Antiangiogenic Variant of TSP-1 Targets Tumor Cells in Glioblastomas
Antiangiogenic Variant of TSP-1 Targets Tumor Cells in Glioblastomas
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DOI：
10.1038/mt.2014.214
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发表时间：
2015-02-01
影响因子：
12.4
通讯作者：
Shah, Khalid
中科院分区：
文献类型：
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作者：
Choi, Sung Hugh;Tamura, Kaoru;Shah, Khalid
已知血栓反应蛋白-1的3个1型重复（3TSR）结构域通过靶向肿瘤相关内皮细胞具有抗血管生成作用，但其对肿瘤细胞的作用尚不清楚。本研究在体外和体内探讨了3TSR靶向胶质母细胞瘤（GBM）细胞的潜力。我们发现3TSR以cd36依赖的方式上调死亡受体（DR） 4/5的表达，并启动对肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的caspase 8/3/7介导的凋亡的抗性GBMs。我们设计了人间充质干细胞（MSC），用于现场递送3TSR和一种强效且可分泌的TRAIL变体（S-TRAIL），以同时靶向肿瘤细胞和相关内皮细胞，并规避药物穿过血脑屏障的全身递送问题。我们发现MSC-3TSR/S-TRAIL在扩大的GBMs范围内抑制肿瘤生长。在体内，单次给药MSC-3TSR/S-TRAIL可显著靶向肿瘤细胞和GBMs的血管成分，抑制肿瘤进展，延长血管化程度较高的GBM小鼠的存活时间。3TSR/S-TRAIL同时作用于肿瘤细胞和肿瘤相关内皮细胞的能力为靶向广泛的癌症提供了巨大的潜力，并将3TSR/TRAIL疗法转化为临床治疗。
Three type-1 repeat (3TSR) domain of thrombospondin-1 is known to have anti-angiogenic effects by targeting tumor-associated endothelial cells, but its effect on tumor cells is unknown. This study explored the potential of 3TSR to target glioblastoma (GBM) cells in vitro and in vivo. We show that 3TSR upregulates death receptor (DR) 4/5 expression in a CD36-dependent manner and primes resistant GBMs to tumor necrosis factor related apoptosis-inducing ligand (TRAIL)-induced caspase-8/3/7 mediated apoptosis. We engineered human mesenchymal stem cells (MSC) for on-site delivery of 3TSR and a potent and secretable variant of TRAIL (S-TRAIL) in an effort to simultaneously target tumor cells and associated endothelial cells and circumvent issues of systemic delivery of drugs across the blood brain barrier. We show that MSC-3TSR/S-TRAIL inhibits tumor growth in an expanded spectrum of GBMs. In vivo, a single administration of MSC-3TSR/S-TRAIL significantly targets both tumor cells and vascular component of GBMs, inhibits tumor progression, and extends survival of mice bearing highly vascularized GBM. The ability of 3TSR/S-TRAIL to simultaneously act on tumor cells and tumor-associated endothelial cells offers a great potential to target a broad spectrum of cancers and translate 3TSR/TRAIL therapies into clinics.