Artikel
Monitoring antitumorigenic effects of differentiation on brain tumor stem cells in vivo using intravital microscopy
Suche in Medline nach
Autoren
-
M. Farhadi
- Neurochirurgische Klinik, Universitätsklinikum Heidelberg
-
B. Campos
- Neurochirurgische Klinik, Universitätsklinikum Heidelberg
-
V. Rosenstiel-Goidts
- DKFZ, Heidelberg
-
P. Beckhove
- DKFZ, Heidelberg
-
C. Herold-Mende
- Neurochirurgische Klinik, Universitätsklinikum Heidelberg
-
A. Unterberg
- Neurochirurgische Klinik, Universitätsklinikum Heidelberg
| Veröffentlicht: | 20. Mai 2009 |
|---|
Gliederung
Text
Objective: Brain Tumor Stem Cells (BTSCs) are held responsible for tumor initiation and therapy resistance in several brain tumors. Recently, differentiation of BTSCs has been discussed as a possible approach to eradicate this tumor-driving cell population disrooting the actively proliferating tumor bulk. However, the promising effects of such a differentiation therapy on BTSCs need to be tested in a preclinical animal system. For this purpose we aimed to develop an intravital microscopy analysis model to study the direct effect of differentiation on BTSCs in vivo.
Methods: NOD/SCID mice were subjected to partial craniotomy with removal of the underlying dura and replacement of the skull with a thin transparent plastic lid. BTSCs were stably transfected with green fluorescent protein (GFP) and grown as spheres comprising approximately 10000 cells. Two BTSC spheres were then implanted into the cranial window preparation over the right and left hemisphere, respectively. Animals received either 0,2mg differentiation-inducing retinoic acid (RA) in DMSO intraperitoneally (n=4) or solvent alone (n=4). Cell growth and migration as well as spheroid vascularisation were analyzed using multi-fluorescent intravital microscopy.
Results: Shortly after implantation BTSCs started to migrate on the brain surface. Animals treated with RA ,however, showed a significantly decreased invasiveness by up to 48% (p<0.05) after 6 days. Furthermore untreated BTSCs markedly influenced the surrounding blood vessels inducing elongation and dilatation of capillaries as well as recruitment of new vessel sprouts. This process was notably reduced in animals treated with RA however.
Conclusions: In our present work we tested intravital microscopy using GFP-transfected BTSCs as a model to study potential therapeutic approaches such as differentiation therapy in a preclinical animal setting. Not only could we show the efficacy of RA-induced differentiation to exert anti-invasive and anti-angiogenic effects on BTSCs in vivo but we were also able to establish a suitable in vivo system to test new therapeutic approaches to eradicate this tumor-driving cell population.
