TY  - THES
T1  - The role of Snail and Slug in invasion and cancer stem cell maintenance in glioblastoma multiforme
A1  - Goos,Sarah
Y1  - 2016/05/03
N2  - Glioblastoma multiforme (GBM) is the most common tumour of the central nervous system. Despite some progress in the therapy of the disease, patients still have a poor prognosis and a median survival of approximately 15 months. The biggest obstacle for successful surgical removal of glioblastoma is the high infiltration of invasive cancer cells throughout the brain. This makes it impossible to remove the complete tumour tissue, eventually resulting in relapse. Recent evidence suggests that glial-to-mesenchymal transition (GMT), a cellular program comparable to epithelial-to-mesenchymal transition (EMT), could play a major role in controlling the invasiveness of glioma cells. The transcription factors Snail and Slug are known to be major regulators of EMT in epithelial cancers. We therefore hypothesized that they may act as key components of GMT in glioma. Analysis of the expression of Snail and Slug in GBMs of different molecular subclasses revealed that these two EMT regulators are mainly expressed in the mesenchymal GBM subclass. By profiling a panel of signature markers we demonstrate that the combined loss of Snail and Slug impaired the TGFβ1-induced transition from a glial/proneural phenotype to a mesenchymal phenotype in GBM cells. Furthermore, we show that Snail and Slug play a crucial role in controlling glioblastoma stem cell properties, such as self-renewal and the expression of cancer stem cell markers. In line with their role in GMT, Snail and Slug silencing led to a severely impaired invasive behaviour of GBM cells in vitro. Importantly, we found that Snail and Slug silenced GBM cells showed significantly reduced tumour growth in an orthotopic mouse xenograft model. Detailed analysis revealed that the reduced growth did not result from changes in proliferation and apoptosis due to the silencing of Snail and Slug. Instead, the invasiveness of Snail and Slug silenced cells was drastically reduced. In summary, this work demonstrates that Snail and Slug are major regulators of GMT in glioma, controlling the transition from a glial/proneural to a mesenchymal phenotype. Importantly, the mesenchymal phenotype is closely connected to the adoption of invasive and stem cell properties indicating that these are the major mechanisms through which Snail and Slug regulate GBM growth. This improved understanding of GMT in glioma could help to optimize existing GBM treatments and provide a basis for the development of novel therapeutic strategies.	  
KW  - Glioblastoma multiforme
KW  - Snail
KW  - Slug
KW  - Krebsstammzellen
KW  - Invasion
CY  - Gießen
PB  - Universitätsbibliothek
AD  - Otto-Behaghel-Str. 8, 35394 Gießen
UR  - http://geb.uni-giessen.de/geb/volltexte/2016/12042
ER  -