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From Mechanisms to Therapeutics: Wnt Signaling in Cancer
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From Mechanisms to Therapeutics: Wnt Signaling in Cancer

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 20325

Special Issue Editors

Dr. Anitha K. Shenoy

E-Mail Website
Guest Editor
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Health Sciences University, Clovis, California, USA
Interests: Wnt signaling; signal transduction; cancer biology; stem cells; cancer stem cells; angiogenesis
Special Issues, Collections and Topics in MDPI journals
Dr. Liya Pi

E-Mail Website
Guest Editor
Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, LA 70112, USA
Interests: hepatic progenitor cell activation; liver regeneration; alcoholic fibrosis; liver cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Wnt Signaling pathway plays a central role in human development, tissue homeostasis, and a plethora of diseases including cancer.  It is well-recognized that the canonical, as well as non-canonical Wnt signaling pathways, are closely associated with tumor initiation, progression, and metastasis. The canonical Wnt signaling also regulates the formation and maintenance of embryonic, adult, and cancer stem cells. In addition, there exists a complex relationship between Wnt signaling and the tumor microenvironment that promotes cancer cell proliferation.  As a result, the Wnt signaling pathway and its components have become attractive drug targets for cancer treatment.

However, cancer drug development efforts aimed at Wnt signaling have been largely unsuccessful due to the ubiquitous nature of this pathway in health and disease. A thorough understanding of the Wnt mechanism in cancer pathophysiology, its role in conferring drug resistance, and the impact of its inhibition on cancer treatment are warranted to develop effective therapeutic strategies. In this regard, we welcome original articles and reviews for this special issue. The subtopics may include but are not limited to:

  1. Wnt signaling in tumorigenesis and development of cancer;
  2. Targeting Wnt signaling in cancer;
  3. Wnt signaling and Drug resistance in cancer;
  4. Wnt signaling and the tumor microenvironment;
  5. Wnt signaling and Cancer Stem Cells;
  6. Strategies to employ Wnt signaling pathway modulators in cancer treatment.

Dr. Anitha K. Shenoy
Dr. Liya Pi
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Wnt
  • β-catenin
  • development
  • homeostasis
  • cancer
  • cancer stem cells (CSC)
  • targeted cancer therapy
  • canonical Wnt signaling
  • non-canonical Wnt signaling

Related Special Issue

Published Papers (7 papers)

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Research

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16 pages, 9877 KiB  
Article
Chalcone Derivative CX258 Suppresses Colorectal Cancer via Inhibiting the TOP2A/Wnt/β-Catenin Signaling
by Xi Chen, Xiaocheng Lv, Lijie Gao, Jiawei Liu, Wei Wang, Lichao Guo, Mykhaylo S. Frasinyuk, Wen Zhang, David S. Watt, Chunming Liu and Xifu Liu
Cells 2023, 12(7), 1066; https://doi.org/10.3390/cells12071066 - 31 Mar 2023
Cited by 3 | Viewed by 1830
Abstract
The deregulation in the Wnt/β-catenin signaling pathway is associated with many human cancers, particularly colorectal cancer (CRC) and, therefore, represents a promising target for drug development. We have screened over 300 semisynthetic and natural compounds using a Wnt reporter assay and identified a [...] Read more.
The deregulation in the Wnt/β-catenin signaling pathway is associated with many human cancers, particularly colorectal cancer (CRC) and, therefore, represents a promising target for drug development. We have screened over 300 semisynthetic and natural compounds using a Wnt reporter assay and identified a family of novel chalcone derivatives (CXs) that inhibited Wnt signaling and CRC cell proliferation. Among them, we selected CX258 for further in vitro and in vivo study to investigate the molecular mechanisms. We found that CX258 significantly inhibited β-catenin expression and nuclear translocation, inducing cell cycle arrest at the G2/M phase in CRC cells. Additionally, CX258 reduced the expression of DNA Topoisomerase II alpha (TOP2A) in CRC cells. Moreover, knocking down TOP2A by siRNAs inhibited the Wnt/β-catenin signaling pathway, a finding suggesting that CX258 inhibited Wnt/β-catenin signaling and CRC cell proliferation at least partially by modulating TOP2A. Further studies showed that CDK1 that interacts with TOP2A was significantly reduced after TOP2A knockdown. We demonstrated that CX258 significantly inhibited DLD-1 CRC cell xenografts in SCID mice. In summary, we identified CX258 as a promising candidate for colorectal cancer treatment by targeting the TOP2A/Wnt/β-catenin signaling pathway. Full article
(This article belongs to the Special Issue From Mechanisms to Therapeutics: Wnt Signaling in Cancer)
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Review

