Artikel
The role of canonical WNT/beta-catenin signaling in glial brain tumors
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Autoren
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J. Maciaczyk
- University Medical Center Freiburg, Department of General Neurosurgery, Freiburg Brain Tumor Stem Cell Research Group, Freiburg, Germany
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U. Kahlert
- University Medical Center Freiburg, Stereotactic Neurosurgery, Freiburg Brain Tumor Stem Cell Research Group, Freiburg, Germany
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D. Maciaczyk
- University Medical Center Freiburg, Stereotactic Neurosurgery, Freiburg Brain Tumor Stem Cell Research Group, Freiburg, Germany
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B. Simons
- Johns Hopkins Medical Institutions, Department of Pathology, Baltimore, MD, USA
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B. Orr
- Johns Hopkins Medical Institutions, Department of Pathology, Baltimore, MD, USA
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C. Eberhart
- Johns Hopkins Medical Institutions, Department of Pathology, Baltimore, MD, USA
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G. Nikkhah
- University Medical Center Freiburg, Stereotactic Neurosurgery, Freiburg Brain Tumor Stem Cell Research Group, Freiburg, Germany
| Veröffentlicht: | 28. April 2011 |
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Gliederung
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Objective: The canonical WNT/β-catenin pathway plays an important role in embryo- and carcinogenesis. Although β-catenin has been abnormally expressed in a variety of human cancers, little is known about its involvement in the biology of glial tumors. In this project the role of WNT/β-catenin signalling in tumorigenesis of glial brain tumors, focused on migratory properties and invasiveness of the brain tumor stem-like cells (BTSC) has been investigated.
Methods: The intrinsic activity of WNT/β-catenin pathway in a collection of paediatric and adult gliomas has been assessed using tissue microarray technique in paraffin embedded tumor samples. Additionally, we established a lentiviral transfection system with a point-mutated β-catenin and human DICKKOPF (DKK1) under EF1alpha or CMV promoter enabling to genetically modify patient-derived glioma cultures and select for transfected cells based on eGFP expression. The quantitative gene expression analysis of the pathway-related downstream genes and stem cell-related genes has been performed according to a standard real-time qPCR protocol. The migration and invasion of the transfected cells have been assessed in Boyden Chamber-based in vitro assay.
Results: The histological evaluation of glial tumor samples (WHO grade II-IV) revealed about 15% of all specimens showing active WNT/β-catenin signaling, as assessed by the intranuclear β-catenin staining. The lentiviral β-catenin transfection resulted in an efficient overexpression of downstream terget genes i.e AXIN2 (up to 150-fold increase) as well as stem cell-related genes i.e. CD133, Nanog and Nestin (up to 4-fold increase) as compared to wild-type cells indicating an efficient pathway activation and induction of BTSC. Transfected cells displayed significantly higher (up tp 4-fold) in vitro migration and invasion as compared to control cells.
Conclusions: The activation of WNT/β-catenin pathway leads to overexpression of stem cell-related genes and to significant increase of the in vitro migration and invasion of patient-derived glioma cultures. This might be responsible for the invasive growth of gliomas making them refractory to common treatment regimes. Therefore, better understanding of the regulation of WNT/β-catenin signalling in the glial brain tumors, with special emphasis on BTSC might contribute to the development of novel therapies aiming at the elimination of the migratory cell subpopulation by pathway inhibition.
