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      Wnt Pathway: An Integral Hub for Developmental and Oncogenic Signaling Networks

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          Abstract

          The Wnt pathway is an integral cell-to-cell signaling hub which regulates crucial development processes and maintenance of tissue homeostasis by coordinating cell proliferation, differentiation, cell polarity, cell movement, and stem cell renewal. When dysregulated, it is associated with various developmental diseases, fibrosis, and tumorigenesis. We now better appreciate the complexity and crosstalk of the Wnt pathway with other signaling cascades. Emerging roles of the Wnt signaling in the cancer stem cell niche and drug resistance have led to development of therapeutics specifically targeting various Wnt components, with some agents currently in clinical trials. This review highlights historical and recent findings on key mediators of Wnt signaling and how they impact antitumor immunity and maintenance of cancer stem cells. This review also examines current therapeutics being developed that modulate Wnt signaling in cancer and discusses potential shortcomings associated with available therapeutics.

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          Wnt signaling in cancer

          T Zhan, N Rindtorff, M Boutros (2016)
          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.
          Article 0 comments Cited 726 times – based on 0 reviews     Review now
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            Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.

            Shih-Min A Huang, Yuji M. Mishina, Shanming Liu … (2009)
            The stability of the Wnt pathway transcription factor beta-catenin is tightly regulated by the multi-subunit destruction complex. Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. However, the development of targeted Wnt pathway inhibitors has been hampered by the limited number of pathway components that are amenable to small molecule inhibition. Here, we used a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits beta-catenin-mediated transcription. XAV939 stimulates beta-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. Thus, our study provides new mechanistic insights into the regulation of axin protein homeostasis and presents new avenues for targeted Wnt pathway therapies.
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              Wnt signalling and its impact on development and cancer.

              Alexandra Klaus, Walter Birchmeier (2008)
              The Wnt signalling pathway is an ancient system that has been highly conserved during evolution. It has a crucial role in the embryonic development of all animal species, in the regeneration of tissues in adult organisms and in many other processes. Mutations or deregulated expression of components of the Wnt pathway can induce disease, most importantly cancer. The first gene to be identified that encodes a Wnt signalling component, Int1 (integration 1), was molecularly characterized from mouse tumour cells 25 years ago. In parallel, the homologous gene Wingless in Drosophila melanogaster, which produces developmental defects in embryos, was characterized. Since then, further components of the Wnt pathway have been identified and their epistatic relationships have been defined. This article is a Timeline of crucial discoveries about the components and functions of this essential pathway.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 28 October 2020
                Publication date Collection: November 2020
                Volume: 21
                Issue: 21
                Electronic Location Identifier: 8018
                Affiliations
                Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; monica.sharma@ 123456ttuhsc.edu
                Author notes
                [* ]Correspondence: kevin.pruitt@ 123456ttuhsc.edu ; Tel.: +1-806-743-2523; Fax: +1-806-743-2334
                Article
                Publisher ID: ijms-21-08018
                DOI: 10.3390/ijms21218018
                PMC ID: 7663720
                PubMed ID: 33126517
                SO-VID: 7df4d4ba-ab59-4e06-bdb2-b8f1e413c693
                Copyright © © 2020 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 26 September 2020
                Date accepted : 26 October 2020
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: wnt signaling,human diseases,cancer,antitumor immunity,cancer stemness,therapeutic strategies
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: wnt signaling, human diseases, cancer, antitumor immunity, cancer stemness, therapeutic strategies

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