Department of Obstetrics and Gynecology and Reproductive Science, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Stem Cells. 2009 Oct;27(10):2405-13. doi: 10.1002/stem.191.
Neovascularization is required for solid tumor maintenance, progression, and metastasis. The most described contribution of cancer cells in tumor neovascularization is the secretion of factors, which attract various cell types to establish a microenvironment that promotes blood vessel formation. The cancer stem cell hypothesis suggests that tumors are composed of cells that may share the differentiation capacity of normal stem cells. Similar to normal stem cells, cancer stem cells (CSCs) have the capacity to acquire different phenotypes. Thus, it is possible that CSCs have a bigger role in the process of tumor neovascularization. In this study, we show the capacity of a specific population of ovarian cancer cells with stem-like properties to give rise to xenograft tumors containing blood vessels, which are lined by human CD34+ cells. In addition, when cultured in high-density Matrigel, these cells mimic the behavior of normal endothelial cells and can form vessel-like structures in 24 hours. Microscopic analysis showed extensive branching and maturation of vessel-like structures in 7 days. Western blot and flow cytometry analysis showed that this process is accompanied by the acquisition of classic endothelial markers, CD34 and VE-cadherin. More importantly, we show that this process is vascular endothelial growth factor-independent, but IKK beta-dependent. Our findings suggest that anti-angiogenic therapies should take into consideration the inherent capacity of these cells to serve as vascular progenitors.
血管生成对于实体瘤的维持、进展和转移是必需的。癌细胞在肿瘤血管生成中最被描述的贡献是分泌因子，这些因子吸引各种细胞类型形成促进血管形成的微环境。癌症干细胞假说表明，肿瘤由可能具有正常干细胞分化能力的细胞组成。与正常干细胞相似，癌症干细胞（CSC）具有获得不同表型的能力。因此，CSC 可能在肿瘤血管生成过程中发挥更大的作用。在这项研究中，我们展示了具有干细胞样特性的特定卵巢癌细胞群体产生含有由人 CD34+细胞衬里的血管的异种移植肿瘤的能力。此外，当在高密度 Matrigel 中培养时，这些细胞模拟正常内皮细胞的行为，并在 24 小时内形成类似血管的结构。显微镜分析显示，在 7 天内血管样结构广泛分支和成熟。Western blot 和流式细胞术分析表明，这一过程伴随着经典内皮标记物 CD34 和 VE-cadherin 的获得。更重要的是，我们表明这个过程不依赖血管内皮生长因子，而是依赖 IKK beta。我们的研究结果表明，抗血管生成疗法应该考虑到这些细胞作为血管祖细胞的固有能力。
