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The Wnt Signaling Pathway in Cancer
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The Wnt Signaling Pathway in Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 67872

Special Issue Editor

Prof. Dr. Yong-mi Kim

E-Mail Website
Guest Editor
Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Interests: leukemia; drug resistance; microenvironment; integrin; acute lymphoblastic leukemia
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue focuses on the Wnt Signaling Pathway in Cancer. Wnt signaling has been of considerable interest in both setm cell and cancer biology, both in homeostatic maintenance of tissues and organs through their respective somatic stem cells (SSCs) and in cancer stem cells (CSCs). The functions include cellular processes, including self-renewal capacity, proliferation, differentiation potential, and maintenance of the stem cell niche. The role of aberrant wnt signaling in cancer stem cells (CSCs) has been demonstrated in a wide variety of cancers, including brain tumors, melanoma, breast, liver, pancreatic, and colon cancer, but also hematological malignancies. Wnt siangling has been shown to be involved in initiation of disease, therapeutic resistance, and ultimately, disease relapse. One key focus in cancer research has been to develop therapies to safely eliminate CSCs. The precise understanding of the regulation of wnt signaling, the crosstalk of wnt signaling with other signaling pathways, and downstream targets are key for successful translational efforts, which will be the focus of this Special Edition. Original investigations as well as concise review manuscripts from experts in the relevant research fields will be considered for publication.

Assoc. Prof. Dr. Yong-mi Kim
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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
  • Cancer
  • Drug resistance
  • Therapy
  • Microenvironment
  • Self-renewal
  • Differentiation

Published Papers (14 papers)

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Research

Jump to: Review

25 pages, 7760 KiB  
Article
Targeting of Deregulated Wnt/β-Catenin Signaling by PRI-724 and LGK974 Inhibitors in Germ Cell Tumor Cell Lines
by Silvia Schmidtova, Katarina Kalavska, Veronika Liskova, Jana Plava, Svetlana Miklikova, Lucia Kucerova, Miroslava Matuskova, Lucia Rojikova, Zuzana Cierna, Adriana Rogozea, Heiko Konig, Costantine Albany, Michal Mego and Michal Chovanec
Int. J. Mol. Sci. 2021, 22(8), 4263; https://doi.org/10.3390/ijms22084263 - 20 Apr 2021
Cited by 10 | Viewed by 2777
Abstract
The majority of patients with testicular germ cell tumors (GCTs) can be cured with cisplatin-based chemotherapy. However, for a subset of patients present with cisplatin-refractory disease, which confers a poor prognosis, the treatment options are limited. Novel therapies are therefore urgently needed to [...] Read more.
The majority of patients with testicular germ cell tumors (GCTs) can be cured with cisplatin-based chemotherapy. However, for a subset of patients present with cisplatin-refractory disease, which confers a poor prognosis, the treatment options are limited. Novel therapies are therefore urgently needed to improve outcomes in this challenging patient population. It has previously been shown that Wnt/β-catenin signaling is active in GCTs suggesting that its inhibitors LGK974 and PRI-724 may show promise in the management of cisplatin-refractory GCTs. We herein investigated whether LGK-974 and PRI-724 provide a treatment effect in cisplatin-resistant GCT cell lines. Taking a genoproteomic approach and utilizing xenograft models we found the increased level of β-catenin in 2 of 4 cisplatin-resistant (CisR) cell lines (TCam-2 CisR and NCCIT CisR) and the decreased level of β-catenin and cyclin D1 in cisplatin-resistant NTERA-2 CisR cell line. While the effect of treatment with LGK974 was limited or none, the NTERA-2 CisR exhibited the increased sensitivity to PRI-724 in comparison with parental cell line. Furthermore, the pro-apoptotic effect of PRI-724 was documented in all cell lines. Our data strongly suggests that a Wnt/β-catenin signaling is altered in cisplatin-resistant GCT cell lines and the inhibition with PRI-724 is effective in NTERA-2 CisR cells. Further evaluation of Wnt/β-catenin pathway inhibition in GCTs is therefore warranted. Full article
(This article belongs to the Special Issue The Wnt Signaling Pathway in Cancer)
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16 pages, 2622 KiB  
Article
TRAP1 Regulates Wnt/β-Catenin Pathway through LRP5/6 Receptors Expression Modulation
by Giacomo Lettini, Valentina Condelli, Michele Pietrafesa, Fabiana Crispo, Pietro Zoppoli, Francesca Maddalena, Ilaria Laurenzana, Alessandro Sgambato, Franca Esposito and Matteo Landriscina
Int. J. Mol. Sci. 2020, 21(20), 7526; https://doi.org/10.3390/ijms21207526 - 13 Oct 2020
Cited by 8 | Viewed by 2686
Abstract
Wnt/β-Catenin signaling is involved in embryonic development, regeneration, and cellular differentiation and is responsible for cancer stemness maintenance. The HSP90 molecular chaperone TRAP1 is upregulated in 60–70% of human colorectal carcinomas (CRCs) and favors stem cells maintenance, modulating the Wnt/β-Catenin pathway and preventing [...] Read more.
