期刊
STEM CELLS
卷 31, 期 6, 页码 1075-1085出版社
WILEY-BLACKWELL
DOI: 10.1002/stem.1349
关键词
Glioblastoma-initiating cells; Invasion; Integrin alpha V beta 3
资金
- Instituto de Salud Carlos III (ISCIII)
- Spanish Ministry of Science and Innovation [PI10/02002, BFU2011-23983]
- programs Red Tematica de Investigacion Cooperativa en Cancer (RTICC) [RD06/0020/0074, RD06/0020/0041, RD06/0020/0088, RD06/0020/0046]
- Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) [CB06/05/0037]
- Instituto de Formacion e Investigacion Marques de Valdecilla (IFIMAV) [API2011-04]
- [C33043/A12065]
- Cancer Research UK [12065] Funding Source: researchfish
Glioblastoma (GBM) is associated with infiltration of peritumoral (PT) parenchyma by isolated tumor cells that leads to tumor regrowth. Recently, GBM stem-like or initiating cells (GICs) have been identified in the PT area, but whether these GICs have enhanced migratory and invasive capabilities compared with GICs from the tumor mass (TM) is presently unknown. We isolated GICs from the infiltrated PT tissue and the TM of three patients and found that PT cells have an advantage over TM cells in two-dimensional and three-dimensional migration and invasion assays. Interestingly, PT cells display a high plasticity in protrusion formation and cell shape and their migration is insensitive to substrate stiffness, which represent advantages to infiltrate microenvironments of different rigidity. Furthermore, mouse and chicken embryo xenografts revealed that only PT cells showed a dispersed distribution pattern, closely associated to blood vessels. Consistent with cellular plasticity, simultaneous Rac and RhoA activation are required for the enhanced invasive capacity of PT cells. Moreover, Rho GTPase signaling modulators alpha V beta 3 and p27 play key roles in GIC invasiveness. Of note, p27 is upregulated in TM cells and inhibits RhoA activity. Gene silencing of p27 increased the invasive capacity of TM GICs. Additionally, beta 3 integrin is upregulated in PT cells. Blockade of dimeric integrin alpha V beta 3, a Rac activator, reduced the invasive capacity of PT GICs in vitro and abrogated the spreading of PT cells into chicken embryos. Thus, our results describe the invasive features acquired by a unique subpopulation of GICs that infiltrate neighboring tissue.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据