CoChat
Sign Up
Cited by 2,626Wnt/β-catenin signaling in development and cancerCancer Cells and MetastasisHedgehog Signaling Pathway Studies

The DOI matches its Crossref record; 212 of the 213 references it cites were found in a registry or an index.

Wnt signaling in cancer

Open access
Zhan, T, Rindtorff, N, Boutros, M·2017·Oncogene
DOI 10.1038/onc.2016.304PMC PMC5357762
Open this paper in CoChat — free accountOpen PDF

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.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/onc.2016.304

Cites

212 of 212 references verified0 citation errors · 0 not checkable

Statistics

Figures

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-TrCP200 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.201 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.49, 202 (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.203 Dvl binds to the small GTPase Rho by de-inhibition of the cytoplasmic protein DAAM1 (Dvl associated activator of morphogenesis 1).204 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).205 Next to Dvl, Vangl, a key member of Wnt/PCP signaling is activated by phosphorylation in a Wnt5a-dependent manner.206 Wnt/Ca2+ signaling is initiated by G-protein triggered phospholipase C activity207 leading to intracellular calcium fluxes and downstream calcium dependent cytoskeletal and/or transcriptional responses.208
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-TrCP200 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.201 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.49, 202 (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.203 Dvl binds to the small GTPase Rho by de-inhibition of the cytoplasmic protein DAAM1 (Dvl associated activator of morphogenesis 1).204 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).205 Next to Dvl, Vangl, a key member of Wnt/PCP signaling is activated by phosphorylation in a Wnt5a-dependent manner.206 Wnt/Ca2+ signaling is initiated by G-protein triggered phospholipase C activity207 leading to intracellular calcium fluxes and downstream calcium dependent cytoskeletal and/or transcriptional responses.208CC BY-NC-ND · PubMed Central
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 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.CC BY-NC-ND · PubMed Central
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).
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).CC BY-NC-ND · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Research works printed but not linked: 4

  1. Sharma R . Wingless, a new mutant in D. melanogaster. Drosoph Inf Serv 1973; 50: 134.
  2. Yeung J, Esposito MT, Gandillet A, Zeisig BB, Griessinger E, Bonnet D et al. Beta-catenin mediates the establishment and drug resistance of MLL leukemic stem cells. Cancer Cell 2010; 18: 606–618. · DOI
  3. Luga V, Zhang L, Viloria-Petit AM, Ogunjimi A a, Inanlou MR, Chiu E et al. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell 2012; 151: 1542–1556. · DOI · Paper page
  4. van de Wetering M, Francies HE, Francis JM, Bounova G, Iorio F, Pronk A et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 2015; 161: 933–945. · DOI · Paper page

Cited by

Sorted by citations

See all 2,626

Related

See all

Metadata

Authors
Zhan, T., Rindtorff, N., & Boutros, M.
Affiliations
German Cancer Research Center (DE)
Corresponding author
Boutros, M
ORCID
Venue
Oncogene
Publisher
Springer Science and Business Media LLC
Published
2016-09-12
Volume
36
Issue
11
Pages
1461-1473
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
DOI
10.1038/onc.2016.304
PMC
PMC5357762
OpenAlex
W2520632143
Cited by
2,626
References
213
Citations by year
2026: 136 · 2025: 230 · 2024: 273 · 2023: 348 · 2022: 382 · 2021: 380 · 2020: 321 · 2019: 274 · 2018: 181 · 2017: 80 · 2016: 15
FWCI
16.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Oncogene (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
Deutsches Krebsforschungszentrum
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
Keywords
Wnt signaling, carcinogenesis, colorectal cancer, cancer stem cells, metastasis, liquid tumors, stemness
MeSH terms
Animals, Antineoplastic Agents, Cell Transformation, Neoplastic, Humans, Mutation, Neoplasm Metastasis, Neoplasms, Protein Binding, Neoplastic Stem Cells, Tumor Escape, Wnt Proteins, beta Catenin, Molecular Targeted Therapy, Wnt Signaling Pathway

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review