Abstract
Wnt is a complex signaling pathway involved in the regulation of crucial biological functions such as development, proliferation, differentiation and migration of cells, mainly stem cells, which are virtually present in all embryonic and adult tissues. Conversely, dysregulation of Wnt signal is implicated in development/progression/invasiveness of different kinds of tumors, wherein a certain number of multipotent cells, namely “cancer stem cells”, are characterized by high self-renewal and aggressiveness. Hence, the pharmacological modulation of Wnt pathway could be of particular interest, especially in tumors for which the current standard therapy results to be unsuccessful. This might be the case of glioblastoma multiforme (GBM), one of the most lethal, aggressive and recurrent brain cancers, probably due to the presence of highly malignant GBM stem cells (GSCs) as well as to a dysregulation of Wnt system. By examining the most recent literature, here we point out several factors in the Wnt pathway that are altered in human GBM and derived GSCs, as well as new molecular strategies or experimental drugs able to modulate/inhibit aberrant Wnt signal. Altogether, these aspects serve to emphasize the existence of alternative pharmacological targets that may be useful to develop novel therapies for GBM.
Highlights
General Outline of the Wnt PathwaysThe Wnt pathway is currently recognized as an important regulatory signal able to influence developmental embryonic processes [1] and to modulate self-renewal, maintenance and differentiation of adult tissue stem cells [2,3]
Since the recurrence of glioblastoma multiforme (GBM) is likely due to the presence of a population of cancer stem cells (CSCs) named GBM stem cells (GSCs), with features similar to normal neural stem cells (NSCs), here we examined the role of Wnt signaling in the processes involved in the growth and maturation, up to the adult life, of the nervous system formation, or in the development and expansion of GBM
As for GBM, Kahlert et al [82] showed that the modulation of Wnt signaling altered the expression of epithelial-to-mesenchymal transition (EMT) activators and, more recently, another group showed that resveratrol, a drug able to impair GSC
Summary
The Wnt pathway is currently recognized as an important regulatory signal able to influence developmental embryonic processes [1] and to modulate self-renewal, maintenance and differentiation of adult tissue stem cells [2,3]. Binding of Wnt proteins to the FZD receptors activates, via DVL, small GTPases, Rho and Rac, and JNK kinase The activation of this signaling cascade leads to changes in the cytoskeleton and activation of transcription factors of activator protein-1 (AP-1) family. Since the recurrence of GBM is likely due to the presence of a population of cancer stem cells (CSCs) named GBM stem cells (GSCs), with features similar to normal neural stem cells (NSCs), here we examined the role of Wnt signaling in the processes involved in the growth and maturation, up to the adult life, of the nervous system formation, or in the development and expansion of GBM For this reason, we tried to highlight the role of several factors associated to Wnt system dysregulation in this tumor, thereby supporting GBM onset and progression. We discussed the possibility to consider those factors as alternative pharmacological targets for the therapeutic management and control of this tumor
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