The physiological role of Wnt pathway in normal development and cancer

Abstract

Over the decades, many studies have illustrated the critical roles of Wnt signaling pathways in both developmental processes as well as tumorigenesis. Due to the complexity of Wnt signaling regulation, there are still questions to be addressed about ways cells are able to manipulate different types of Wnt pathways in order to fulfill the requirements for normal or cancer development. In this review, we will describe different types of Wnt signaling pathways and their roles in both normal developmental processes and their role in cancer development and progression. Additionally, we will briefly introduce new strategies currently in clinical trials targeting Wnt signaling pathway components for cancer therapy.

Impact statement: Wnt pathway does not only play a critical role in mammalian development but has been hijacked by cancer cells and the tumor microenvironment to promote tumor progression and metastasis. Recent evidence supports further interrogation of the Wnt pathway for bench-to-bedside translation into cancer therapy. This review highlights the role of the Wnt pathway in normal development and tumorigenesis, along with an overview of new therapies currently undergoing clinical trials.

Keywords: Wnt signaling; development; tumorigenesis.

Figure 1.

Crystal structure of the Wnt–Frizzled binding complex. Overall cryo-EM structure of the interaction between X. laevis Wnt8 and the CRD of Frizzled 8 receptor, shown in a ‘face on’ presentation. Purple: the core of the X. laevis Wnt8. Deep purple: lipid thumb domain on the amino-terminal (N-terminal) of the X. laevis Wnt8. Light pink: The index finger domain on the carboxy-terminal of the X. laevis Wnt8. Red: the palmitoleic acid motif on the X. laevis Wnt8. Yellow: N-glycans motifs on the X. laevis Wnt8. Blue: The CRD of the Frizzle 8 receptor. Source: Figure cited from Niehrs. CRD: cysteine rich domain; PAM: palmitoleic acid motif.

Figure 2.

Wnt signaling pathways. (a) In the absence of Wnt molecules, the canonical Wnt/β-catenin pathway is inactivated due to the existence of the β-catenin destruction complex, which is made of scaffold protein APC, Axin, Hippo pathway proteins YAP–TAZ, and kinases CK1a, GSK3a/b. The destruction complex mediates β-catenin phosphorylation for its following proteasome degradation. The canonical Wnt pathway can be negatively regulated by extracellular Wnt-binding protein like sFRPs, or by proteins like Dkk1 that downregulate membrane co-receptors (LRP5/6) of the canonical pathway. (b) In the presence of canonical Wnt molecules, Wnt binding to Fzd receptors promotes dimerization of the Fzd receptor to its co-receptor LRP5/6. Then, LRP5/6 recruits components of the β-catenin destruction complex to its cellular carboxy-terminal tails, which dissociates the destruction complex and leads to β-catenin stabilization and accumulation in cells to allow β-catenin nuclear translocation for its mediated downstream transcriptional responses. Also, the dissociation of the destruction complex prevents GSK3a/b’s substrates phosphorylation and degradation, which is called Wnt–STOP mechanism. (c) In the presence of non-canonical Wnt molecules, Wnt binding to Fzd receptors promotes dimerization of the Fzd receptor to variable types of co-receptors for recruitment of the adaptor protein DVL. The recruitment of DVL triggers multiple β-catenin independent non-canonical downstream events to mediate cellular actin remodeling processes, variable types of transcriptional responses, or canonical Wnt pathway downregulations. (d) For multiple types of cancers, a novel Wnt5a-mediated non-canonical pathway is found to mediate the EMT. In this pathway, Wnt5A binding to Frizzled-2 receptors activates Src family kinases Fyn by promoting its phosphorylation. Then, Fyn activates the STAT3 to trigger STAT3-mediated EMT processes. This non-canonical pathway is negatively regulated by Abl interactor 1 (ABI1). ABI1 can directly interact with either Fyn or STAT3, although roles of these interactions in regulating the Wnt5a–STAT3 pathway remain unknown. (A color version of this figure is available in the online journal.) Source: Figure modified from Wang et al. and Murillo-Garzon and Kypta. DVL: Dishevelled; EMT: epithelial–mesenchymal-transition; JNK: JUN-N-terminal kinase; LATS1: larger tumor suppressor 1; LATS2: larger tumor suppressor 2; LGR: leucine-rich repeat-containing G-protein coupled receptor; LRP: lipoprotein receptor related protein; RNF43: ring finger protein 43; ROCK: Rho-associated kinase; sFRP: secreted frizzled related protein; ZNRF3: zinc and ring finger 3.

Figure 3.

Roles of Wnt/β-catenin pathways in early X. laevis embryo body axis formation. The post-fertilization cortical rotation (black dotted arrow) leads to early accumulation of maternal β-catenin in the dorsal equatorial region, which activates canonical Wnt pathway genes to generate the Spemann organizer. At the same time, several Wnt antagonists are upregulated at the dorsal site and translocated to the anterior site to inhibit anterior activation of canonical Wnt pathway for anterior site development. During gastrulation, the zygotic activation of the canonical Wnt8 molecule leads to asymmetric β-catenin accumulation, specifically in the ventral and posterior sites of the embryo. The ventral and posterior activation of the canonical Wnt pathway upregulates genes important for ventroposterior mesodermal fate determination and subsequent tail formation. (A color version of this figure is available in the online journal.) Source: Figure modified from McMahon and Moon and Hikasa and Sokol.

Figure 4.

Roles of Wnt/β-catenin pathways in mice embryo somitogenesis and left–right axis determination. The expression of canonical Wnt3a molecules along the primitive streak upregulates the transcription factor T which sustains mesoderm production. In addition, the canonical Wnt3a pathway initiates the expression of the Notch pathway ligand Dll1 to regulate somitogenesis in the adjacent PSM. The expression of Dll1 in the PSM also mediates Nodal expression at the periphery of the node by activating the Notch signaling pathway. The leftward flow generated by rotating nodal cilia leads to left side Nodal accumulation to eventually enhance Nodal signaling on the left side for left–right body axis determination. (A color version of this figure is available in the online journal.) Source: Figure modified from Barker et al. and Wang et al. LPM: lateral plate mesoderm; PSM: paraxial presomitic mesoderm.

Figure 5.

Drugs targeting Wnt pathways in cancer treatments. All depicted drugs are currently undergoing phase1/2 clinical trials against various types of cancers. (A color version of this figure is available in the online journal.) LRP 5/6: lipoprotein receptor related protein 5/6.