Artikel
Functional activation of the Wnt signalling pathway in medulloblastoma cell lines.
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Autoren
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Maren Bradtmöller
- Charite Universitätsmedizin Berlin, Institute of Neuropathology, Berlin, Germany
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Katrin Guse
- Charite Universitätsmedizin Berlin, Institute of Neuropathology, Berlin, Germany
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Werner Stenzel
- Charite Universitätsmedizin Berlin, Institute of Neuropathology, Berlin, Germany
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Thomale Ulrich
- Charite Universitätsmedizin Berlin, Pediatric Neurosurgery, Berlin, Germany
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Frank Heppner
- Charite Universitätsmedizin Berlin, Institute of Neuropathology, Berlin, Germany
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Arend Koch
- Charite Universitätsmedizin Berlin, Institute of Neuropathology, Berlin, Germany
| Veröffentlicht: | 11. September 2012 |
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Gliederung
Text
Medulloblastoma (MBs) are the most frequent malignant brain tumors of childhood. The Wnt signalling pathway, which controls important regulatory mechanisms in stem cell biology and development, plays also an important role in the pathology of a subset of these malignant embryonic tumors. In particular, it has been shown that genetic alterations in genes which codes for important regulatory components of the Wnt multiproteincomplex (β-catenin-, AXIN2- mutations) results in a pathological activation of this pathway. To understand the mechanism how the pathological activated Wnt signalling pathway regulates MB formation and progression, further functional in vitro and in vivo analysis is essential.
As, to our knowledge, no medulloblastoma cells with a constitutive active Wnt pathway are available for further functional analysis. For this reason we generated three human medulloblastoma cell lines in which the Wnt pathway was activated by stable lentiviral infection of mutated β-catenin. In brief, we constructed a lentiviral vector that expresses an activated form of human β-catenin,because of an N-terminal Deletion (ΔN131). Wnt pathway activation within the stable Δβ-catenin infected cells was confirmed by an over expression of the Wnt dependent target gene AXIN2 and an elevated TCF-responsive-luciferase reporter activity.
To investigate whether Wnt activation in medulloblastoma cells is sufficient to influence the cell metabolism, we started to analyse the activated cells for proliferation, differentiation and migration. Using an impedance technology, the xcelligence system, we found that Wnt activation results in reduced proliferative activity of the activated medulloblastoma cells.
Taken our data together, we generated three human medulloblastoma cell lines in which the Wnt pathway is constantly active. This system allows us to further investigate the Wnt-medulloblastoma subgroup in vitro concerning cell differentiation and migration. Furthermore, it allows us to use these medulloblastoma cells in xenograft mouse models to generate treatment options with Wnt-antagonists.
