Inhibition of Mouse Breast Tumor-Initiating Cells by Calcitriol and Dietary Vitamin D.
Inhibition of Mouse Breast Tumor-Initiating Cells by Calcitriol and Dietary Vitamin D.
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DOI：
10.1158/1535-7163.mct-15-0066
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发表时间：
2015-08
影响因子：
5.7
通讯作者：
Diehn M
中科院分区：
文献类型：
--
作者：
Jeong Y;Swami S;Krishnan AV;Williams JD;Martin S;Horst RL;Albertelli MA;Feldman BJ;Feldman D;Diehn M
维生素 D 及其激素活性形式骨化三醇的抗癌作用已在临床和临床前研究中得到广泛记录。然而，这些作用的机制尚未完全阐明。在这里，我们研究了膳食维生素 D 和骨化三醇对小鼠乳腺肿瘤起始细胞（TIC，也称为癌症干细胞）的影响。我们专注于 MMTV-Wnt1 乳腺肿瘤，用于分离 TIC 的标记物之前已得到验证。我们证实这些肿瘤表达功能性维生素 D 受体 (VDR) 和雌激素受体 (ER)，并表现出骨化三醇诱导的分子反应，包括 ER 下调。将 MMTV-Wnt1 乳腺肿瘤细胞原位植入小鼠体内后，骨化三醇注射或补充维生素 D 的饮食导致肿瘤出现和生长显着延迟，而缺乏维生素 D 的饮食则会加速肿瘤出现和生长。骨化三醇在原代培养物中以剂量依赖性方式抑制 TIC 肿瘤球体形成，并在二次传代中抑制 TIC 自我更新。骨化三醇和电离辐射的组合比单独的任何一种治疗更能抑制球状体的形成。此外，通过体内有限稀释分析评估，骨化三醇显着降低了 TIC 频率。骨化三醇对 TIC 球体形成的抑制可以通过 β-catenin 的过表达来克服，这表明 Wnt/β-catenin 通路的抑制是介导骨化三醇在该肿瘤模型中的 TIC 抑制活性的重要机制。我们的研究结果表明，维生素 D 化合物可靶向乳腺 TIC，从而减少肿瘤起始活性。我们的数据还表明，将维生素 D 化合物与标准疗法相结合将增强抗癌活性，并可能改善治疗效果。
The anti-cancer actions of vitamin D and its hormonally active form, calcitriol, have been extensively documented in clinical and pre-clinical studies. However, the mechanisms underlying these actions have not been completely elucidated. Here we examined the effect of dietary vitamin D and calcitriol on mouse breast tumor-initiating cells (TICs, also known as cancer stem cells). We focused on MMTV-Wnt1 mammary tumors, for which markers for isolating TICs have previously been validated. We confirmed that these tumors expressed functional vitamin D receptors (VDRs) and estrogen receptors (ERs) and exhibited calcitriol-induced molecular responses including ER down-regulation. Following orthotopic implantation of MMTV-Wnt1 mammary tumor cells into mice, calcitriol injections or a vitamin D-supplemented diet caused a striking delay in tumor appearance and growth while a vitamin D-deficient diet accelerated tumor appearance and growth. Calcitriol inhibited TIC tumor spheroid formation in a dose-dependent manner in primary cultures and inhibited TIC self-renewal in secondary passages. A combination of calcitriol and ionizing radiation inhibited spheroid formation more than either treatment alone. Further, calcitriol significantly decreased TIC frequency as evaluated by in vivo limiting dilution analyses. Calcitriol inhibition of TIC spheroid formation could be overcome by the overexpression of β-catenin, suggesting that the inhibition of Wnt/β-catenin pathway is an important mechanism mediating the TIC inhibitory activity of calcitriol in this tumor model. Our findings indicate that vitamin D compounds target breast TICs reducing tumor-initiating activity. Our data also suggest that combining vitamin D compounds with standard therapies will enhance anti-cancer activity and may improve therapeutic outcomes.