RESUMO
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 αVß3 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, ß3 integrin is upregulated in PT cells. Blockade of dimeric integrin αVß3, 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.
Assuntos
Neoplasias Encefálicas/patologia , Movimento Celular/fisiologia , Glioblastoma/patologia , Células-Tronco Neoplásicas/patologia , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/genética , Embrião de Galinha , Regulação para Baixo , Feminino , Glioblastoma/genética , Glioblastoma/metabolismo , Xenoenxertos , Humanos , Integrina alfaVbeta3/genética , Integrina alfaVbeta3/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Invasividade Neoplásica , Células-Tronco Neoplásicas/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas , Regulação para Cima , Proteínas rac de Ligação ao GTP/genética , Proteínas rac de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
Cancer initiating cells have been described to be the only cell population with tumorigenic capacity in glioblastoma multiforme, one of the most aggressive and untreatable cancers. Recent work from our group described that NFκB pathway was activated in glioblastoma initiating cells undergoing differentiation, and that blockade of this activation promoted senescence of differentiating cells. NFκB activation in cancer may be the result of either exposure to proinflammatory stimuli in the tumor microenvironment or upregulation of the signaling pathway by upstream regulators. Appropriate control of NFκB activity, which can be achieved by gene modification or pharmacological strategies, would provide a potential approach for the management of NFκB related tumors, including glioblastoma. Here, we summarize the current knowledge of the relevance of NFκB in cancer and its possible role as a target of therapeutic intervention..
