Special Issue "Wnt Signaling in Cancer"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 March 2016)

Special Issue Editors

Guest Editor
Dr. Renée Van Amerongen

Section of Molecular Cytology and Van Leeuwenhoek Centre for Advanced Microscopy, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands
Website | E-Mail
Interests: breast cancer; stem cells; mammary gland development; Wnt-signal transduction
Guest Editor
Prof. Dr. Walter Birchmeier

Max Delbrueck Center for Molecular Medicine, Robert-Roessle-Strasse 10, 13125 Berlin, Germany
Website | E-Mail
Interests: the major research interests have been the role of cell adhesion and signal transduction in development and tumor progression

Special Issue Information

Dear Colleagues,

The Wnt pathway is crucial for development and tissue homeostasis in all multicellular animals. It is characterized by a large genetic complexity (the mammalian genome encodes 19 Wnt proteins) and dynamic spatiotemporal activities. Ever since its discovery, Wnt signaling has also been closely associated with tumor initiation and progression. This ranges from the identification of the APC tumor suppressor gene as the quintessential gatekeeper in colorectal cancer formation, to more subtle changes in Wnt-pathway activity in breast and other cancers that are only beginning to be recognized. Following the realization that Wnt signaling controls stem cell maintenance in multiple tissues, it has also become a prime candidate for driving cancer stem cell self-renewal in different tumor types.

While much of the focus has so far been on Wnt/beta-catenin signaling (the so-called ‘canonical’ Wnt pathway), alternative Wnt-signaling responses also play an important role. In melanoma, for instance, cells may change from a Wnt/beta-catenin to a Wnt5a/Ror2 signaling state, thereby simultaneously switching from a more proliferative to a more invasive phenotype. As we develop a better understanding of the molecular complexity underlying the different intracellular responses, we can ultimately hope to devise specific interventions for each of these different signaling mechanisms.

Unfortunately, drug development efforts directly aimed at blocking Wnt signaling at the level of the best-known downstream effector, beta-catenin, have been largely unsuccessful. More recently, however, Wnt-secretion inhibitors as well as drugs that block the interaction between Wnt proteins and their receptors have entered clinical trials. This Special Issue will highlight the role of Wnt signaling in cancer in all its diversity, covering both basic and more (pre)clinical aspects that advance our understanding of targeting this complex pathway in human tumors.

Dr. Renée van Amerongen
Prof. Dr. Walter Birchmeier
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 papers will be 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 monthly 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 1800 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 signaling
  • Oncogenesis
  • Targeted therapy
  • Cancer stem cells
  • APC
  • CTNNB1
  • Frizzled
  • Ror 2

Published Papers (20 papers)

