PURPOSE: Medulloblastomas represent the most frequent malignant brain tumors of 
childhood. They are supposed to originate from cerebellar neural precursor 
cells. Recently, it has been shown that Sonic Hedgehog-induced formation of 
medulloblastoma in an animal model is significantly enhanced by activation of 
the phosphatidylinositol 3'-kinase (PI3K) signaling pathway.
EXPERIMENTAL DESIGN: To examine a role for PI3K/AKT signaling in the molecular 
pathogenesis of human medulloblastoma, we did an immunohistochemical study of 
the expression of Ser473-phosphorylated (p)-AKT protein in 22 medulloblastoma 
samples: All samples displayed p-AKT expression. To investigate if an activated 
PI3K/AKT pathway is required for medulloblastoma cell growth, we treated five 
human medulloblastoma cell lines with increasing concentrations of the PI3K 
inhibitor LY294002 and analyzed cellular proliferation and apoptosis. The 
antiproliferative effect could be antagonized by overexpressing constitutively 
active AKT. As the activation of PI3K/AKT signaling may be associated with 
alterations of the PTEN gene located at 10q23.3, a chromosomal region subject to 
frequent allelic losses in medulloblastoma, we screened PTEN for mutations and 
mRNA expression.
RESULTS: Proliferation of all of the medulloblastoma cell lines was dependent on 
PI3K/AKT signaling, whereas apoptosis was not prominently affected. Allelic loss 
was detected in 16% of the cases. One medulloblastoma cell line was found to 
carry a truncating mutation in the PTEN coding sequence. Even more important, 
PTEN mRNA and protein levels were found to be significantly lower in 
medulloblastomas compared with normal cerebellar tissue of different 
developmental stages. Reduction of PTEN expression was found to be associated 
with PTEN promoter hypermethylation in 50% of the tumor samples.
CONCLUSIONS: We conclude that activation of the PI3K/AKT pathway constitutes an 
important step in the molecular pathogenesis of medulloblastoma and that 
dysregulation of PTEN may play a significant role in this context.