Wnt/β-Catenin signaling is involved in embryonic development, regeneration, and cellular differentiation and is responsible for cancer stemness maintenance. The HSP90 molecular chaperone TRAP1 is upregulated in 60–70% of human colorectal carcinomas (CRCs) and favors stem cells maintenance, modulating the Wnt/β-Catenin pathway and preventing β-Catenin phosphorylation/degradation. The role of TRAP1 in the regulation of Wnt/β-Catenin signaling was further investigated in human CRC cell lines, patient-derived spheroids, and CRC specimens. TRAP1 relevance in the activation of Wnt/β-Catenin signaling was highlighted by a TCF/LEF Cignal Reporter Assay in Wnt-off HEK293T and CRC HCT116 cell lines. Of note, this regulation occurs through the modulation of Wnt ligand receptors LRP5 and LRP6 that are both downregulated in TRAP1-silenced cell lines. However, while LRP5 mRNA is significantly downregulated upon TRAP1 silencing, LRP6 mRNA is unchanged, suggesting independent mechanisms of regulation by TRAP1. Indeed, LRP5 is regulated upon promoter methylation in CRC cell lines and human CRCs, whereas LRP6 is controlled at post-translational level by protein ubiquitination/degradation. Consistently, human CRCs with high TRAP1 expression are characterized by the co-upregulation of active β-Catenin, LRP5 and LRP6. Altogether, these data suggest that Wnt/β-Catenin signaling is modulated at multiple levels by TRAP1. Full article
(This article belongs to the Special Issue The Wnt Signaling Pathway in Cancer)
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11 pages, 2132 KiB  
Article
Wnt/CTNNB1 Signal Transduction Pathway Inhibits the Expression of ZFP36 in Squamous Cell Carcinoma, by Inducing Transcriptional Repressors SNAI1, SLUG and TWIST
by Emma D. Zanfi, Sebastian Fantini, Roberta Lotti, Matteo Bertesi, Alessandra Marconi, Alexis Grande, Rossella Manfredini, Carlo Pincelli and Tommaso Zanocco-Marani
Int. J. Mol. Sci. 2020, 21(16), 5692; https://doi.org/10.3390/ijms21165692 - 8 Aug 2020
Cited by 6 | Viewed by 2481
Abstract
The Wnt/CTNNB1 pathway is often deregulated in epithelial tumors. The ZFP36 gene, encoding the mRNA binding protein Tristetraprolin (TTP), is downregulated in several cancers, where it has been described to behave as a tumor suppressor. By this report, we show that Wnt/CTNNB1 pathway [...] Read more.