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17 pages, 1593 KiB  
Review
When You Come to a Fork in the Road, Take It: Wnt Signaling Activates Multiple Pathways through the APC/Axin/GSK-3 Complex
by Chenchen Li, Emma E. Furth, Anil K. Rustgi and Peter S. Klein
Cells 2023, 12(18), 2256; https://doi.org/10.3390/cells12182256 - 12 Sep 2023
Cited by 3 | Viewed by 1635
Abstract
The Wnt signaling pathway is a highly conserved regulator of metazoan development and stem cell maintenance. Activation of Wnt signaling is an early step in diverse malignancies. Work over the past four decades has defined a “canonical” Wnt pathway that is initiated by [...] Read more.
The Wnt signaling pathway is a highly conserved regulator of metazoan development and stem cell maintenance. Activation of Wnt signaling is an early step in diverse malignancies. Work over the past four decades has defined a “canonical” Wnt pathway that is initiated by Wnt proteins, secreted glycoproteins that bind to a surface receptor complex and activate intracellular signal transduction by inhibiting a catalytic complex composed of the classical tumor suppressor Adenomatous Polyposis Coli (APC), Axin, and Glycogen Synthase Kinase-3 (GSK-3). The best characterized effector of this complex is β-catenin, which is stabilized by inhibition of GSK-3, allowing β-catenin entrance to the nucleus and activation of Wnt target gene transcription, leading to multiple cancers when inappropriately activated. However, canonical Wnt signaling through the APC/Axin/GSK-3 complex impinges on other effectors, independently of β-catenin, including the mechanistic Target of Rapamycin (mTOR), regulators of protein stability, mitotic spindle orientation, and Hippo signaling. This review focuses on these alternative effectors of the canonical Wnt pathway and how they may contribute to cancers. Full article
(This article belongs to the Special Issue From Mechanisms to Therapeutics: Wnt Signaling in Cancer)
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23 pages, 2929 KiB  
Review
A New Wave of Targeting ‘Undruggable’ Wnt Signaling for Cancer Therapy: Challenges and Opportunities
by Woo-Jung Park and Moon Jong Kim
Cells 2023, 12(8), 1110; https://doi.org/10.3390/cells12081110 - 08 Apr 2023
Cited by 9 | Viewed by 3997
Abstract
Aberrant Wnt signaling activation is frequently observed in many cancers. The mutation acquisition of Wnt signaling leads to tumorigenesis, whereas the inhibition of Wnt signaling robustly suppresses tumor development in various in vivo models. Based on the excellent preclinical effect of targeting Wnt [...] Read more.
Aberrant Wnt signaling activation is frequently observed in many cancers. The mutation acquisition of Wnt signaling leads to tumorigenesis, whereas the inhibition of Wnt signaling robustly suppresses tumor development in various in vivo models. Based on the excellent preclinical effect of targeting Wnt signaling, over the past 40 years, numerous Wnt-targeted therapies have been investigated for cancer treatment. However, Wnt signaling-targeting drugs are still not clinically available. A major obstacle to Wnt targeting is the concomitant side effects during treatment due to the pleiotropic role of Wnt signaling in development, tissue homeostasis, and stem cells. Additionally, the complexity of the Wnt signaling cascades across different cancer contexts hinders the development of optimized targeted therapies. Although the therapeutic targeting of Wnt signaling remains challenging, alternative strategies have been continuously developed alongside technological advances. In this review, we give an overview of current Wnt targeting strategies and discuss recent promising trials that have the potential to be clinically realized based on their mechanism of action. Furthermore, we highlight new waves of Wnt targeting that combine recently developed technologies such as PROTAC/molecular glue, antibody–drug conjugates (ADC), and anti-sense oligonucleotides (ASO), which may provide us with new opportunities to target ‘undruggable’ Wnt signaling. Full article
(This article belongs to the Special Issue From Mechanisms to Therapeutics: Wnt Signaling in Cancer)
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20 pages, 2683 KiB  
Review
The Role of WNT Pathway Mutations in Cancer Development and an Overview of Therapeutic Options
by Wibke Groenewald, Anders H. Lund and David Michael Gay
Cells 2023, 12(7), 990; https://doi.org/10.3390/cells12070990 - 24 Mar 2023
Cited by 3 | Viewed by 3909
Abstract
It is well established that mutations in the canonical WNT-signalling pathway play a major role in various cancers. Critical to developing new therapeutic strategies is understanding which cancers are driven by WNT pathway activation and at what level these mutations occur within the [...] Read more.
It is well established that mutations in the canonical WNT-signalling pathway play a major role in various cancers. Critical to developing new therapeutic strategies is understanding which cancers are driven by WNT pathway activation and at what level these mutations occur within the pathway. Some cancers harbour mutations in genes whose protein products operate at the receptor level of the WNT pathway. For instance, tumours with RNF43 or RSPO mutations, still require exogenous WNT ligands to drive WNT signalling (ligand-dependent mutations). Conversely, mutations within the cytoplasmic segment of the Wnt pathway, such as in APC and CTNNB1, lead to constitutive WNT pathway activation even in the absence of WNT ligands (ligand-independent). Here, we review the predominant driving mutations found in cancer that lead to WNT pathway activation, as well as explore some of the therapeutic interventions currently available against tumours harbouring either ligand-dependent or ligand-independent mutations. Finally, we discuss a potentially new therapeutic avenue by targeting the translational apparatus downstream from WNT signalling. Full article
(This article belongs to the Special Issue From Mechanisms to Therapeutics: Wnt Signaling in Cancer)
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22 pages, 2351 KiB  
Review
Advances of Wnt Signalling Pathway in Colorectal Cancer
by Yaoyao Zhu and Xia Li
Cells 2023, 12(3), 447; https://doi.org/10.3390/cells12030447 - 30 Jan 2023
Cited by 14 | Viewed by 4002
Abstract
Colorectal cancer (CRC) represents one of the most common cancers worldwide, with a high mortality rate despite the decreasing incidence and new diagnostic and therapeutic strategies. CRC arises from both epidemiologic and molecular backgrounds. In addition to hereditary factor and genetic mutations, the [...] Read more.
Colorectal cancer (CRC) represents one of the most common cancers worldwide, with a high mortality rate despite the decreasing incidence and new diagnostic and therapeutic strategies. CRC arises from both epidemiologic and molecular backgrounds. In addition to hereditary factor and genetic mutations, the strongly varying incidence of CRC is closely linked to chronic inflammatory disorders of the intestine and terrible dietary habits. The Wnt signalling pathway is a complex regulatory network that is implicated in many CRC physiological processes, including cancer occurrence, development, prognosis, invasion, and metastasis. It is currently believed to include classical Wnt/β-catenin, Wnt/PCP, and Wnt/Ca2+. In this review, we summarise the recent mechanisms and potential regulators of the three branches of the Wnt signalling pathway in CRC. Full article
(This article belongs to the Special Issue From Mechanisms to Therapeutics: Wnt Signaling in Cancer)
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19 pages, 1844 KiB  
Review
Wnt Signaling in the Development of Bone Metastasis
by Noa Ben-Ghedalia-Peled and Razi Vago
Cells 2022, 11(23), 3934; https://doi.org/10.3390/cells11233934 - 05 Dec 2022
Cited by 9 | Viewed by 2807
Abstract
Wnt signaling occurs through evolutionarily conserved pathways that affect cellular proliferation and fate decisions during development and tissue maintenance. Alterations in these highly regulated pathways, however, play pivotal roles in various malignancies, promoting cancer initiation, growth and metastasis and the development of drug [...] Read more.
Wnt signaling occurs through evolutionarily conserved pathways that affect cellular proliferation and fate decisions during development and tissue maintenance. Alterations in these highly regulated pathways, however, play pivotal roles in various malignancies, promoting cancer initiation, growth and metastasis and the development of drug resistance. The ability of cancer cells to metastasize is the primary cause of cancer mortality. Bone is one of the most frequent sites of metastases that generally arise from breast, prostate, lung, melanoma or kidney cancer. Upon their arrival to the bone, cancer cells can enter a long-term dormancy period, from which they can be reactivated, but can rarely be cured. The activation of Wnt signaling during the bone metastasis process was found to enhance proliferation, induce the epithelial-to-mesenchymal transition, promote the modulation of the extracellular matrix, enhance angiogenesis and immune tolerance and metastasize and thrive in the bone. Due to the complexity of Wnt pathways and of the landscape of this mineralized tissue, Wnt function during metastatic progression within bone is not yet fully understood. Therefore, we believe that a better understanding of these pathways and their roles in the development of bone metastasis could improve our understanding of the disease and may constitute fertile ground for potential therapeutics. Full article
(This article belongs to the Special Issue From Mechanisms to Therapeutics: Wnt Signaling in Cancer)
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Other