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Research

Jump to: Review

Open AccessArticle The MYC 3′ Wnt-Responsive Element Drives Oncogenic MYC Expression in Human Colorectal Cancer Cells
Received: 1 April 2016 / Revised: 11 May 2016 / Accepted: 18 May 2016 / Published: 23 May 2016
Cited by 7 | PDF Full-text (2740 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Mutations in components of the Wnt/β-catenin signaling pathway drive colorectal cancer (CRC) by deregulating expression of downstream target genes including the c-MYC proto-oncogene (MYC). The critical regulatory DNA enhancer elements that control oncogenic MYC expression in CRC have yet to be [...] Read more.
Mutations in components of the Wnt/β-catenin signaling pathway drive colorectal cancer (CRC) by deregulating expression of downstream target genes including the c-MYC proto-oncogene (MYC). The critical regulatory DNA enhancer elements that control oncogenic MYC expression in CRC have yet to be fully elucidated. In previous reports, we correlated T-cell factor (TCF) and β-catenin binding to the MYC 3′ Wnt responsive DNA element (MYC 3′ WRE) with MYC expression in HCT116 cells. Here we used CRISPR/Cas9 to determine whether this element is a critical driver of MYC. We isolated a clonal population of cells that contained a deletion of a single TCF binding element (TBE) within the MYC 3′ WRE. This deletion reduced TCF/β-catenin binding to this regulatory element and decreased MYC expression. Using RNA-Seq analysis, we found altered expression of genes that regulate metabolic processes, many of which are known MYC target genes. We found that 3′ WRE-Mut cells displayed a reduced proliferative capacity, diminished clonogenic growth, and a decreased potential to form tumors in vivo. These findings indicate that the MYC 3′ WRE is a critical driver of oncogenic MYC expression and suggest that this element may serve as a therapeutic target for CRC. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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Open AccessArticle In Hyperthermia Increased ERK and WNT Signaling Suppress Colorectal Cancer Cell Growth
Received: 5 January 2016 / Revised: 15 April 2016 / Accepted: 10 May 2016 / Published: 14 May 2016
Cited by 3 | PDF Full-text (3098 KB) | HTML Full-text | XML Full-text
Abstract
Although neoplastic cells exhibit relatively higher sensitivity to hyperthermia than normal cells, hyperthermia has had variable success as an anti-cancer therapy. This variable outcome might be due to the fact that cancer cells themselves have differential degrees of sensitivity to high temperature. We [...] Read more.
Although neoplastic cells exhibit relatively higher sensitivity to hyperthermia than normal cells, hyperthermia has had variable success as an anti-cancer therapy. This variable outcome might be due to the fact that cancer cells themselves have differential degrees of sensitivity to high temperature. We hypothesized that the varying sensitivity of colorectal cancer (CRC) cells to hyperthermia depends upon the differential induction of survival pathways. Screening of such pathways revealed that Extracellular Signal-Regulated Kinase (ERK) signaling is augmented by hyperthermia, and the extent of this modulation correlates with the mutation status of V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS). Through clonal growth assays, apoptotic analyses and transcription reporter assays of CRC cells that differ only in KRAS mutation status we established that mutant KRAS cells are more sensitive to hyperthermia, as they exhibit sustained ERK signaling hyperactivation and increased Wingless/Integrated (WNT)/beta-catenin signaling. We propose that whereas increased levels of WNT and ERK signaling and a positive feedback between the two pathways is a major obstacle in anti-cancer therapy today, under hyperthermia the hyperinduction of the pathways and their positive crosstalk contribute to CRC cell death. Ascertaining the causative association between types of mutations and hyperthermia sensitivity may allow for a mutation profile-guided application of hyperthermia as an anti-cancer therapy. Since KRAS and WNT signaling mutations are prevalent in CRC, our results suggest that hyperthermia-based therapy might benefit a significant number, but not all, CRC patients. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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Open AccessArticle Characterization of Adenomatous Polyposis Coli Protein Dynamics and Localization at the Centrosome
Received: 14 March 2016 / Revised: 20 April 2016 / Accepted: 26 April 2016 / Published: 30 April 2016
Cited by 5 | PDF Full-text (3043 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The adenomatous polyposis coli (APC) tumor suppressor is a multifunctional regulator of Wnt signaling and acts as a mobile scaffold at different cellular sites. APC was recently found to stimulate microtubule (MT) growth at the interphase centrosome; however, little is known about its [...] Read more.
The adenomatous polyposis coli (APC) tumor suppressor is a multifunctional regulator of Wnt signaling and acts as a mobile scaffold at different cellular sites. APC was recently found to stimulate microtubule (MT) growth at the interphase centrosome; however, little is known about its dynamics and localization at this site. To address this, we analysed APC dynamics in fixed and live cells by fluorescence microscopy. In detergent-extracted cells, we discovered that APC was only weakly retained at the centrosome during interphase suggesting a rapid rate of exchange. This was confirmed in living cells by fluorescence recovery after photobleaching (FRAP), which identified two pools of green fluorescent protein (GFP)-APC: a major rapidly exchanging pool (~86%) and minor retained pool (~14%). The dynamic exchange rate of APC was unaffected by C-terminal truncations implicating a targeting role for the N-terminus. Indeed, we mapped centrosome localization to N-terminal armadillo repeat (ARM) domain amino acids 334–625. Interestingly, the rate of APC movement to the centrosome was stimulated by intact MTs, and APC dynamics slowed when MTs were disrupted by nocodazole treatment or knockdown of γ-tubulin. Thus, the rate of APC recycling at the centrosome is enhanced by MT growth, suggesting a positive feedback to stimulate its role in MT growth. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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Review

