Phung Thuy L, Eyiah-Mensah Godfred, O'Donnell Rebekah K, Bieniek Radoslaw, Shechter Sharon, Walsh Kenneth, Kuperwasser Charlotte, Benjamin Laura E
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Cancer Res. 2007 Jun 1;67(11):5070-5. doi: 10.1158/0008-5472.CAN-06-3341.
Chronic activation of Akt signaling in the endothelium recapitulates the salient features of a tumor vasculature and can be inhibited by rapamycin, an inhibitor of mammalian target of rapamycin. This led to the hypothesis that the antitumor efficacy of rapamycin may be partially dependent on its ability to inhibit endothelial Akt signaling, making rapamycin an antiangiogenic agent and endothelial Akt pathway inhibitor. Dose-response studies with rapamycin showed that primary human endothelial cells and fibroblasts had a bimodal Akt response with effective reductions in phosphorylated Akt (pAkt) achieved at 10 ng/mL. In contrast, rapamycin increased pAkt levels in tumor cell lines. When tumor-bearing mice were treated with rapamycin doses comparable to those used clinically in transplant patients, we observed strong inhibition of mammary tumor growth. To test whether Akt activation in the endothelium was rate-limiting for this antitumor response, we engineered mouse mammary tumor virus-polyoma virus middle T antigen mice with endothelial cell-specific expression of constitutively activated Akt. We observed that the antitumor efficacy of rapamycin was reduced in the presence of elevated endothelial Akt activation. Just as we observed in MCF7 cells in vitro, rapamycin doses that were antiangiogenic resulted in increased pAkt levels in total mouse mammary tumor virus-polyoma virus middle T antigen tumor lysates, suggesting that tumor cells had an opposite Akt response following mammalian target of rapamycin inhibition compared with tumor endothelial cells. Together, these data support the hypothesis that endothelial Akt signaling in the tumor vasculature is an important target of the novel anticancer drug rapamycin.
内皮细胞中Akt信号的慢性激活概括了肿瘤血管系统的显著特征，并且可以被雷帕霉素（一种雷帕霉素哺乳动物靶点抑制剂）所抑制。这引发了一个假说，即雷帕霉素的抗肿瘤功效可能部分依赖于其抑制内皮细胞Akt信号的能力，使雷帕霉素成为一种抗血管生成剂和内皮细胞Akt途径抑制剂。雷帕霉素的剂量反应研究表明，原代人内皮细胞和成纤维细胞对Akt有双峰反应，在10 ng/mL时可有效降低磷酸化Akt（pAkt）水平。相比之下，雷帕霉素会增加肿瘤细胞系中的pAkt水平。当用与移植患者临床使用剂量相当的雷帕霉素治疗荷瘤小鼠时，我们观察到乳腺肿瘤生长受到强烈抑制。为了测试内皮细胞中的Akt激活是否是这种抗肿瘤反应的限速因素，我们构建了具有内皮细胞特异性表达组成型激活Akt的小鼠乳腺肿瘤病毒-多瘤病毒中间T抗原小鼠。我们观察到，在内皮细胞Akt激活升高的情况下，雷帕霉素的抗肿瘤功效降低。正如我们在体外MCF7细胞中观察到的那样，具有抗血管生成作用的雷帕霉素剂量导致总小鼠乳腺肿瘤病毒-多瘤病毒中间T抗原肿瘤裂解物中的pAkt水平升高，这表明与肿瘤内皮细胞相比，肿瘤细胞在雷帕霉素哺乳动物靶点抑制后对Akt的反应相反。总之，这些数据支持了这样一个假说，即肿瘤血管系统中的内皮细胞Akt信号是新型抗癌药物雷帕霉素的一个重要靶点。
