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Cancers
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WNT Signaling Pathways in Cancer
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WNT Signaling Pathways in Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 23757

Special Issue Editor

Dr. Masaru Katoh

E-Mail Website
Guest Editor
Department of Omics Network, National Cancer Center, Tokyo 104‑0045, Japan.
Interests: precision medicine; human genetics; FGF signaling; Hedgehog signaling; Notch signaling; WNT signaling; tumor microenvironment; angiogenesis; immuno-oncology

Special Issue Information

WNT signals are transduced through Frizzled receptors (FZD1 ~ FZD10) and co-receptors (LRP5, LRP6, PTK7, ROR1, ROR2 and RYK) to the canonical β-catenin-TCF/LEF signaling cascade and/or other non-canonical signaling cascades. WNT signaling cascades crosstalk with the FGF, Hedgehog, Notch, and TGFβ/BMP signaling cascades to regulate embryogenesis, tissue homeostasis, and tumorigenesis.

Germline mutations in the WNT signaling molecules cause hereditary colorectal cancer, bone diseases, exudative vitreoretinopathy, intellectual disability syndrome, and PCP-related diseases. In contrast, somatic alterations in the WNT signaling components, such as APC, AXIN2, CTNNB1, RSPO2, RSPO3, and RNF43, occur in colorectal cancer, gastric cancer, liver cancer, pancreatic cancer and other types of human cancers.

I have been working in the fields of clinical gastroenterology (1986~1990), molecular biology (1990~2002), genome science (2003~2014) and precision medicine (2015~present). In this Special Issue, I would like to call for original and/or review articles of WNT signaling in cancers with a strong emphasis on the improvement of knowledge for clinical application. Specific sub-topics covered may include but are not limited to the following:

(1) Cutting-edge technologies, such as clinical genomic sequencing, CRISPR-Cas9 gene editing and single-cell RNA sequencing, to elucidate the involvements of WNT signaling aberrations in human cancers;

(2) Model systems (patient-derived organoids, xenografts and cell lines) as well as model animals (engineered mice, Xenopus, zebrafish and others) to demonstrate the mechanisms of WNT-related pathologies in cancer patients;

(3) Artificial intelligence for basic research (epigenetic dysregulation, genetic alterations and signaling aberration) and translational research (biomarker screening and therapeutic development) on WNT-related human cancers;

(4) Translational research on the WNT signaling cascades in association with clinical trials.

Dr. Masaru Katoh
Guest Editor

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. Cancers 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 2900 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
  • Frizzled
  • β-catenin
  • ROR1/2
  • planar cell polarity
  • colorectal cancer
  • gastric cancer
  • pancreatic cancer
  • serrated adenoma
  • artificial intelligence

Published Papers (6 papers)

