Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer.
Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer.
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DOI：
10.1158/0008-5472.can-08-4698
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发表时间：
2009-05-15
期刊：
影响因子：
11.2
通讯作者：
Janes SM
中科院分区：
文献类型：
--
作者：
Loebinger MR;Eddaoudi A;Davies D;Janes SM
癌症是世界各地死亡的主要原因，迫切需要新的治疗方法。最近的研究表明，骨髓来源的间充质干细胞（MSC）的家和纳入肿瘤组织。我们假设经工程化以产生和递送TNF相关凋亡诱导配体（TRAIL）（一种引起肿瘤细胞选择性凋亡的跨膜蛋白）的MSC将在肺转移癌模型中归巢并杀死癌细胞。使用慢病毒载体，在四环素启动子的控制下，用TRAIL和IRES-eGFP报告基因转导人MSC。在共培养实验中，转导和活化的MSC引起肺癌（A549）、乳腺癌（MDAMB 231）、鳞状癌（H357）和宫颈癌（Hela）细胞凋亡和死亡。皮下异种移植实验证实，直接递送的表达TRAIL的MSC能够显著减少肿瘤生长（0.12cm 3（0.04-0.21）对0.66cm 3（0.21-1.11）（p<0.001））。然后，我们发现使用肺转移模型，全身递送的MSC定位于肺转移，并且与对照组的0%相比，TRAIL的受控局部递送在38%的小鼠中完全清除了转移性疾病（p<0.05）。这是第一项研究，以证明一个显着减少转移性肿瘤负荷与频繁根除转移使用诱导型TRAIL表达的MSC。这具有广泛的潜在治疗作用，包括原发性肿瘤及其转移瘤的治疗，可能作为原发性肿瘤切除后清除微转移性疾病的辅助治疗。
Cancer is a leading cause of mortality throughout the world and new treatments are urgently needed. Recent studies suggest that bone marrow-derived mesenchymal stem cells (MSCs) home to and incorporate within tumor tissue. We hypothesised that MSCs engineered to produce and deliver TNF-related apoptosis-inducing ligand (TRAIL), a transmembrane protein which causes selective apoptosis of tumor cells, would home to and kill cancer cells in a lung metastatic cancer model. Human MSCs were transduced with TRAIL and the IRES-eGFP reporter gene, under the control of a tetracycline promoter using a lentiviral vector. Transduced and activated MSCs caused lung (A549), breast (MDAMB231), squamous (H357), and cervical (Hela) cancer cell apoptosis and death in co-culture experiments. Subcutaneous xenograft experiments confirmed directly delivered TRAIL-expressing MSCs were able to significantly reduce tumor growth (0.12 cm3 (0.04-0.21) vs 0.66 cm3 (0.21-1.11) (p<0.001)). We then found using a pulmonary metatastasis model, systemically delivered MSCs localised to lung metastases and the controlled local delivery of TRAIL completely cleared the metastatic disease in 38% of mice compared to 0% of controls (p<0.05). This is the first study to demonstrate a significant reduction in metastatic tumor burden with frequent eradication of metastases using inducible TRAIL-expressing MSCs. This has a wide potential therapeutic role, which includes the treatment of both primary tumors and their metastases, possibly as an adjuvant therapy in clearing micrometastatic disease following primary tumor resection.