Department of Internal Medicine, Molecular Biotechnology Center, University of Torino, Turin, Italy.
Cancer Res. 2011 Aug 1;71(15):5346-56. doi: 10.1158/0008-5472.CAN-11-0241. Epub 2011 Jun 13.
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.
最近的研究表明，肿瘤来源的微泡 (MV) 充当了肿瘤和基质细胞之间遗传信息交换的载体，为癌症发展营造了有利的微环境。在肿瘤块内，所有细胞类型都可能有助于 MV 的释放，但特定的肿瘤进展贡献仍有待确定。在这里，我们报告在人类肾细胞癌中表达间充质干细胞标记物 CD105 的肿瘤起始细胞亚群释放 MV，触发血管生成并促进前转移龛的形成。仅来自 CD105 阳性癌症干细胞的 MV 将激活的血管生成表型赋予正常的人内皮细胞，在体内植入免疫缺陷严重联合免疫缺陷 (SCID) 小鼠后刺激其生长和血管形成。此外，用源自 CD105 阳性细胞的 MV 处理 SCID 小鼠可大大增强通过静脉注射肾癌细胞引起的肺转移。对 CD105 阳性 MV 的分子表征定义了一组与肿瘤进展和转移相关的促血管生成 mRNAs 和 microRNAs。我们的研究结果定义了一种特定的癌症干细胞衍生 MV 来源，有助于触发血管生成开关并协调肿瘤进展过程中的转移扩散。