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Research

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19 pages, 3832 KiB  
Article
Histone Deacetylase Inhibitors Impair Glioblastoma Cell Motility and Proliferation
by Elena Rampazzo, Lorenzo Manfreda, Silvia Bresolin, Alice Cani, Elena Mariotto, Roberta Bortolozzi, Alessandro Della Puppa, Giampietro Viola and Luca Persano
Cancers 2022, 14(8), 1897; https://doi.org/10.3390/cancers14081897 - 09 Apr 2022
Cited by 9 | Viewed by 2185
Abstract
Despite being subjected to high-dose chemo and radiotherapy, glioblastoma (GBM) patients still encounter almost inevitable relapse, due to the capability of tumor cells to disseminate and invade normal brain tissues. Moreover, the presence of a cancer stem cell (CSC) subpopulation, already demonstrated to [...] Read more.
Despite being subjected to high-dose chemo and radiotherapy, glioblastoma (GBM) patients still encounter almost inevitable relapse, due to the capability of tumor cells to disseminate and invade normal brain tissues. Moreover, the presence of a cancer stem cell (CSC) subpopulation, already demonstrated to better resist and evade treatments, further frustrates potential therapeutic approaches. In this context, we previously demonstrated that GBM is characterized by a tightly-regulated balance between the β-catenin cofactors TCF1 and TCF4, with high levels of TCF4 responsible for sustaining CSC in these tumors; thus, supporting their aggressive features. Since histone deacetylase inhibitors (HDI) have been reported to strongly reduce TCF4 levels in colon cancer cells, we hypothesized that they could also exert a similar therapeutic action in GBM. Here, we treated primary GBM cultures with Trichostatin-A and Vorinostat, demonstrating their ability to strongly suppress the Wnt-dependent pathways; thus, promoting CSC differentiation and concomitantly impairing GBM cell viability and proliferation. More interestingly, analysis of their molecular effects suggested a prominent HDI action against GBM cell motility/migration, which we demonstrated to rely on the inhibition of the RhoA-GTPase and interferon intracellular cascades. Our results suggest HDI as potential therapeutic agents in GBM, through their action on multiple cancer hallmarks. Full article
(This article belongs to the Special Issue WNT Signaling Pathways in Cancer)
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24 pages, 2838 KiB  
Article
HER2–CDH1 Interaction via Wnt/B-Catenin Is Associated with Patients’ Survival in HER2-Positive Metastatic Gastric Adenocarcinoma
by Valli De Re, Lara Alessandrini, Giulia Brisotto, Laura Caggiari, Mariangela De Zorzi, Mariateresa Casarotto, Gianmaria Miolo, Fabio Puglisi, Silvio Ken Garattini, Sara Lonardi, Renato Cannizzaro, Vincenzo Canzonieri, Matteo Fassan and Agostino Steffan
Cancers 2022, 14(5), 1266; https://doi.org/10.3390/cancers14051266 - 28 Feb 2022
Cited by 3 | Viewed by 2811
Abstract
Trastuzumab is a human epidermal growth factor receptor 2 (HER2) inhibitor used to treat HER2+ metastatic gastric cancer (mGC). The present study aims to investigate the relationship between CDH1 mRNA expression and HER2-positivity in mGC using a multiplexed gene expression profile in two [...] Read more.
