Microvesicles Released from Human Renal Cancer Stem Cells Stimulate Angiogenesis and Formation of Lung Premetastatic Niche
Microvesicles Released from Human Renal Cancer Stem Cells Stimulate Angiogenesis and Formation of Lung Premetastatic Niche
复制标题
DOI：
10.1158/0008-5472.can-11-0241
复制
发表时间：
2011-08-01
期刊：
影响因子：
11.2
通讯作者：
Camussi, Giovanni
中科院分区：
文献类型：
--
作者：
Grange, Cristina;Tapparo, Marta;Camussi, Giovanni
最近的研究表明，肿瘤源性微泡（MV）作为肿瘤和基质细胞之间交换遗传信息的载体，为癌症的发展提供了有利的微环境。在肿瘤块内，所有细胞类型都可能有助于MV脱落，但对肿瘤进展的具体贡献尚未确定。在这里，我们报告说，在人肾细胞癌中表达间充质干细胞标记物CD 105的肿瘤起始细胞亚群释放MV，触发血管生成，促进转移前小生境的形成。仅来源于CD 105阳性癌症干细胞的MV赋予正常人内皮细胞活化的血管生成表型，在免疫功能低下的严重联合免疫缺陷（SCID）小鼠体内植入后刺激其生长和血管形成。此外，用从CD 105阳性细胞脱落的MV治疗SCID小鼠大大增强了由静脉内注射肾癌细胞诱导的肺转移。CD 105阳性MV的分子表征定义了一组与肿瘤进展和转移有关的促血管生成mRNA和microRNA。我们的研究结果定义了癌症干细胞衍生的MV的特定来源，这些MV有助于触发血管生成开关并协调肿瘤进展期间的转移扩散。Cancer Res; 71（15）; 5346-56. (C)2011年AACR。
Recent studies suggest that tumor-derived microvesicles (MV) act as a vehicle for exchange of genetic information between tumor and stromal cells, engendering a favorable microenvironment for cancer development. Within the tumor mass, all cell types may contribute to MV shedding, but specific contributions to tumor progression have yet to be established. Here we report that a subset of tumor-initiating cells expressing the mesenchymal stem cell marker CD105 in human renal cell carcinoma releases MVs that trigger angiogenesis and promote the formation of a premetastatic niche. MVs derived only from CD105-positive cancer stem cells conferred an activated angiogenic phenotype to normal human endothelial cells, stimulating their growth and vessel formation after in vivo implantation in immunocompromised severe combined immunodeficient (SCID) mice. Furthermore, treating SCID mice with MVs shed from CD105-positive cells greatly enhanced lung metastases induced by i.v. injection of renal carcinoma cells. Molecular characterization of CD105-positive MVs defines a set of proangiogenic mRNAs and microRNAs implicated in tumor progression and metastases. Our results define a specific source of cancer stem cell-derived MVs that contribute to triggering the angiogenic switch and coordinating metastatic diffusion during tumor progression. Cancer Res; 71(15); 5346-56. (C) 2011 AACR.