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Review
. 2017 Mar;36(11):1461-1473.
doi: 10.1038/onc.2016.304. Epub 2016 Sep 12.

Wnt signaling in cancer

T Zhan  1   2 , N Rindtorff  1 , M Boutros  1   3
Affiliations
Review

Wnt signaling in cancer

T Zhan et al. Oncogene. 2017 Mar.

Abstract

Wnt signaling is one of the key cascades regulating development and stemness, and has also been tightly associated with cancer. The role of Wnt signaling in carcinogenesis has most prominently been described for colorectal cancer, but aberrant Wnt signaling is observed in many more cancer entities. Here, we review current insights into novel components of Wnt pathways and describe their impact on cancer development. Furthermore, we highlight expanding functions of Wnt signaling for both solid and liquid tumors. We also describe current findings how Wnt signaling affects maintenance of cancer stem cells, metastasis and immune control. Finally, we provide an overview of current strategies to antagonize Wnt signaling in cancer and challenges that are associated with such approaches.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Overview of canonical and non-canonical Wnt signaling. (a) In canonical Wnt signaling, absence of Wnt ligands (Wnt signaling inactive state, left) leads to phosphorylation of β-catenin by the destruction complex, which contains the scaffold protein Axin, APC and the kinases GSK3β and casein kinase (CK1α). In this state, β-catenin is phosphorylated by GSK3β, ubiquitinated by β-TrCP and targeted for proteasomal degradation. In the absence of nuclear β-catenin, a repressive complex containing TCF/LEF and transducing-like enhancer protein (TLE/Groucho) recruits HDACs to repress target genes. The canonical pathway is activated upon binding of secreted Wnt ligands (for example, Wnt3a and Wnt1) to Fzd receptors and LRP co-receptors (Wnt signaling active, right). LRP receptors are then phosphorylated by CK1α and GSK3β, which recruits Dishevelled (Dvl) proteins to the plasma membrane where they polymerize and are activated. The Dvl polymers inactivate the destruction complex, for example, by sequestration in multivesicular bodies. This results in stabilization and accumulation of β-catenin which then translocates into the nucleus. There, β-catenin forms an active complex with LEF (lymphoid enhancer factor) and TCF (T-cell factor) proteins by displacing TLE/Groucho complexes and recruitment of histone modifying co-activators such as CBP/p300, BRG1, BCL9 and Pygo (reviewed in Lien and Fuchs48). This transcriptional switch leads to a change of multiple cellular processes., (b) Non-canonical Wnt signaling is defined by β-catenin-independent mechanisms of signal transduction. During Wnt/PCP signaling, Wnt ligands bind to the ROR-Frizzled receptor complex to recruit and activate Dvl. Dvl binds to the small GTPase Rho by de-inhibition of the cytoplasmic protein DAAM1 (Dvl associated activator of morphogenesis 1). The small GTPase Rac1 and Rho together trigger ROCK (Rho kinase) and JNK. This leads to rearrangements of the cytoskeleton and/or transcriptional responses via for example, ATF2 (activating transcription factor 2). Next to Dvl, Vangl, a key member of Wnt/PCP signaling is activated by phosphorylation in a Wnt5a-dependent manner. Wnt/Ca2+ signaling is initiated by G-protein triggered phospholipase C activity leading to intracellular calcium fluxes and downstream calcium dependent cytoskeletal and/or transcriptional responses.
Figure 2
Figure 2
Mutation rates of Wnt pathway components in selected cancer entities. Percentage of cancer patients with mutations of selected canonical Wnt pathway related genes. Information was retrieved from the ICGC data portal (accessed 5/2016). The frequency of exonic mutations was determined based on cases with single nucleotide variant data in the MELA-AU, SKCA-BR, SKCM-US, PACA-US, PACA-CA, COAD-US, COCA-CN, READ-US, BRCA-UK and BRCA-US studies.
Figure 3
Figure 3
Currently tested pharmaceuticals targeting the Wnt pathway in cancer. Schematic representation of the canonical Wnt signaling pathway with pharmaceutical modulators. All depicted drugs are currently undergoing testing in Phase 1/2 against various types of cancer (see also Table 1).
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