Trastuzumab is a human epidermal growth factor receptor 2 (HER2) inhibitor used to treat HER2+ metastatic gastric cancer (mGC). The present study aims to investigate the relationship between CDH1 mRNA expression and HER2-positivity in mGC using a multiplexed gene expression profile in two series of gastric cancer (GC): Series 1 (n = 38): HER2+ and HER2- mGC; Series 2 (n = 36) HER2- GC with and without metastasis. To confirm the results, the same expression profiles were analyzed in 354 GC from The Cancer Genome Atlas (TCGA) dataset. The difference in gene expression connected HER2 overexpression with canonical wingless-type (Wnt)/β-catenin pathway and immunohistochemical (IHC) expression loss of E-cadherin (E-CAD). CDH1 mRNA expression was simultaneously associated with the rs16260-A variant and an increase in E-CAD expression. Differences in retinoic acid receptor alfa (RARA), RPL19 (coding for the 60S ribosomal L19 protein), catenin delta 1 (CTNND1), and epidermal growth factor (EGF) mRNA levels—all included in the Wnt/β-catenin pathway—were found associated with overall survival (OS). RARA, CTNND1, and EGF resulted in independent OS prognostic factors. EGF was confirmed as an independent factor along with TNM stage in HER2-overpressed mGC from TCGA collection. Our study highlighted factors involved in the WNT/β-catenin pathway that interconnected E-CAD with HER2 overexpression and patient survival. Full article
(This article belongs to the Special Issue WNT Signaling Pathways in Cancer)
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14 pages, 2189 KiB  
Article
Captopril, a Renin-Angiotensin System Inhibitor, Attenuates Features of Tumor Invasion and Down-Regulates C-Myc Expression in a Mouse Model of Colorectal Cancer Liver Metastasis
by Georgina E. Riddiough, Theodora Fifis, Katrina A. Walsh, Vijayaragavan Muralidharan, Christopher Christophi, Bang M. Tran, Elizabeth Vincan and Marcos V. Perini
Cancers 2021, 13(11), 2734; https://doi.org/10.3390/cancers13112734 - 31 May 2021
Cited by 10 | Viewed by 2920
Abstract
(1) Background: Recent clinical and experimental data suggests that the liver’s regenerative response following partial hepatectomy can stimulate tumor recurrence in the liver remnant. The Wnt/β-catenin pathway plays important roles in both colorectal cancer carcinogenesis and liver regeneration. Studies have shown that the [...] Read more.
(1) Background: Recent clinical and experimental data suggests that the liver’s regenerative response following partial hepatectomy can stimulate tumor recurrence in the liver remnant. The Wnt/β-catenin pathway plays important roles in both colorectal cancer carcinogenesis and liver regeneration. Studies have shown that the Wnt/β-catenin pathway regulates multiple renin-angiotensin system (RAS) genes, whilst RAS inhibition (RASi) reduces tumor burden and progression. This study explores whether RASi attenuates features of tumor progression in the regenerating liver post-hepatectomy by modulating Wnt/β-catenin signaling. (2) Methods: Male CBA mice underwent CRLM induction, followed one week later by 70% partial hepatectomy. Mice were treated daily with captopril, a RASi, at 250 mg/kg/day or vehicle control from experimental Day 4. Tumor and liver samples were analyzed for RAS and Wnt signaling markers using qRT-PCR and immunohistochemistry. (3) Results: Treatment with captopril reduced the expression of down-stream Wnt target genes, including a significant reduction in both c-myc and cyclin-D1, despite activating Wnt signaling. This was a tumor-specific response that was not elicited in corresponding liver samples. (4) Conclusions: We report for the first time decreased c-myc expression in colorectal tumors following RASi treatment in vivo. Decreased c-myc expression was accompanied by an attenuated invasive phenotype, despite increased Wnt signaling. Full article
(This article belongs to the Special Issue WNT Signaling Pathways in Cancer)
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Review

