WNT signaling in glioblastoma and therapeutic opportunities

Abstract

WNTs and their downstream effectors regulate proliferation, death, and migration and cell fate decision. Deregulation of WNT signaling is associated with various cancers including GBM, which is the most malignant primary brain cancer. In this review, we will summarize the experimental evidence supporting oncogenic roles of WNT signaling in GBM and discuss current progress in the targeting of WNT signaling as an anti-cancer approach. In particular, we will focus on (1) genetic and epigenetic alterations that lead to aberrant WNT pathway activation in GBM, (2) WNT-mediated control of GBM stem cell maintenance and invasion, and (3) cross-talk between WNT and other signaling pathways in GBM. We will then review the discovery of agents that can inhibit WNT signaling in preclinical models and the current status of human clinical trials.

Wnt5a Drives an Invasive Phenotype in Human Glioblastoma Stem-like Cells

“…Findings on Wnt5a roles and functions in these tumors are restricted to the observed increased motility in cultured cell lines (25,27). Recently, however, it has been shown that the enhanced migration caused in hGBMs by reduced Wnt inhibitor 1 activity is mediated by Wnt5a (48).…”

“…It has been shown that Wnt5a is overexpressed in high-grade gliomas, but the role for Wnt5a in regulating proliferation and migration in gliomas has only been demonstrated, in a few cell lines, in vitro (23)(24)(25)(26)(27). Here, we explore whether Wnt5a can function as a master regulator of the invasive capacity of hGBMs.…”

Wnt/FZD Genetics in Glioblastoma

“…Epigenetic changes including promoter hypermethylation reduce the expression of these inhibitors and, as a consequence, there is a hyperactivation of WNT/FZD signalling. In turn, this effect yields to β-cat activation in GBM cells and contributes to tumor progression (reviewed in [14]). …”

The role of micro-RNA in the regulation of signal pathways in gliomas

“…Комбинированная гипорегуляция SFRP1 одновременно с гиперрегуляцией SFRP4 и FZD7 значительно снижала медиану выживаемости пациентов с глиомами [41]. Эпигенетические изменения играют бóльшую роль в активации Wnt-сигналинга, чем геномные мутации [42].…”