The Wnt/CTNNB1 pathway is often deregulated in epithelial tumors. The ZFP36 gene, encoding the mRNA binding protein Tristetraprolin (TTP), is downregulated in several cancers, where it has been described to behave as a tumor suppressor. By this report, we show that Wnt/CTNNB1 pathway is constitutively activated, and ZFP36 expression is downregulated in Squamous Cell Carcinoma (SCC) cell lines compared to normal keratinocytes. Moreover, we suggest that the decrease of ZFP36 expression might depend on the activity of transcriptional repressors SNAI1, SLUG and TWIST, whose expression is induced by Wnt/CTNNB1, highlighting a potential regulatory mechanism underlying ZFP36 downregulation in epithelial cancers. Full article
(This article belongs to the Special Issue The Wnt Signaling Pathway in Cancer)
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15 pages, 3788 KiB  
Article
Role of miR-96/EVI1/miR-449a Axis in the Nasopharyngeal Carcinoma Cell Migration and Tumor Sphere Formation
by Lai-Sheung Chan, Hong-Lok Lung, Roger Kai-Cheong Ngan, Anne Wing-Mui Lee, Sai Wah Tsao, Kwok-Wai Lo, Michael Kahn, Maria Li Lung, Rotraud Wieser and Nai-Ki Mak
Int. J. Mol. Sci. 2020, 21(15), 5495; https://doi.org/10.3390/ijms21155495 - 31 Jul 2020
Cited by 8 | Viewed by 2307
Abstract
The Wnt signaling pathway is one of the major signaling pathways used by cancer stem cells (CSC). Ecotropic Viral Integration Site 1 (EVI1) has recently been shown to regulate oncogenic development of tumor cells by interacting with multiple signaling pathways, including the Wnt [...] Read more.
The Wnt signaling pathway is one of the major signaling pathways used by cancer stem cells (CSC). Ecotropic Viral Integration Site 1 (EVI1) has recently been shown to regulate oncogenic development of tumor cells by interacting with multiple signaling pathways, including the Wnt signaling. In the present study, we found that the Wnt modulator ICG-001 could inhibit the expression of EVI1 in nasopharyngeal carcinoma (NPC) cells. Results from loss-of-function and gain-of-function studies revealed that EVI1 expression positively regulated both NPC cell migration and growth of CSC-enriched tumor spheres. Subsequent studies indicated ICG-001 inhibited EVI1 expression via upregulated expression of miR-96. Results from EVI1 3′UTR luciferase reporter assay confirmed that EVI1 is a direct target of miR-96. Further mechanistic studies revealed that ICG-001, overexpression of miR-96, or knockdown of EVI1 expression could restore the expression of miR-449a. The suppressive effect of miR-449a on the cell migration and tumor sphere formation was confirmed in NPC cells. Taken together, the miR-96/EVI1/miR-449a axis is a novel pathway involved in ICG-001-mediated inhibition of NPC cell migration and growth of the tumor spheres. Full article
(This article belongs to the Special Issue The Wnt Signaling Pathway in Cancer)
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17 pages, 3366 KiB  
Article
LY75 Suppression in Mesenchymal Epithelial Ovarian Cancer Cells Generates a Stable Hybrid EOC Cellular Phenotype, Associated with Enhanced Tumor Initiation, Spreading and Resistance to Treatment in Orthotopic Xenograft Mouse Model
by Sadia Mehdi, Elizabeth Macdonald, Kristianne Galpin, David A. Landry, Galaxia Rodriguez, Barbara Vanderhyden and Dimcho Bachvarov
Int. J. Mol. Sci. 2020, 21(14), 4992; https://doi.org/10.3390/ijms21144992 - 15 Jul 2020
Cited by 2 | Viewed by 2784
Abstract
The implications of the epithelial–mesenchymal transition (EMT) mechanisms in the initiation and progression of epithelial ovarian cancer (EOC) remain poorly understood. We have previously shown that suppression of the antigen receptor LY75 directs mesenchymal–epithelial transition (MET) in EOC cell lines with the mesenchymal [...] Read more.
