Inhibition of mTOR Radiosensitizes Soft Tissue Sarcoma and Tumor Vasculature
Inhibition of mTOR Radiosensitizes Soft Tissue Sarcoma and Tumor Vasculature
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DOI：
10.1158/1078-0432.ccr-08-1019
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发表时间：
2009-01-15
影响因子：
11.5
通讯作者：
Hamstra, Daniel A.
中科院分区：
文献类型：
--
作者：
Murphy, James D.;Spalding, Aaron C.;Hamstra, Daniel A.
目的：PI3K/Akt/mTOR 促生存通路在软组织肉瘤中经常上调，哺乳动物雷帕霉素靶点 (mTOR) 抑制剂（例如雷帕霉素）最近在软组织肉瘤中显示出临床益处，并且 mTOR 抑制也与癌和内皮细胞的放射增敏有关。本研究测试了雷帕霉素通过抑制 mTCR 在体外和体内使软组织肉瘤和内皮细胞放射增敏的假设。实验设计：进行集落形成测定以确定雷帕霉素对三种人软组织肉瘤细胞系（SK-LMS-1、SW-872 和 HT-1080）和人真皮微血管的放射增敏特性 内皮细胞（HDMEC）。通过微血管出芽测定评估雷帕霉素和辐射对内皮室的功能影响，通过皮下注射评估雷帕霉素的体内放射增敏活性。 SK-LMS-1 裸鼠异种移植物每天同时接受雷帕霉素、放射或两者治疗三周。 结果：在所有三种软组织肉瘤细胞系中，使用最低细胞毒性剂量的雷帕霉素均显示出体外放射增敏作用。与单独治疗相比，雷帕霉素和放射治疗的 SK-LMS-1 异种移植物显示出显着的肿瘤生长延迟。辐射导致 mTOR 功能短暂增加，而雷帕霉素在受辐射和未受辐射的样品中消除了这种信号传导。在 HDMEC 中，雷帕霉素和辐射减少了微血管萌芽，但没有改变集落形成。结论：最低细胞毒性浓度的雷帕霉素抑制培养物和体内的 mTOR 级联，同时对软组织肉瘤进行放射增敏，并通过靶向肿瘤和内皮细胞，与辐射对 HDMEC 微血管形成产生协同作用。 隔室中，雷帕霉素对软组织肉瘤异种移植物产生有效的放射增敏作用。雷帕霉素和放射治疗相结合治疗软组织肉瘤的临床试验是必要的。
Purpose: The PI3K/Akt/mTOR prosurvival pathway is frequently up-regulated in soft tissue sarcoma, Mammalian target of rapamycin (mTOR) inhibitors, Such as rapamycin, have recently shown clinical benefit in soft tissue sarcoma, and mTOR inhibition has also been associated with radiosensitization of carcinoma and endothelial cells. This study tested the hypothesis that rapamycin radiosensitizes soft tissue sarcoma and endothelial cells in vitro and in vivo through the inhibition of mTCR.Experimental Design: Colony formation assays were done to determine the radiosensitizing properties of rapamycin on three human soft tissue sarcoma cell lines (SK-LMS-1, SW-872, and HT-1080) and human dermal microvascular endothelial cells (HDMEC). The functional effects of rapamycin and radiation on the endothelial compartment were evaluated with microvascular sprouting assays, The in vivo radiosensitizing activity of rapamycin was assessed with s.c. SK-LMS-1 nude mice xenografts treated with concurrent daily rapamycin, radiation, or both for three weeks.Results: In vitro radiosensitization was shown in all three soft tissue sarcoma cell lines with minimally cytotoxic doses of rapamycin. SK-LMS-1 xenografts displayed significant tumor growth delay with rapamycin and radiation compared with either treatment alone. Radiation resulted in transient increased mTOR function, whereas rapamycin abolished this signaling in irradiated and unirradiated samples. In HDMEC, rapamycin and radiation reduced microvessel sprouting, but did not alter colony formation.Conclusions: Minimally cytotoxic concentrations of rapamycin inhibited the mTOR cascade in culture and in vivo while radiosensitizing soft tissue sarcoma, and produced synergistic effects with radiation on HDMEC microvessel formation, By targeting both tumor and endothelial compartments, rapamycin produced potent radiosensitization of soft tissue sarcoma xenografts. Clinical trials combining rapamycin and radiotherapy in soft tissue sarcoma are warranted.