Blocking Tumor-Educated MSC Paracrine Activity Halts Osteosarcoma Progression
Blocking Tumor-Educated MSC Paracrine Activity Halts Osteosarcoma Progression
复制标题
DOI：
10.1158/1078-0432.ccr-16-2726
复制
发表时间：
2017-07-15
影响因子：
11.5
通讯作者：
Pegtel, D. Michiel
中科院分区：
文献类型：
--
作者：
Baglio, S. Rubina;Lagerweij, Tonny;Pegtel, D. Michiel
目的：骨肉瘤是一种遗传异质性的骨恶性肿瘤，尽管采用了积极的化疗方案，但预后较差。由于可药物驱动基因突变尚未建立，解剖骨肉瘤细胞和支持基质之间的相互作用可能为新的治疗靶点提供见解。实验设计：通过使用生物发光的骨肉瘤原位移植小鼠模型，我们评估了肿瘤细胞外小泡(EV)教育的间充质干细胞(TEMSC)对骨肉瘤进展的影响。设计了表征和功能研究来评估MSC教育的基础机制。结果：高度恶性骨肉瘤细胞分泌的EVS选择性地掺入膜相关形式的转化生长因子β，从而诱导MSCs产生促炎因子IL6。TEMSCs促进肿瘤生长，同时伴有肿瘤内STAT3的激活和肺转移的形成，这是对照MSCs没有观察到的。重要的是，静脉注射抗IL6受体抗体的cilizumab可消除TEMSCs的肿瘤促进作用。人骨肉瘤组织的RNA-SEQ分析显示了明显的转化生长因子β诱导的前转移基因特征。组织芯片免疫染色显示在人骨肉瘤中STAT3信号活跃，这与在TEMSC治疗的小鼠中的观察结果一致。最后，我们从血清中分离出EV的纯种群，并证明在骨肉瘤患者中EV相关的转化生长因子β的循环水平增加。结论：我们的研究结果表明，TEMSCs促进了骨肉瘤的进展，并为测试IL6和转化生长因子β阻滞剂作为骨肉瘤患者新的治疗选择提供了基础。(C)2017年AACR。
Purpose: Human osteosarcoma is a genetically heterogeneous bone malignancy with poor prognosis despite the employment of aggressive chemotherapy regimens. Because druggable driver mutations have not been established, dissecting the interactions between osteosarcoma cells and supporting stroma may provide insights into novel therapeutic targets.Experimental Design: By using a bioluminescent orthotopic xenograft mouse model of osteosarcoma, we evaluated the effect of tumor extracellular vesicle (EV)-educated mesenchymal stem cells (TEMSC) on osteosarcoma progression. Characterization and functional studies were designed to assess the mechanisms underlying MSC education. Independent series of tissue specimens were analyzed to corroborate the preclinical findings, and the composition of patient serum EVs was analyzed after isolation with size-exclusion chromatography.Results: We show that EVs secreted by highly malignant osteosarcoma cells selectively incorporate a membrane-associated form of TGF beta, which induces proinflammatory IL6 production by MSCs. TEMSCs promote tumor growth, accompanied with intratumor STAT3 activation and lung metastasis formation, which was not observed with control MSCs. Importantly, intravenous administration of the anti-IL6 receptor antibody tocilizumab abrogated the tumor-promoting effects of TEMSCs. RNA-seq analysis of human osteosarcoma tissues revealed a distinct TGF beta-induced prometastatic gene signature. Tissue microarray immunostaining indicated active STAT3 signaling in human osteosarcoma, consistent with the observations in TEMSC-treated mice. Finally, we isolated pure populations of EVs from serum and demonstrated that circulating levels of EV-associated TGF beta are increased in osteosarcoma patients.Conclusions: Collectively, our findings suggest that TEMSCs promote osteosarcoma progression and provide the basis for testing IL6- and TGF beta-blocking agents as new therapeutic options for osteosarcoma patients. (C) 2017 AACR.