Jump to: Research

Open AccessReview Wnt Signaling in Cell Motility and Invasion: Drawing Parallels between Development and Cancer
Received: 16 June 2016 / Revised: 9 August 2016 / Accepted: 22 August 2016 / Published: 29 August 2016
Cited by 12 | PDF Full-text (1417 KB) | HTML Full-text | XML Full-text
Abstract
The importance of canonical and non-canonical Wnt signal transduction cascades in embryonic development and tissue homeostasis is well recognized. The aberrant activation of these pathways in the adult leads to abnormal cellular behaviors, and tumor progression is frequently a consequence. Here we discuss [...] Read more.
The importance of canonical and non-canonical Wnt signal transduction cascades in embryonic development and tissue homeostasis is well recognized. The aberrant activation of these pathways in the adult leads to abnormal cellular behaviors, and tumor progression is frequently a consequence. Here we discuss recent findings and analogies between Wnt signaling in developmental processes and tumor progression, with a particular focus on cell motility and matrix invasion and highlight the roles of the ARF (ADP-Ribosylation Factor) and Rho-family small GTP-binding proteins. Wnt-regulated signal transduction from cell surface receptors, signaling endosomes and/or extracellular vesicles has the potential to profoundly influence cell movement, matrix degradation and paracrine signaling in both development and disease. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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Open AccessReview Wnt5a Signaling in Cancer
Received: 27 May 2016 / Revised: 9 August 2016 / Accepted: 22 August 2016 / Published: 26 August 2016
Cited by 42 | PDF Full-text (1688 KB) | HTML Full-text | XML Full-text
Abstract
Wnt5a is involved in activating several non-canonical WNT signaling pathways, through binding to different members of the Frizzled- and Ror-family receptors. Wnt5a signaling is critical for regulating normal developmental processes, including proliferation, differentiation, migration, adhesion and polarity. However, the aberrant activation or inhibition [...] Read more.
Wnt5a is involved in activating several non-canonical WNT signaling pathways, through binding to different members of the Frizzled- and Ror-family receptors. Wnt5a signaling is critical for regulating normal developmental processes, including proliferation, differentiation, migration, adhesion and polarity. However, the aberrant activation or inhibition of Wnt5a signaling is emerging as an important event in cancer progression, exerting both oncogenic and tumor suppressive effects. Recent studies show the involvement of Wnt5a in regulating cancer cell invasion, metastasis, metabolism and inflammation. In this article, we review findings regarding the molecular mechanisms and roles of Wnt5a signaling in various cancer types, and highlight Wnt5a in ovarian cancer. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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Open AccessReview Aberrant Wnt Signaling in Leukemia
Received: 13 April 2016 / Revised: 25 July 2016 / Accepted: 22 August 2016 / Published: 26 August 2016
Cited by 15 | PDF Full-text (1080 KB) | HTML Full-text | XML Full-text
Abstract
The Wnt signaling pathway is essential in the development and homeostasis of blood and immune cells, but its exact role is still controversial and is the subject of intense research. The malignant counterpart of normal hematopoietic cells, leukemic (stem) cells, have hijacked the [...] Read more.
The Wnt signaling pathway is essential in the development and homeostasis of blood and immune cells, but its exact role is still controversial and is the subject of intense research. The malignant counterpart of normal hematopoietic cells, leukemic (stem) cells, have hijacked the Wnt pathway for their self-renewal and proliferation. Here we review the multiple ways dysregulated Wnt signaling can contribute to leukemogenesis, both cell autonomously as well as by changes in the microenvironment. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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Open AccessReview The Role of the C-Clamp in Wnt-Related Colorectal Cancers
Received: 9 May 2016 / Revised: 28 July 2016 / Accepted: 29 July 2016 / Published: 3 August 2016
Cited by 4 | PDF Full-text (1545 KB) | HTML Full-text | XML Full-text
Abstract
T-cell Factor/Lymphoid Enhancer Factor (TCF/LEF) transcription factors are major regulators of Wnt targets, and the products of the TCF7 and TCF7L2 genes have both been implicated in the progression of colorectal cancer in animal models and humans. TCFs recognize specific DNA sequences through [...] Read more.
T-cell Factor/Lymphoid Enhancer Factor (TCF/LEF) transcription factors are major regulators of Wnt targets, and the products of the TCF7 and TCF7L2 genes have both been implicated in the progression of colorectal cancer in animal models and humans. TCFs recognize specific DNA sequences through their high mobility group (HMG) domains, but invertebrate TCFs and some isoforms of vertebrate TCF7 and TCF7L2 contain a second DNA binding domain known as the C-clamp. This review will cover the basic properties of C-clamps and their importance in Wnt signaling, using data from Drosophila, C. elegans, and mammalian cell culture. The connection between C-clamp containing TCFs and colorectal cancer will also be discussed. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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Open AccessReview Developmental Drift and the Role of Wnt Signaling in Aging