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27 pages, 3325 KiB  
Review
The Key Role of the WNT/β-Catenin Pathway in Metabolic Reprogramming in Cancers under Normoxic Conditions
by Alexandre Vallée, Yves Lecarpentier and Jean-Noël Vallée
Cancers 2021, 13(21), 5557; https://doi.org/10.3390/cancers13215557 - 05 Nov 2021
Cited by 37 | Viewed by 5365
Abstract
The canonical WNT/β-catenin pathway is upregulated in cancers and plays a major role in proliferation, invasion, apoptosis and angiogenesis. Nuclear β-catenin accumulation is associated with cancer. Hypoxic mechanisms lead to the activation of the hypoxia-inducible factor (HIF)-1α, promoting glycolytic and energetic metabolism and [...] Read more.
The canonical WNT/β-catenin pathway is upregulated in cancers and plays a major role in proliferation, invasion, apoptosis and angiogenesis. Nuclear β-catenin accumulation is associated with cancer. Hypoxic mechanisms lead to the activation of the hypoxia-inducible factor (HIF)-1α, promoting glycolytic and energetic metabolism and angiogenesis. However, HIF-1α is degraded by the HIF prolyl hydroxylase under normoxia, conditions under which the WNT/β-catenin pathway can activate HIF-1α. This review is therefore focused on the interaction between the upregulated WNT/β-catenin pathway and the metabolic processes underlying cancer mechanisms under normoxic conditions. The WNT pathway stimulates the PI3K/Akt pathway, the STAT3 pathway and the transduction of WNT/β-catenin target genes (such as c-Myc) to activate HIF-1α activity in a hypoxia-independent manner. In cancers, stimulation of the WNT/β-catenin pathway induces many glycolytic enzymes, which in turn induce metabolic reprogramming, known as the Warburg effect or aerobic glycolysis, leading to lactate overproduction. The activation of the Wnt/β-catenin pathway induces gene transactivation via WNT target genes, c-Myc and cyclin D1, or via HIF-1α. This in turn encodes aerobic glycolysis enzymes, including glucose transporter, hexokinase 2, pyruvate kinase M2, pyruvate dehydrogenase kinase 1 and lactate dehydrogenase-A, leading to lactate production. The increase in lactate production is associated with modifications to the tumor microenvironment and tumor growth under normoxic conditions. Moreover, increased lactate production is associated with overexpression of VEGF, a key inducer of angiogenesis. Thus, under normoxic conditions, overstimulation of the WNT/β-catenin pathway leads to modifications of the tumor microenvironment and activation of the Warburg effect, autophagy and glutaminolysis, which in turn participate in tumor growth. Full article
(This article belongs to the Special Issue WNT Signaling Pathways in Cancer)
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30 pages, 1897 KiB  
Review
WNT/β-Catenin Pathway in Soft Tissue Sarcomas: New Therapeutic Opportunities?
by Esther Martinez-Font, Marina Pérez-Capó, Oliver Vögler, Javier Martín-Broto, Regina Alemany and Antònia Obrador-Hevia
Cancers 2021, 13(21), 5521; https://doi.org/10.3390/cancers13215521 - 03 Nov 2021
Cited by 7 | Viewed by 3159
Abstract
Soft tissue sarcomas (STS) are a very heterogeneous group of rare tumors, comprising more than 50 different histological subtypes that originate from mesenchymal tissue. Despite their heterogeneity, chemotherapy based on doxorubicin (DXR) has been in use for forty years now and remains the [...] Read more.
Soft tissue sarcomas (STS) are a very heterogeneous group of rare tumors, comprising more than 50 different histological subtypes that originate from mesenchymal tissue. Despite their heterogeneity, chemotherapy based on doxorubicin (DXR) has been in use for forty years now and remains the standard first-line treatment for locally advanced unresectable or metastatic STS, although overall survival could not be improved by combination with other chemotherapeutics. In this sense, the development of new therapeutic approaches continues to be a largely unmatched goal. The WNT/β-catenin signaling pathway is involved in various fundamental processes for embryogenic development, including the proliferation and differentiation of mesenchymal stem cells. Although the role of this pathway has been widely researched in neoplasms of epithelial origin, little is known about its relevance for mesenchymal neoplasms. This review covers the most important molecular alterations of the WNT signaling pathway in STS. The detection of these alterations and the understanding of their functional consequences for those pathways controlling sarcomagenesis development and progression are crucial to broaden the current knowledge about STS as well as to identify novel drug targets. In this regard, the current therapeutic options and drug candidates to modulate WNT signaling, which are usually classified by their interaction site upstream or downstream of β-catenin, and their presumable clinical impact on STS are also discussed. Full article
(This article belongs to the Special Issue WNT Signaling Pathways in Cancer)
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20 pages, 1992 KiB  
Review
Regulation of Wnt Signaling by FOX Transcription Factors in Cancer
by Stefan Koch
Cancers 2021, 13(14), 3446; https://doi.org/10.3390/cancers13143446 - 09 Jul 2021
Cited by 14 | Viewed by 5569
Abstract
Aberrant activation of the oncogenic Wnt signaling pathway is a hallmark of numerous types of cancer. However, in many cases, it is unclear how a chronically high Wnt signaling tone is maintained in the absence of activating pathway mutations. Forkhead box (FOX) family [...] Read more.
Aberrant activation of the oncogenic Wnt signaling pathway is a hallmark of numerous types of cancer. However, in many cases, it is unclear how a chronically high Wnt signaling tone is maintained in the absence of activating pathway mutations. Forkhead box (FOX) family transcription factors are key regulators of embryonic development and tissue homeostasis, and there is mounting evidence that they act in part by fine-tuning the Wnt signaling output in a tissue-specific and context-dependent manner. Here, I review the diverse ways in which FOX transcription factors interact with the Wnt pathway, and how the ectopic reactivation of FOX proteins may affect Wnt signaling activity in various types of cancer. Many FOX transcription factors are partially functionally redundant and exhibit a highly restricted expression pattern, especially in adults. Thus, precision targeting of individual FOX proteins may lead to safe treatment options for Wnt-dependent cancers. Full article
(This article belongs to the Special Issue WNT Signaling Pathways in Cancer)
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