Lindoso Rafael Soares, Collino Federica, Camussi Giovanni
Department of Medical Sciences and Molecular Biotechnology Center University of Torino, Torino, Italy.
Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Oncotarget. 2015 Apr 10;6(10):7959-69. doi: 10.18632/oncotarget.3503.
Renal carcinomas have been shown to contain a population of cancer stem cells (CSCs) that present self-renewing capacity and support tumor growth and metastasis. CSCs were shown to secrete large amount of extracellular vesicles (EVs) that can transfer several molecules (proteins, lipids and nucleic acids) and induce epigenetic changes in target cells. Mesenchymal Stromal Cells (MSCs) are susceptible to tumor signalling and can be recruited to tumor regions. The precise role of MSCs in tumor development is still under debate since both pro- and anti-tumorigenic effects have been reported. In this study we analysed the participation of renal CSC-derived EVs in the interaction between tumor and MSCs. We found that CSC-derived EVs promoted persistent phenotypical changes in MSCs characterized by an increased expression of genes associated with cell migration (CXCR4, CXCR7), matrix remodeling (COL4A3), angiogenesis and tumor growth (IL-8, Osteopontin and Myeloperoxidase). EV-stimulated MSCs exhibited in vitro an enhancement of migration toward the tumor conditioned medium. Moreover, EV-stimulated MSCs enhanced migration of renal tumor cells and induced vessel-like formation. In vivo, EV-stimulated MSCs supported tumor development and vascularization, when co-injected with renal tumor cells. In conclusion, CSC-derived EVs induced phenotypical changes in MSCs that are associated with tumor growth.
肾癌已被证明含有一群具有自我更新能力并支持肿瘤生长和转移的癌症干细胞（CSCs）。研究表明，CSCs会分泌大量细胞外囊泡（EVs），这些囊泡能够传递多种分子（蛋白质、脂质和核酸）并诱导靶细胞发生表观遗传变化。间充质基质细胞（MSCs）易受肿瘤信号影响，可被招募至肿瘤区域。由于既有促肿瘤作用又有抗肿瘤作用的报道，MSCs在肿瘤发展中的精确作用仍存在争议。在本研究中，我们分析了肾CSC来源的EVs在肿瘤与MSCs相互作用中的参与情况。我们发现，CSC来源的EVs促进了MSCs持续的表型变化，其特征是与细胞迁移（CXCR4、CXCR7）、基质重塑（COL4A3）、血管生成和肿瘤生长（IL-8、骨桥蛋白和髓过氧化物酶）相关的基因表达增加。EV刺激的MSCs在体外表现出向肿瘤条件培养基迁移的增强。此外，EV刺激的MSCs增强了肾肿瘤细胞的迁移并诱导了血管样形成。在体内，当与肾肿瘤细胞共同注射时，EV刺激的MSCs支持肿瘤发展和血管生成。总之，CSC来源的EVs诱导了与肿瘤生长相关的MSCs表型变化。