The implications of the epithelial–mesenchymal transition (EMT) mechanisms in the initiation and progression of epithelial ovarian cancer (EOC) remain poorly understood. We have previously shown that suppression of the antigen receptor LY75 directs mesenchymal–epithelial transition (MET) in EOC cell lines with the mesenchymal phenotype, associated with the loss of Wnt/β-catenin signaling activity. In the present study, we used the LY75-mediated modulation of EMT in EOC cells as a model in order to investigate in vivo the specific role of EOC cells, with an epithelial (E), mesenchymal (M) or mixed epithelial plus mesenchymal (E+M) phenotype, in EOC initiation, dissemination and treatment response, following intra-bursal (IB) injections of SKOV3-M (control), SKOV3-E (Ly75KD) and a mixed population of SKOV3-E+M cells, into severe combined immunodeficiency (SCID) mice. We found that the IB-injected SKOV3-E cells displayed considerably higher metastatic potential and resistance to treatment as compared to the SKOV3-M cells, due to the acquisition of a Ly75KD-mediated hybrid phenotype and stemness characteristics. We also confirmed in vivo that the LY75 depletion directs suppression of the Wnt/β-catenin pathway in EOC cells, suggestive of a protective role of this pathway in EOC etiology. Moreover, our data raise concerns regarding the use of LY75-targeted vaccines for dendritic-cell EOC immunotherapy, due to the possible occurrence of undesirable side effects. Full article
(This article belongs to the Special Issue The Wnt Signaling Pathway in Cancer)
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20 pages, 2385 KiB  
Article
LY75 Ablation Mediates Mesenchymal-Epithelial Transition (MET) in Epithelial Ovarian Cancer (EOC) Cells Associated with DNA Methylation Alterations and Suppression of the Wnt/β-Catenin Pathway
by Sadia Mehdi, Magdalena Bachvarova, Marie-Pier Scott-Boyer, Arnaud Droit and Dimcho Bachvarov
Int. J. Mol. Sci. 2020, 21(5), 1848; https://doi.org/10.3390/ijms21051848 - 7 Mar 2020
Cited by 6 | Viewed by 3232
Abstract
Growing evidence demonstrates that epithelial–mesenchymal transition (EMT) plays an important role in epithelial ovarian cancer (EOC) progression and spreading; however, its molecular mechanisms remain poorly defined. We have previously shown that the antigen receptor LY75 can modulate EOC cell phenotype and metastatic potential, [...] Read more.
Growing evidence demonstrates that epithelial–mesenchymal transition (EMT) plays an important role in epithelial ovarian cancer (EOC) progression and spreading; however, its molecular mechanisms remain poorly defined. We have previously shown that the antigen receptor LY75 can modulate EOC cell phenotype and metastatic potential, as LY75 depletion directed mesenchymal–epithelial transition (MET) in EOC cell lines with mesenchymal phenotype. We used the LY75-mediated modulation of EMT as a model to investigate for DNA methylation changes during EMT in EOC cells, by applying the reduced representation bisulfite sequencing (RRBS) methodology. Numerous genes have displayed EMT-related DNA methylation patterns alterations in their promoter/exon regions. Ten selected genes, whose DNA methylation alterations were further confirmed by alternative methods, were further identified, some of which could represent new EOC biomarkers/therapeutic targets. Moreover, our methylation data were strongly indicative for the predominant implication of the Wnt/β-catenin pathway in the EMT-induced DNA methylation variations in EOC cells. Consecutive experiments, including alterations in the Wnt/β-catenin pathway activity in EOC cells with a specific inhibitor and the identification of LY75-interacting partners by a proteomic approach, were strongly indicative for the direct implication of the LY75 receptor in modulating the Wnt/β-catenin signaling in EOC cells. Full article
(This article belongs to the Special Issue The Wnt Signaling Pathway in Cancer)
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Review

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14 pages, 1172 KiB  
Review
Inhibition of the Wnt Signalling Pathway: An Avenue to Control Breast Cancer Aggressiveness
by Lorenzo Castagnoli, Elda Tagliabue and Serenella M. Pupa
Int. J. Mol. Sci. 2020, 21(23), 9069; https://doi.org/10.3390/ijms21239069 - 28 Nov 2020
Cited by 17 | Viewed by 3054
Abstract
Breast cancer (BC) is the most common tumour in women. Although the introduction of novel therapeutic approaches in clinical practice has dramatically improved the clinical outcome of BC patients, this malignant disease remains the second leading cause of cancer-related death worldwide. The wingless/integrated [...] Read more.
