High metastatic efficiency of human sarcoma cells in Rag2/γc double knockout mice provides a powerful test system for antimetastatic targeted therapy
High metastatic efficiency of human sarcoma cells in Rag2/γc double knockout mice provides a powerful test system for antimetastatic targeted therapy
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DOI：
10.1016/j.ejca.2009.11.018
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发表时间：
2010-02-01
影响因子：
8.4
通讯作者：
Lollini, Pier-Luigi
中科院分区：
文献类型：
--
作者：
Nanni, Patrizia;Nicoletti, Giordano;Lollini, Pier-Luigi
免疫缺陷动物模型是研究人类肿瘤转移倾向的宝贵工具。然而，残留的免疫反应，特别是自然杀伤(NK)细胞，严重阻碍了人类肿瘤细胞的运输和生长。我们研究了缺乏T、B和NK免疫的转基因小鼠宿主是否都能改善人类恶性肿瘤转移表型的表达。研究了一组人肉瘤细胞百合在双基因敲除Rag2(-/-)；Gamma c(-/-)小鼠体内的转移扩散，并与NK耗尽的裸鼠进行了比较。Rag2(-/-)、Gamma c(-/-)小鼠静脉注射。或皮下(S.C.)人肉瘤细胞系发生广泛的多器官转移。Rag2(-/-)；Gamma c(-/-)的转移效率在转移部位和转移数目上均优于裸鼠。Rag2(-/-)；Gamma c(-/-)小鼠的转移生长速度比裸鼠快，因此可以更早地进行转移评估。大多数人肉瘤在Rag2(-/-)；Gamma c(-/-)小鼠的肝脏中转移，这是一种在裸鼠中检测不到的器官偏好，是肉瘤的特异性，因为几种癌细胞百合未能在Rag2(-/-)；Gamma C(-/-)小鼠的肝脏中定植，独立于它们向其他部位的转移。肉瘤肝转移的分子机制的体外分析涉及肝脏产生的生长和运动因子，特别是胰岛素样生长因子(IGF)轴。NVP-BEZ235是针对PI3K和mTOR下游信号转导的特异性抑制剂，可强烈抑制人肉瘤细胞的肝转移。总而言之，Rag2(-/-)；Gamma c(-/-)小鼠模型允许人类转移表型在常规免疫缺陷小鼠中不明显的表达，并允许进行适当靶向治疗的临床前测试。(C)2009爱思唯尔有限公司。保留所有权利。
Immunodeficient animal models are invaluable tools to investigate the metastatic propensity of human tumours. However residual immune responses, in particular natural killer (NK) cells, severely hamper the traffic and growth of human tumour cells. We studied whether a genetically modified mouse host lacking T, B and NK immunity allowed all improved expression of the metastatic phenotype of malignant human tumours. Metastatic spread of a panel of human sarcoma cell lilies was studied in double knockout Rag2(-/-);gamma c(-/-) mice in comparison with NK-depleted nude mice. Rag2(-/-),gamma c(-/-) mice receiving intravenous (i.v.) or subcutaneous (s.c.) human sarcoma cell lines developed extensive multiorgan metastases. Metastatic efficiency in Rag2(-/-);gamma c(-/-) was superior than in nude mice in terms of both metastatic sites and metastasis number. Metastatic growth in Rag2(-/-);gamma c(-/-) mice was faster than that in nude mice, thus allowing an earlier metastasis evaluation. Most human sarcomas metastasised in the liver of Rag2(-/-);gamma c(-/-) mice, a kind of organ preference undetectable in nude mice and specific of sarcomas, as several carcinoma cell lilies failed to colonise the liver of Rag2(-/-);gamma c(-/-) mice, independently of their metastatic spread to other sites. In vitro analysis of the molecular mechanisms of liver metastasis of sarcomas implicated liver-produced growth and motility factors, in particular the insulin-like growth factor (IGF) axis. NVP-BEZ235, a specific inhibitor of downstream signal transduction targeting PI3K and mTOR, strongly inhibited liver metastasis of human sarcoma cells. In conclusion, the Rag2(-/-);gamma c(-/-) mouse model allowed the expression of human metastatic phenotypes inapparent in conventional immunodeficient mice and the preclinical testing of appropriate targeted therapies. (C) 2009 Elsevier Ltd. All rights reserved.