Genetically modified "obligate" anaerobic Salmonella typhimurium as a therapeutic strategy for neuroblastoma.
Genetically modified "obligate" anaerobic Salmonella typhimurium as a therapeutic strategy for neuroblastoma.
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DOI：
10.1186/s13045-015-0196-3
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发表时间：
2015-08-19
影响因子：
28.5
通讯作者：
Chan GC
中科院分区：
文献类型：
--
作者：
Guo ZL;Yu B;Ning BT;Chan S;Lin QB;Li JC;Huang JD;Chan GC
目前神经母细胞瘤的预后较差，因此我们提出了一种新的策略，即用基因工程厌氧沙门氏菌（Sal-YB 1）靶向神经母细胞瘤。使用裸和非肥胖糖尿病-严重联合免疫缺陷（NOD-SCID）原位小鼠模型，并通过尾静脉施用Sal-YB 1。研究其疗效、生物安全性及作用机制。没有小鼠死于治疗相关并发症。裸小鼠和NOD-SCID小鼠的肿瘤尺寸分别缩小了70%和30%。尿液中未检测到沙门氏菌;如果添加二氨基庚二酸，75%的小鼠粪便培养呈阳性，但随后全部转为阴性。Sal-YB 1治疗组小鼠肿瘤组织有更多的Sal-YB 1浸润、坏死和萎缩。Sal-YB 1治疗组肿瘤组织中TLR 4、TNF刺激基因6蛋白（TSG 6）和裂解型半胱氨酸蛋白酶1、3、8和9的表达显著升高，白细胞介素1受体相关激酶（IRAK）和B细胞抑制剂α中κ轻链多肽基因增强子核因子（IκBα）的表达降低。Sal-YB 1处理后，人巨噬细胞和小鼠肿瘤组织中TNFα的释放量均增加。Sal-YB 1处理的巨噬细胞上清液的抗肿瘤作用可被TNFα和pan-caspase抑制剂逆转。这种通过生物工程沙门氏菌间接辅助巨噬细胞靶向神经母细胞瘤的新方法可能在未来产生临床治疗影响。
Neuroblastoma currently has poor prognosis, therefore we proposed a new strategy by targeting neuroblastoma with genetically engineered anaerobic Salmonella (Sal-YB1). Nude and nonobese diabetic-severe combined immunodeficiency (NOD-SCID) orthotopic mouse models were used, and Sal-YB1 was administered via tail vein. The therapeutic effectiveness, bio-safety, and mechanisms were studied. No mice died of therapy-related complications. Tumor size reduction was 70 and 30 % in nude and NOD-SCID mice, respectively. No Salmonella was detected in the urine; 75 % mice had positive stool culture if diaminopimelic acid was added, but all turned negative subsequently. Tumor tissues had more Sal-YB1 infiltration, necrosis, and shrinkage in Sal-YB1-treated mice. Significantly higher expression of TLR4, TNF-stimulated gene 6 protein (TSG6), and cleaved caspase 1, 3, 8, and 9 was found in the tumor masses of the Sal-YB1-treated group with a decrease of interleukin 1 receptor-associated kinase (IRAK) and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα). There was a high release of TNFα both in human macrophages and mouse tumor tissues with Sal-YB1 treatment. The antitumor effect of the supernatant derived from macrophages treated with Sal-YB1 could be reversed with TNFα and pan-caspase inhibitors. This new approach in targeting neuroblastoma by bio-engineered Salmonella with the assistance of macrophages indirectly may have a clinical therapeutic impact in the future.