Received: 20 May 2016 / Revised: 12 July 2016 / Accepted: 25 July 2016 / Published: 2 August 2016
Cited by 11 | PDF Full-text (812 KB) | HTML Full-text | XML Full-text
Abstract
Population aging is a public health problem affecting the majority of the developed world. As populations age, the incidence of degenerative diseases increases exponentially, leading to large increases in public spending on healthcare. Here we summarize recent findings on the developmental drift theory [...] Read more.
Population aging is a public health problem affecting the majority of the developed world. As populations age, the incidence of degenerative diseases increases exponentially, leading to large increases in public spending on healthcare. Here we summarize recent findings on the developmental drift theory of aging, and the links that have been established between aging and the Wnt signaling pathways. We focus on insights derived from model organisms connecting the evolutionary basis of aging and the link to developmental programming. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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Open AccessReview Wnt Lipidation and Modifiers in Intestinal Carcinogenesis and Cancer
Received: 1 June 2016 / Revised: 14 July 2016 / Accepted: 14 July 2016 / Published: 18 July 2016
Cited by 6 | PDF Full-text (743 KB) | HTML Full-text | XML Full-text
Abstract
The wingless (Wnt) signaling is suggested as a fundamental hierarchical pathway in regulation of proliferation and differentiation of cells. The Wnt ligands are small proteins of about 40 kDa essentially for regulation and initiation of the Wnt activity. They are secreted proteins requiring [...] Read more.
The wingless (Wnt) signaling is suggested as a fundamental hierarchical pathway in regulation of proliferation and differentiation of cells. The Wnt ligands are small proteins of about 40 kDa essentially for regulation and initiation of the Wnt activity. They are secreted proteins requiring acylation for activity in the Wnt signaling cascade and for functional interactivity with transmembrane proteins. Dual lipidation is important for posttranslational activation of the overwhelming number of Wnt proteins and is probably involved in their spatial distribution. The intestinal mucosa, where Wnt signaling is essential in configuration and maintenance, is an established model to study Wnt proteins and their role in carcinogenesis and cancer. The intestinal crypt-villus/crypt-plateau axis, a cellular system with self-renewal, proliferation, and differentiation, is tightly coordinated by a Wnt gradient. In the review, some attention is given to Wnt3, Wnt3A, and Wnt2B as important members of the Wnt family to address the role of lipidation and modifiers of Wnt proteins in intestinal carcinogenesis. Wnt3 is an important player in establishing the Wnt gradient in intestinal crypts and is mainly produced by Paneth cells. Wnt2B is characterized as a mitochondrial protein and shuttles between mitochondria and the nucleus. Porcupine and ACSL5, a long-chain fatty acid activating enzyme, are introduced as modifiers of Wnts and as interesting strategy to targeting Wnt-driven carcinogenesis. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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Open AccessReview Ptk7 and Mcc, Unfancied Components in Non-Canonical Wnt Signaling and Cancer
Received: 20 May 2016 / Revised: 29 June 2016 / Accepted: 7 July 2016 / Published: 16 July 2016
Cited by 9 | PDF Full-text (1423 KB) | HTML Full-text | XML Full-text
Abstract
Human development uses a remarkably small number of signal transduction pathways to organize vastly complicated tissues. These pathways are commonly associated with disease in adults if activated inappropriately. One such signaling pathway, Wnt, solves the too few pathways conundrum by having many alternate [...] Read more.
Human development uses a remarkably small number of signal transduction pathways to organize vastly complicated tissues. These pathways are commonly associated with disease in adults if activated inappropriately. One such signaling pathway, Wnt, solves the too few pathways conundrum by having many alternate pathways within the Wnt network. The main or “canonical” Wnt pathway has been studied in great detail, and among its numerous downstream components, several have been identified as drug targets that have led to cancer treatments currently in clinical trials. In contrast, the non-canonical Wnt pathways are less well characterized, and few if any possible drug targets exist to tackle cancers caused by dysregulation of these Wnt offshoots. In this review, we focus on two molecules—Protein Tyrosine Kinase 7 (Ptk7) and Mutated in Colorectal Cancer (Mcc)—that do not fit perfectly into the non-canonical pathways described to date and whose roles in cancer are ill defined. We will summarize work from our laboratories as well as many others revealing unexpected links between these two proteins and Wnt signaling both in cancer progression and during vertebrate and invertebrate embryonic development. We propose that future studies focused on delineating the signaling machinery downstream of Ptk7 and Mcc will provide new, hitherto unanticipated drug targets to combat cancer metastasis. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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Open AccessReview Molecular Genetics of Intracranial Meningiomas with Emphasis on Canonical Wnt Signalling
