TGFβ1 inhibition increases the radiosensitivity of breast cancer cells in vitro and promotes tumor control by radiation in vivo.
TGFβ1 inhibition increases the radiosensitivity of breast cancer cells in vitro and promotes tumor control by radiation in vivo.
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DOI：
10.1158/1078-0432.ccr-11-0544
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发表时间：
2011-11-01
期刊：
影响因子：
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通讯作者：
Barcellos-Hoff MH
中科院分区：
文献类型：
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作者：
Bouquet F;Pal A;Pilones KA;Demaria S;Hann B;Akhurst RJ;Babb JS;Lonning SM;DeWyngaert JK;Formenti SC;Barcellos-Hoff MH
确定照射前抑制TGFβ信号传导是否在体外和体内使人和鼠癌细胞增敏。研究了MCF 7、Hs 578 T、MDA-MB-231和T47 D人乳腺癌细胞系的TGFβ介导的生长和Smad磷酸化，并将其与分级辐射剂量后的克隆形成存活率相关，有和没有用LY 364947预处理，LY 364947是TGFβ I型受体激酶的小分子抑制剂。在体外用LY 364947预处理的辐射MDA-MB-231细胞和体内用LY 2109761（一种药代动力学稳定的TGFβ信号传导抑制剂）预处理的辐射MDA-MB-231细胞中评估DNA损伤反应。使用TGFβ中和抗体1D 11，在单次或分次体内辐射剂量下，测试了同系小鼠肿瘤4 T1的体外反应。用TGFβ小分子抑制剂预处理的人乳腺癌细胞系是放射增敏的，与对TGFβ生长抑制的敏感性无关。与增加的克隆源性细胞死亡一致，当在体外或体内用TGF β 1型受体激酶抑制剂预处理时，MDA-MB-231三阴性乳腺癌细胞中辐射诱导的H2 AX和p53磷酸化显著降低。此外，TGFβ中和抗体增加了4 T1小鼠乳腺肿瘤对单次和分次辐射暴露的辐射敏感性，阻断了γ H2 AX病灶形成，并显著增加了肿瘤生长延迟。这些结果表明，在放射之前抑制TGFβ可减弱DNA损伤反应，增加克隆形成细胞死亡，并促进肿瘤生长延迟，因此可能是癌症放射治疗的有效辅助手段。
To determine whether inhibition of TGFβ signaling prior to irradiation sensitizes human and murine cancer cells in vitro and in vivo. TGFβ-mediated growth and Smad phosphorylation of MCF7, Hs578T, MDA-MB-231, and T47D human breast cancer cell lines were examined and correlated with clonogenic survival following graded radiation doses with and without pretreatment with LY364947, a small molecule inhibitor of the TGFβ type I receptor kinase. The DNA damage response was assessed in irradiated MDA-MB-231 cells pretreated with LY364947 in vitro and LY2109761, a pharmacokinetically stable inhibitor of TGFβ signaling, in vivo. The in vitro response of a syngeneic murine tumor, 4T1, was tested using a TGFβ neutralizing antibody, 1D11, with single or fractionated radiation doses in vivo. Human breast cancer cell lines pretreated with TGFβ small molecule inhibitor were radio-sensitized, irrespective of sensitivity to TGFβ growth inhibition. Consistent with increased clonogenic cell death, radiation-induced phosphorylation of H2AX and p53 was significantly reduced in MDA-MB-231 triple-negative breast cancer cells when pretreated in vitro or in vivo with a TGFfS type I receptor kinase inhibitor. Moreover, TGFβ neutralizing antibodies increased radiation sensitivity, blocked γH2AX foci formation, and significantly increased tumor growth delay in 4T1 murine mammary tumors in response to single and fractionated radiation exposures. These results show that TGFβ inhibition prior to radiation attenuated DNA damage responses, increased clonogenic cell death, and promoted tumor growth delay, and thus may be an effective adjunct in cancer radiotherapy.