Breast cancer (BC) is the most common tumour in women. Although the introduction of novel therapeutic approaches in clinical practice has dramatically improved the clinical outcome of BC patients, this malignant disease remains the second leading cause of cancer-related death worldwide. The wingless/integrated (Wnt) signalling pathway represents a crucial molecular node relevantly implicated in the regulation of normal somatic stem cells as well as cancer stem cell (CSC) traits and the epithelial–mesenchymal transition cell program. Accordingly, Wnt signalling is heavily dysregulated in BC, and the altered expression of different Wnt genes is significantly associated with cancer-related aggressive behaviours. For all these reasons, Wnt signalling represents a promising therapeutic target currently under clinical investigation to achieve cancer eradication by eliminating CSCs, considered by most to be responsible for tumour initiation, relapse, and drug resistance. In this review, we summarized the current knowledge on the Wnt signalling pathway in BC and have presented evidence implicating the suitability of Wnt targeting in an attempt to improve the outcome of patients without affecting the normal somatic stem cell population. Full article
(This article belongs to the Special Issue The Wnt Signaling Pathway in Cancer)
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16 pages, 1148 KiB  
Review
Wnt-Independent and Wnt-Dependent Effects of APC Loss on the Chemotherapeutic Response
by Casey D. Stefanski and Jenifer R. Prosperi
Int. J. Mol. Sci. 2020, 21(21), 7844; https://doi.org/10.3390/ijms21217844 - 22 Oct 2020
Cited by 17 | Viewed by 2790
Abstract
Resistance to chemotherapy occurs through mechanisms within the epithelial tumor cells or through interactions with components of the tumor microenvironment (TME). Chemoresistance and the development of recurrent tumors are two of the leading factors of cancer-related deaths. The Adenomatous Polyposis Coli (APC) tumor [...] Read more.
Resistance to chemotherapy occurs through mechanisms within the epithelial tumor cells or through interactions with components of the tumor microenvironment (TME). Chemoresistance and the development of recurrent tumors are two of the leading factors of cancer-related deaths. The Adenomatous Polyposis Coli (APC) tumor suppressor is lost in many different cancers, including colorectal, breast, and prostate cancer, and its loss correlates with a decreased overall survival in cancer patients. While APC is commonly known for its role as a negative regulator of the WNT pathway, APC has numerous binding partners and functional roles. Through APC’s interactions with DNA repair proteins, DNA replication proteins, tubulin, and other components, recent evidence has shown that APC regulates the chemotherapy response in cancer cells. In this review article, we provide an overview of some of the cellular processes in which APC participates and how they impact chemoresistance through both epithelial- and TME-derived mechanisms. Full article
(This article belongs to the Special Issue The Wnt Signaling Pathway in Cancer)
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26 pages, 2417 KiB  
Review
The Wnt Signalling Pathway: A Tailored Target in Cancer
by Malvina Koni, Veronica Pinnarò and Maria Felice Brizzi
Int. J. Mol. Sci. 2020, 21(20), 7697; https://doi.org/10.3390/ijms21207697 - 18 Oct 2020
Cited by 102 | Viewed by 14466
Abstract
Cancer is one of the greatest public health challenges. According to the World Health Organization (WHO), 9.6 million cancer deaths have been reported in 2018. The most common cancers include lung, breast, colorectal, prostate, skin (non-melanoma) and stomach cancer. The unbalance of physiological [...] Read more.
Cancer is one of the greatest public health challenges. According to the World Health Organization (WHO), 9.6 million cancer deaths have been reported in 2018. The most common cancers include lung, breast, colorectal, prostate, skin (non-melanoma) and stomach cancer. The unbalance of physiological signalling pathways due to the acquisition of mutations in tumour cells is considered the most common cancer driver. The Wingless-related integration site (Wnt)/β-catenin pathway is crucial for tissue development and homeostasis in all animal species and its dysregulation is one of the most relevant events linked to cancer development and dissemination. The canonical and the non-canonical Wnt/β-catenin pathways are known to control both physiological and pathological processes, including cancer. Herein, the impact of the Wnt/β-catenin cascade in driving cancers from different origin has been examined. Finally, based on the impact of Extracellular Vesicles (EVs) on tumour growth, invasion and chemoresistance, and their role as tumour diagnostic and prognostic tools, an overview of the current knowledge linking EVs to the Wnt/β-catenin pathway is also discussed. Full article
(This article belongs to the Special Issue The Wnt Signaling Pathway in Cancer)
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20 pages, 1249 KiB  
Review
Wnt Signaling in Leukemia and Its Bone Marrow Microenvironment
by Yongsheng Ruan, Hye Na Kim, Heather Ogana and Yong-Mi Kim
Int. J. Mol. Sci. 2020, 21(17), 6247; https://doi.org/10.3390/ijms21176247 - 28 Aug 2020
Cited by 20 | Viewed by 6431
Abstract
Leukemia is an aggressive hematologic neoplastic disease. Therapy-resistant leukemic stem cells (LSCs) may contribute to the relapse of the disease. LSCs are thought to be protected in the leukemia microenvironment, mainly consisting of mesenchymal stem/stromal cells (MSC), endothelial cells, and osteoblasts. Canonical and [...] Read more.