Received: 13 April 2016 / Revised: 27 June 2016 / Accepted: 7 July 2016 / Published: 15 July 2016
Cited by 8 | PDF Full-text (1368 KB) | HTML Full-text | XML Full-text
Abstract
Research over the last decade recognized the importance of novel molecular pathways in pathogenesis of intracranial meningiomas. In this review, we focus on human brain tumours meningiomas and the involvement of Wnt signalling pathway genes and proteins in this common brain tumour, describing [...] Read more.
Research over the last decade recognized the importance of novel molecular pathways in pathogenesis of intracranial meningiomas. In this review, we focus on human brain tumours meningiomas and the involvement of Wnt signalling pathway genes and proteins in this common brain tumour, describing their known functional effects. Meningiomas originate from the meningeal layers of the brain and the spinal cord. Most meningiomas have benign clinical behaviour and are classified as grade I by World Health Organization (WHO). However, up to 20% histologically classified as atypical (grade II) or anaplastic (grade III) are associated with higher recurrent rate and have overall less favourable clinical outcome. Recently, there is emerging evidence that multiple signalling pathways including Wnt pathway contribute to the formation and growth of meningiomas. In the review we present the synopsis on meningioma histopathology and genetics and discuss our research regarding Wnt in meningioma. Epithelial-to-mesenchymal transition, a process in which Wnt signalling plays an important role, is shortly discussed. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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Open AccessReview A Second WNT for Old Drugs: Drug Repositioning against WNT-Dependent Cancers
Received: 28 May 2016 / Revised: 24 June 2016 / Accepted: 7 July 2016 / Published: 14 July 2016
Cited by 12 | PDF Full-text (575 KB) | HTML Full-text | XML Full-text
Abstract
Aberrant WNT signaling underlies cancerous transformation and growth in many tissues, such as the colon, breast, liver, and others. Downregulation of the WNT pathway is a desired mode of development of targeted therapies against these cancers. Despite the urgent need, no WNT signaling-directed [...] Read more.
Aberrant WNT signaling underlies cancerous transformation and growth in many tissues, such as the colon, breast, liver, and others. Downregulation of the WNT pathway is a desired mode of development of targeted therapies against these cancers. Despite the urgent need, no WNT signaling-directed drugs currently exist, and only very few candidates have reached early phase clinical trials. Among different strategies to develop WNT-targeting anti-cancer therapies, repositioning of existing drugs previously approved for other diseases is a promising approach. Nonsteroidal anti-inflammatory drugs like aspirin, the anti-leprotic clofazimine, and the anti-trypanosomal suramin are among examples of drugs having recently revealed WNT-targeting activities. In total, 16 human-use drug compounds have been found to be working through the WNT pathway and show promise for their prospective repositioning against various cancers. Advances, hurdles, and prospects of developing these molecules as potential drugs against WNT-dependent cancers, as well as approaches for discovering new ones for repositioning, are the foci of the current review. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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Open AccessReview Mammary Development and Breast Cancer: A Wnt Perspective
Received: 23 April 2016 / Revised: 30 June 2016 / Accepted: 7 July 2016 / Published: 13 July 2016
Cited by 22 | PDF Full-text (1123 KB) | HTML Full-text | XML Full-text
Abstract
The Wnt pathway has emerged as a key signaling cascade participating in mammary organogenesis and breast oncogenesis. In this review, we will summarize the current knowledge of how the pathway regulates stem cells and normal development of the mammary gland, and discuss how [...] Read more.
The Wnt pathway has emerged as a key signaling cascade participating in mammary organogenesis and breast oncogenesis. In this review, we will summarize the current knowledge of how the pathway regulates stem cells and normal development of the mammary gland, and discuss how its various components contribute to breast carcinoma pathology. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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Open AccessReview Modulating Dickkopf-1: A Strategy to Monitor or Treat Cancer?
