Cancer Stem Cells
Version of Record online: 22 MAY 2013
Copyright © 2013 AlphaMed Press
Volume 31, Issue 6, pages 1075–1085, June 2013
How to Cite
Ruiz-Ontañon, P., Orgaz, J. L., Aldaz, B., Elosegui-Artola, A., Martino, J., Berciano, M. T., Montero, J. A., Grande, L., Nogueira, L., Diaz-Moralli, S., Esparís-Ogando, A., Vazquez-Barquero, A., Lafarga, M., Pandiella, A., Cascante, M., Segura, V., Martinez-Climent, J. A., Sanz-Moreno, V. and Fernandez-Luna, J. L. (2013), Cellular Plasticity Confers Migratory and Invasive Advantages to a Population of Glioblastoma-Initiating Cells that Infiltrate Peritumoral Tissue. STEM CELLS, 31: 1075–1085. doi: 10.1002/stem.1349
Author contributions: P.R.-O.: collection of data and data analysis and interpretation; J.L.O.: collection of data and provision of study material; B.A., A.E.-A., M.T.B., J.A.M., L.G., L.N., S.D., and A.E.-O.: collection of data; J.M. and A.V.-B.: collection of data and provision of study patients; M.L., A.P., J.A.M.-C., and M.C.: data analysis and interpretation; V.S.: assembly of data; V.S.-M.: conception and design and data analysis and interpretation; J.L.F.-L.: conception and design, data analysis and interpretation, and manuscript writing.
Disclosure of potential conflicts of interest is found at the end of this article.
first published online in STEM CELLS EXPRESS February 8, 2013.
- Issue online: 22 MAY 2013
- Version of Record online: 22 MAY 2013
- Accepted manuscript online: 8 FEB 2013 09:25PM EST
- Manuscript Accepted: 19 JAN 2013
- Manuscript Received: 19 NOV 2012
- Instituto de Salud Carlos III (ISCIII)
- Spanish Ministry of Science and Innovation. Grant Numbers: PI10/02002, BFU2011-23983
- Red Temática de Investigación Cooperativa en Cáncer (RTICC). Grant Numbers: RD06/0020/0074, RD06/0020/0041, RD06/0020/0088, RD06/0020/0046
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED). Grant Number: CB06/05/0037
- Instituto de Formacion e Investigacion Marques de Valdecilla (IFIMAV). Grant Number: API2011-04
- Victoria Sanz-Moreno is a Cancer Research U.K. (CRUK). Grant Number: C33043/A12065
- Glioblastoma-initiating cells;
- Integrin αVβ3
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 αVβ3 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, β3 integrin is upregulated in PT cells. Blockade of dimeric integrin αVβ3, 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. STEM Cells 2013;31:1075–1085