Leukemia is an aggressive hematologic neoplastic disease. Therapy-resistant leukemic stem cells (LSCs) may contribute to the relapse of the disease. LSCs are thought to be protected in the leukemia microenvironment, mainly consisting of mesenchymal stem/stromal cells (MSC), endothelial cells, and osteoblasts. Canonical and noncanonical Wnt pathways play a critical role in the maintenance of normal hematopoietic stem cells (HSC) and LSCs. In this review, we summarize recent findings on the role of Wnt signaling in leukemia and its microenvironment and provide information on the currently available strategies for targeting Wnt signaling. Full article
(This article belongs to the Special Issue The Wnt Signaling Pathway in Cancer)
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16 pages, 1474 KiB  
Review
Casein Kinase 1α as a Regulator of Wnt-Driven Cancer
by Chen Shen, Anmada Nayak, Ricardo A. Melendez, Daniel T. Wynn, Joshua Jackson, Ethan Lee, Yashi Ahmed and David J. Robbins
Int. J. Mol. Sci. 2020, 21(16), 5940; https://doi.org/10.3390/ijms21165940 - 18 Aug 2020
Cited by 16 | Viewed by 4784
Abstract
Wnt signaling regulates numerous cellular processes during embryonic development and adult tissue homeostasis. Underscoring this physiological importance, deregulation of the Wnt signaling pathway is associated with many disease states, including cancer. Here, we review pivotal regulatory events in the Wnt signaling pathway that [...] Read more.
Wnt signaling regulates numerous cellular processes during embryonic development and adult tissue homeostasis. Underscoring this physiological importance, deregulation of the Wnt signaling pathway is associated with many disease states, including cancer. Here, we review pivotal regulatory events in the Wnt signaling pathway that drive cancer growth. We then discuss the roles of the established negative Wnt regulator, casein kinase 1α (CK1α), in Wnt signaling. Although the study of CK1α has been ongoing for several decades, the bulk of such research has focused on how it phosphorylates and regulates its various substrates. We focus here on what is known about the mechanisms controlling CK1α, including its putative regulatory proteins and alternative splicing variants. Finally, we describe the discovery and validation of a family of pharmacological CK1α activators capable of inhibiting Wnt pathway activity. One of the important advantages of CK1α activators, relative to other classes of Wnt inhibitors, is their reduced on-target toxicity, overcoming one of the major impediments to developing a clinically relevant Wnt inhibitor. Therefore, we also discuss mechanisms that regulate CK1α steady-state homeostasis, which may contribute to the deregulation of Wnt pathway activity in cancer and underlie the enhanced therapeutic index of CK1α activators. Full article
(This article belongs to the Special Issue The Wnt Signaling Pathway in Cancer)
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22 pages, 4416 KiB  
Review
Wnt/β-Catenin Signaling in Oral Carcinogenesis
by Montserrat Reyes, Tania Flores, Diego Betancur, Daniel Peña-Oyarzún and Vicente A. Torres
Int. J. Mol. Sci. 2020, 21(13), 4682; https://doi.org/10.3390/ijms21134682 - 30 Jun 2020
Cited by 32 | Viewed by 4316
Abstract
Oral carcinogenesis is a complex and multifactorial process that involves cumulative genetic and molecular alterations, leading to uncontrolled cell proliferation, impaired DNA repair and defective cell death. At the early stages, the onset of potentially malignant lesions in the oral mucosa, or oral [...] Read more.