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13 pages, 634 KiB  
Perspective
Metformin: A New Inhibitor of the Wnt Signaling Pathway in Cancer
by Domenico Conza, Paola Mirra, Francesca Fiory, Luigi Insabato, Antonella Nicolò, Francesco Beguinot and Luca Ulianich
Cells 2023, 12(17), 2182; https://doi.org/10.3390/cells12172182 - 30 Aug 2023
Viewed by 1413
Abstract
The biguanide drug metformin is widely used in type 2 diabetes mellitus therapy, due to its ability to decrease serum glucose levels, mainly by reducing hepatic gluconeogenesis and glycogenolysis. A considerable number of studies have shown that metformin, besides its antidiabetic action, can [...] Read more.
The biguanide drug metformin is widely used in type 2 diabetes mellitus therapy, due to its ability to decrease serum glucose levels, mainly by reducing hepatic gluconeogenesis and glycogenolysis. A considerable number of studies have shown that metformin, besides its antidiabetic action, can improve other disease states, such as polycystic ovary disease, acute kidney injury, neurological disorders, cognitive impairment and renal damage. In addition, metformin is well known to suppress the growth and progression of different types of cancer cells both in vitro and in vivo. Accordingly, several epidemiological studies suggest that metformin is capable of lowering cancer risk and reducing the rate of cancer deaths among diabetic patients. The antitumoral effects of metformin have been proposed to be mainly mediated by the activation of the AMP-activated protein kinase (AMPK). However, a number of signaling pathways, both dependent and independent of AMPK activation, have been reported to be involved in metformin antitumoral action. Among these, the Wingless and Int signaling pathway have recently been included. Here, we will focus our attention on the main molecular mechanisms involved. Full article
(This article belongs to the Special Issue From Mechanisms to Therapeutics: Wnt Signaling in Cancer)
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