Potential Canonical Wnt Pathway Activation in High-Grade Astrocytomas

Aberrant wnt pathway activation through cytoplasmic stabilization of beta-catenin is crucial for the development of various human malignancies. In gliomagenesis, the role of canonical (i.e., beta-catenin-dependent) signalling is largely unknown. Here, we studied canonical wnt pathway activation in 15 short-term cultures from high-grade gliomas and potential pathomechanisms leading to cytoplasmic beta-catenin accumulation. Furthermore, we assessed the prognostic relevance of beta-catenin expression in a tissue microarray comprising 283 astrocytomas. Expression of beta-catenin, its transcriptional cofactors TCF-1 and TCF-4 as well as GSK-3 beta and APC, constituents of the beta-catenin degradation complex was confirmed by RT-PCR in all cultures. A cytoplasmic beta-catenin pool was detectable in 13/15 cultures leading to some transcriptional activity assessed by luciferase reporter gene assay in 8/13. Unlike other malignancies, characteristic mutations of beta-catenin and APC leading to cytoplasmic stabilization of beta-catenin were excluded by direct sequencing or protein truncation test. In patient tissues, beta-catenin expression was directly and its degradation product's (beta-catenin-P654) expression was inversely correlated with WHO grade. Increased beta-catenin expression and low beta-catenin-P654 expression were associated with shorter survival. Altogether, we report on potential canonical wnt pathway activation in high-grade gliomas and demonstrate that beta-catenin expression in astrocytomas is associated with increased malignancy and adverse outcome.