Deregulation of the Wnt/ß-catenin/Tcf signaling pathway in astrocytomas

Abstract

Astrocytomas are the most common and deadliest primary brain tumors. Despite tremendous improvement in the understanding of molecular aspects of astrocytomas, these tumors have dismal prognosis. Astrocytomas develop as a result of stepwise accumulation of genetic alterations and the consequent disruption and augmentation of the apoptotic pathways and of survival signaling. Recent evidences suggest that neural stem cells and progenitor cells acts as source of brain tumors. The self-renewal and maintenance of neural progenitor cells is tightly regulated by the developmental pathways, particularly by Wnt signaling pathway. The aberrant operation of Wnt signaling may leads to the tumor development and its oncogenic role was evident in various human cancers. Recently, much interest is focused on the understanding of the role of Wnt signaling in astrocytomas and recent investigations provided the evidence that Wnt/ß- catenin/Tcf signaling pathway is deregulated in astrocytomas and contributed to malignant progression. The extracellular inhibitors of Wnt signaling such as sFRPs and Dickkopf family proteins were downregulated and hypermethylated in astrocytomas. Several Wnt proteins and their cognate receptors were activated and their overexpression promotes the proliferation of glioma cell lines. ß-Catenin is overexpressed in astrocytomas and progressively increased from low-grade to higher grades. Knockdown of ß-catenin resulted in the inhibition of proliferation and induction of apoptosis in glioblastoma cell lines. ß-Catenin transcriptional partners Lef1 and Tcf4 and their target genes were upregulated in astrocytomas and correlated with the histological grading of astrocytomas. In essence, Wnt/ß-catenin/Tcf is abnormally activated in astrocytomas and serves as a candidate therapeutic target for astrocytomas.