TGF-β mediates homing of bone marrow-derived human mesenchymal stem cells to glioma stem cells.
TGF-β mediates homing of bone marrow-derived human mesenchymal stem cells to glioma stem cells.
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DOI：
10.1158/0008-5472.can-12-3086
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发表时间：
2013-04-01
期刊：
影响因子：
11.2
通讯作者：
Lang FF
中科院分区：
文献类型：
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作者：
Shinojima N;Hossain A;Takezaki T;Fueyo J;Gumin J;Gao F;Nwajei F;Marini FC;Andreeff M;Kuratsu J;Lang FF
尽管研究表明骨髓间充质干细胞(BM-hMSCs)可能被用作癌症治疗的载体，但目前尚不清楚BM-hMSCs是否能够靶向肿瘤干细胞，包括胶质瘤干细胞(GSCs)，后者是导致治疗失败的肿瘤启动细胞。利用标准的胶质瘤模型，我们确定转化生长因子-β是一种肿瘤因子，通过转化生长因子-β受体(转化生长因子-β受体)吸引骨髓-人MSCs。使用人和大鼠的GSC，我们第一次展示了血管内注射BM-hMSCs是表达转化生长因子-β的GSC-异种移植的归宿。在治疗研究中，我们发现，携带溶瘤腺病毒Delta-24-RGD的BM-hMSCs延长了分泌转化生长因子-β的GSC-异种移植的存活时间，这一策略的有效性可以通过抑制BM-hMSCs的转化生长因子βR而被取消。这些发现揭示了转化生长因子-β/转化生长因子βR轴作为BM-hMSCs对GSCs趋向性的中介，提示转化生长因子-β可以预测BM-hMSC移植的效果。
Although studies have suggested that bone-marrow human mesenchymal stem cells (BM-hMSCs) may be used as delivery vehicles for cancer therapy, it remains unclear whether BM-hMSCs are capable of targeting cancer stem cells, including glioma stem cells (GSCs), which are the tumor-initiating cells responsible for treatment failures. Using standard glioma models, we identify TGF-β as a tumor-factor that attracts BM-hMSCs via TGF-β receptors (TGFβR) on BM-hMSCs. Using human and rat GSCs, we then show for the first time that intravascularly administered BM-hMSCs home to GSC-xenografts that express TGF-β. In therapeutic studies, we show that BM-hMSCs carrying the oncolytic adenovirus Delta-24-RGD prolonged the survival of TGF-β-secreting GSC-xenografts and that the efficacy of this strategy can be abrogated by inhibition of TGFβR on BM-hMSCs. These findings reveal the TGF-β/TGFβR-axis as a mediator of the tropism of BM-hMSCs for GSCs, and suggest that TGF-β predicts patients in whom BM-hMSC delivery will be effective.