Potential Canonical Wnt Pathway Activation in High-Grade Astrocytomas

Abstract EN

Aberrant wnt pathway activation through cytoplasmic stabilization of β-catenin is crucial for the development of various human malignancies.

In gliomagenesis, the role of canonical (i.e., β-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 β-catenin accumulation.

Furthermore, we assessed the prognostic relevance of β-catenin expression in a tissue microarray comprising 283 astrocytomas.

Expression of β-catenin, its transcriptional cofactors TCF-1 and TCF-4 as well as GSK-3β and APC, constituents of the β-catenin degradation complex was confirmed by RT-PCR in all cultures.

A cytoplasmic β-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 β-catenin and APC leading to cytoplasmic stabilization of β-catenin were excluded by direct sequencing or protein truncation test.

In patient tissues, β-catenin expression was directly and its degradation product's (β-catenin-P654) expression was inversely correlated with WHO grade.

Increased β-catenin expression and low β-catenin-P654 expression were associated with shorter survival.

Altogether, we report on potential canonical wnt pathway activation in high-grade gliomas and demonstrate that β-catenin expression in astrocytomas is associated with increased malignancy and adverse outcome.