Oral carcinogenesis is a complex and multifactorial process that involves cumulative genetic and molecular alterations, leading to uncontrolled cell proliferation, impaired DNA repair and defective cell death. At the early stages, the onset of potentially malignant lesions in the oral mucosa, or oral dysplasia, is associated with higher rates of malignant progression towards carcinoma in situ and invasive carcinoma. Efforts have been made to get insights about signaling pathways that are deregulated in oral dysplasia, as these could be translated into novel markers and might represent promising therapeutic targets. In this context, recent evidence underscored the relevance of the Wnt/β-catenin signaling pathway in oral dysplasia, as this pathway is progressively “switched on” through the different grades of dysplasia (mild, moderate and severe dysplasia), with the consequent nuclear translocation of β-catenin and expression of target genes associated with the maintenance of representative traits of oral dysplasia, namely cell proliferation and viability. Intriguingly, recent studies provide an unanticipated connection between active β-catenin signaling and deregulated endosome trafficking in oral dysplasia, highlighting the relevance of endocytic components in oral carcinogenesis. This review summarizes evidence about the role of the Wnt/β-catenin signaling pathway and the underlying mechanisms that account for its aberrant activation in oral carcinogenesis. Full article
(This article belongs to the Special Issue The Wnt Signaling Pathway in Cancer)
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21 pages, 694 KiB  
Review
Wnt Signaling in Gynecologic Malignancies
by Alexandra McMellen, Elizabeth R. Woodruff, Bradley R. Corr, Benjamin G. Bitler and Marisa R. Moroney
Int. J. Mol. Sci. 2020, 21(12), 4272; https://doi.org/10.3390/ijms21124272 - 16 Jun 2020
Cited by 43 | Viewed by 7901
Abstract
Gynecologic malignancies, including ovarian cancer, endometrial cancer, and cervical cancer, affect hundreds of thousands of women worldwide every year. Wnt signaling, specifically Wnt/β-catenin signaling, has been found to play an essential role in many oncogenic processes in gynecologic malignancies, including tumorigenesis, metastasis, recurrence, [...] Read more.
Gynecologic malignancies, including ovarian cancer, endometrial cancer, and cervical cancer, affect hundreds of thousands of women worldwide every year. Wnt signaling, specifically Wnt/β-catenin signaling, has been found to play an essential role in many oncogenic processes in gynecologic malignancies, including tumorigenesis, metastasis, recurrence, and chemotherapy resistance. As such, the Wnt/β-catenin signaling pathway has the potential to be a target for effective treatment, improving patient outcomes. In this review, we discuss the evidence supporting the importance of the Wnt signaling pathways in the development, progression, and treatment of gynecologic malignancies. Full article
(This article belongs to the Special Issue The Wnt Signaling Pathway in Cancer)
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18 pages, 1146 KiB  
Review
Targeting Wnt Signaling for the Treatment of Gastric Cancer
by Sarah Koushyar, Arfon G. Powell, Elizabeth Vincan and Toby J. Phesse
Int. J. Mol. Sci. 2020, 21(11), 3927; https://doi.org/10.3390/ijms21113927 - 30 May 2020
Cited by 44 | Viewed by 6594
Abstract
The Wnt signaling pathway is evolutionarily conserved, regulating both embryonic development and maintaining adult tissue homeostasis. Wnt signaling controls several fundamental cell functions, including proliferation, differentiation, migration, and stemness. It therefore plays an important role in the epithelial homeostasis and regeneration of the [...] Read more.
The Wnt signaling pathway is evolutionarily conserved, regulating both embryonic development and maintaining adult tissue homeostasis. Wnt signaling controls several fundamental cell functions, including proliferation, differentiation, migration, and stemness. It therefore plays an important role in the epithelial homeostasis and regeneration of the gastrointestinal tract. Often, both hypo- or hyper-activation of the pathway due to genetic, epigenetic, or receptor/ligand alterations are seen in many solid cancers, such as breast, colorectal, gastric, and prostate. Gastric cancer (GC) is the fourth commonest cause of cancer worldwide and is the second leading cause of cancer-related death annually. Although the number of new diagnoses has declined over recent decades, prognosis remains poor, with only 15% surviving to five years. Geographical differences in clinicopathological features are also apparent, with epidemiological and genetic studies revealing GC to be a highly heterogeneous disease with phenotypic diversity as a result of etiological factors. The molecular heterogeneity associated with GC dictates that a single ‘one size fits all’ approach to management is unlikely to be successful. Wnt pathway dysregulation has been observed in approximately 50% of GC tumors and may offer a novel therapeutic target for patients who would otherwise have a poor outcome. This mini review will highlight some recent discoveries involving Wnt signaling in GC. Full article
(This article belongs to the Special Issue The Wnt Signaling Pathway in Cancer)
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