarian cancer for preclinical testing of novel PI3K/AKT/mTOR signaling inhibitors and provide evidence for compensatory signaling, suggesting that multiple rather than single agent targeted therapy will be more efficacious for treating ovarian cancers with activated PI3K/AKT/mTOR signaling.
与人类肿瘤高度相似的卵巢癌基因工程小鼠 (GEM) 模型可能是新型治疗药物临床前测试的宝贵工具。我们研究了由经典 WNT 和 PI3K/AKT/mTOR 信号通路的条件失调引起的小鼠卵巢子宫内膜样腺癌 (OEA)，以研究它们对传统化疗药物和 mTOR 或 AKT 抑制剂的反应。
通过向 Apc(flox/flox); Pten(flox/flox) 小鼠的卵巢囊内注射表达 Cre 重组酶 (AdCre) 的腺病毒诱导 OEAs 的发生。对荷瘤小鼠或源自小鼠 OEA 的细胞系进行顺铂和紫杉醇、mTOR 抑制剂雷帕霉素或 AKT 抑制剂 API-2 或 perifosine 治疗。通过肿瘤体积和生物发光成像在体内、通过 WST-1 增殖测定在体外以及通过免疫印迹和免疫染色监测 OEA 组织和细胞中 PI3K/AKT/mTOR 信号通路成分的水平和磷酸化状态来监测治疗效果。
小鼠 OEAs 在 AdCre 注射后 3 周内发展，并且没有子宫内膜异位症的前兆。OEAs 对顺铂+紫杉醇、雷帕霉素和 AKT 抑制剂在体内有反应。体外研究表明，对 mTOR 和 AKT 抑制剂的反应，但不是传统的细胞毒性药物，取决于 PI3K/AKT/mTOR 信号的状态。在 APC(-)/Pten(-) 肿瘤细胞中抑制 AKT 导致 ERK 信号的代偿性上调。
这些研究表明，这种卵巢癌 GEM 模型可用于新型 PI3K/AKT/mTOR 信号抑制剂的临床前测试，并为代偿性信号提供证据，表明针对激活的 PI3K/AKT/mTOR 信号的卵巢癌，采用多种而非单一的靶向治疗将更有效。
