Front.mol neurosci-WNT signaling for neurogenesis and brain tumorigenesis

Neurogenesis refers to the production of neurons from neuroepithelial cells, nervous system stem cells called neural stem cells (NSCs).

NSCs have a typical bipolar shape with the apical plasma membrane lining the lumen of the neural tube, while the basal plasma membrane is adjacent
to the basal lamina.
Prior to neurogenesis, NSCs expanded their populations
by symmetrical proliferative division.
At the onset of neurogenesis, NSCs are transformed into apical radial glial cells (aRGs).

A subset of aRG cells switches to asymmetrically differentiated cell division to generate neurons
directly or by producing intermediate progenitor cells (IPCs) and basal radial glial cells (bRGs).
Active neurogenesis occurs in two main regions, the SVZ of the lateral ventricle and the subgranular region (SGZ)
of the toothed gyrus of the hippocampus.
Primary brain tumors
occur when nerve cells experience uncontrolled cell division in the brain parenchyma.

Neurogenesis and tumorigenesis share signaling molecules/pathways
involved in cell proliferation, differentiation, migration, and death.
The self-renewal of neural stem cells is a tightly regulated process that ensures the accuracy of cell division and eliminates cells
that undergo mitotic errors.
Abnormalities in the molecular mechanisms that control this process can trigger aneuploidy and genomic instability, leading to tumor transformation
.
Mutations that affect cell adhesion, polarity, or migration enhance invasion potential and favor tumor progression
.
The authors from Hamad bin Khalifa University, Qatar Foundation, review the latest evidence on the involvement of the WNT pathway in neurogenesis and tumorigenesis and discuss experimental advances
in therapeutic opportunities targeting components of this pathway.
Study results

01Role of the WNT signaling pathway in neurogenesis and brain tumorigenesis

WNT ligands (19 members in mammals) are secreted proteins that activate different intracellular signal transduction pathways and regulate tissue growth and renewal
.
The classical pathway, also known as the WNT/β-catenin pathway, is highly conserved and regulates stem cell proliferation, while the nonclassical WNT pathway (defined as not dependent on β-catenin) regulates cell polarity, shape, and migration
.
Figure 1 Overview of the WNT signaling path

WNT/β-catenin regulates the balance
between germinal proliferative/symmetric and neurogenic/asymmetric division.
However, the role of classical WNT/β-catenin signaling in neurogenesis is complex
.
This depends on the model, the target component, and the upper level
of the manipulation pathway.
Gene ablation of β-catenin triggers cell cycle withdrawal and premature neuronal differentiation, whereas overexpression of constitunatically active β-catenin or inactivation of glycogen synthase kinase 3 (GSK3) promotes proliferation of apical progenitor cells at the expense of differentiation, thereby reducing the number of
intermediate progenitor cells.

However, the WNT pathway has multiple key roles in neurogenesis (Figure 2), and some conclusions related to the decision of neural stem cells to proliferate or differentiate during neuronal development are contradictory
.
Figure 2 Role of WNT components in neurogenesis

Epithelial-mesenchymal transition (EMT) is a biological process
that plays a key role in cancer invasion.
Cells adopt a migration phenotype
by losing the expression of adhesion molecules and apical-lateral lateral polarity and acquiring the molecular signature of stem cells.
Glioma cells are thought to stimulate adjacent astrocytes for EMT
by degrading the extracellular matrix and promoting tumor aggressiveness by activating WNT/β-catenin.
WNT signaling inhibits GSK3β to stabilize β-catenin, which translocates to the nucleus and promotes gene transcription in favor of EMT
.
During this transition, cells use metalloproteinases to degrade the basement membrane, change their polarity, rearrange the cytoskeleton, and migrate
.

In addition to its role in glioblastoma (GBM) initiation, WNT dysregulation is associated with
GBM progression.
This dysregulation may be due to genetic alterations in transcription factors such as FOXM1 and PLAGL2, which promote nuclear translocation of β-catenin and activate the classical WNT pathway
in GBM.
WNT signaling can be activated by oncogenes such as WNTless (WLS/Gpr177), which are highly expressed in GBM and involved in the secretion
of WNT ligands.

Figure 3 Targeting WNT signaling in glioblastoma therapy

02WNT signaling as a therapeutic target

As different genomic studies have shown, glioblastoma tumors are characterized by genetic and molecular intratumor heterogeneity
.
Multiple genes in the WNT signaling pathway are one of the prognostic factors for the specificity of GBM mesenchymal subtypes, reflecting GBM heterogeneity and the important role
between WNT and other GBM drivers.

The WNT pathway is a multifaceted target in brain tumors and can be a tool
to combat tumor stemness, aggressiveness, angiogenesis and therapeutic resistance.
Inhibitors targeting upstream modifiers, FZD receptors, and DVL target classical and nonclassical pathways, while downstream inhibitors target β-catenin
associated with tumorigenesis.
Therapies used or developed clinically fall into one of three categories: nonsteroidal anti-inflammatory drugs, small molecule chemical inhibitors, and antibodies
that target various components of the WNT pathway.

Figure 3 Drugs targeting different components of WNT signaling

In summary, targeting the WNT signaling pathway to develop drugs presents a great challenge, and identifying effective drugs to correct their imbalanced activity while maintaining physiological functions such as tissue homeostasis, stem cell renewal and survival requires more research and trials to determine
.