Received: 17 May 2016 / Revised: 19 June 2016 / Accepted: 23 June 2016 / Published: 28 June 2016
Cited by 8 | PDF Full-text (204 KB) | HTML Full-text | XML Full-text
Abstract
Dickkopf-1 (DKK1) is a secreted Wnt/β-catenin pathway antagonist involved in embryogenesis. It was first described 25 years ago for its function in head induction and limb morphogenesis. Since then, this protein has been widely studied in the context of active Wnt/β-catenin signalling during [...] Read more.
Dickkopf-1 (DKK1) is a secreted Wnt/β-catenin pathway antagonist involved in embryogenesis. It was first described 25 years ago for its function in head induction and limb morphogenesis. Since then, this protein has been widely studied in the context of active Wnt/β-catenin signalling during cellular differentiation and development. Dysregulation of DKK1 has been associated with bone pathologies and has now emerged as a potential biomarker of cancer progression and prognosis for several types of malignancies. Reducing the amount of circulating DKK1 may reveal a simple and efficient strategy to limit or reverse cancer growth. This review will provide an overview of the role of Dickkopf-1 in cancer and explore its potential use as a biomarker and therapeutic target. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
Open AccessReview Wnt Signaling in Cancer Stem Cell Biology
Received: 18 April 2016 / Revised: 11 June 2016 / Accepted: 20 June 2016 / Published: 27 June 2016
Cited by 31 | PDF Full-text (799 KB) | HTML Full-text | XML Full-text
Abstract
Aberrant regulation of Wnt signaling is a common theme seen across many tumor types. Decades of research have unraveled the epigenetic and genetic alterations that result in elevated Wnt pathway activity. More recently, it has become apparent that Wnt signaling levels identify stem-like [...] Read more.
Aberrant regulation of Wnt signaling is a common theme seen across many tumor types. Decades of research have unraveled the epigenetic and genetic alterations that result in elevated Wnt pathway activity. More recently, it has become apparent that Wnt signaling levels identify stem-like tumor cells that are responsible for fueling tumor growth. As therapeutic targeting of these tumor stem cells is an intense area of investigation, a concise understanding on how Wnt activity relates to cancer stem cell traits is needed. This review attempts at summarizing the intricacies between Wnt signaling and cancer stem cell biology with a special emphasis on colorectal cancer. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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Open AccessReview S100A4 in Cancer Metastasis: Wnt Signaling-Driven Interventions for Metastasis Restriction
Received: 28 April 2016 / Revised: 27 May 2016 / Accepted: 9 June 2016 / Published: 20 June 2016
Cited by 20 | PDF Full-text (702 KB) | HTML Full-text | XML Full-text
Abstract
The aberrant activity of Wnt signaling is an early step in the transformation of normal intestinal cells to malignant tissue, leading to more aggressive tumors, and eventually metastases. In colorectal cancer (CRC), metastasis accounts for about 90% of patient deaths, representing the most [...] Read more.
The aberrant activity of Wnt signaling is an early step in the transformation of normal intestinal cells to malignant tissue, leading to more aggressive tumors, and eventually metastases. In colorectal cancer (CRC), metastasis accounts for about 90% of patient deaths, representing the most lethal event during the course of the disease and is directly linked to patient survival, critically limiting successful therapy. This review focuses on our studies of the metastasis-inducing gene S100A4, which we identified as transcriptional target of β-catenin. S100A4 increased migration and invasion in vitro and metastasis in mice. In patient CRC samples, high S100A4 levels predict metastasis and reduced patient survival. Our results link pathways important for tumor progression and metastasis: the Wnt signaling pathway and S100A4, which regulates motility and invasiveness. S100A4 suppression by interdicting Wnt signaling has potential for therapeutic intervention. As proof of principle, we applied S100A4 shRNA systemically and prevented metastasis in mice. Furthermore, we identified small molecule inhibitors from high-throughput screens of pharmacologically active compounds employing an S100A4 promoter-driven reporter. Best hits act, as least in part, via intervening in the Wnt pathway and restricted metastasis in mouse models. We currently translate our findings on restricting S100A4-driven metastasis into clinical practice. The repositioned FDA-approved drug niclosamide, targeting Wnt signaling, is being tested in a prospective phase II clinical trial for treatment of CRC patients. Our assay for circulating S100A4 transcripts in patient blood is used to monitor treatment success. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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Open AccessReview Wnt Signaling in Renal Cell Carcinoma
Received: 31 March 2016 / Revised: 31 May 2016 / Accepted: 12 June 2016 / Published: 17 June 2016
Cited by 18 | PDF Full-text (766 KB) | HTML Full-text | XML Full-text
Abstract
Renal cell carcinoma (RCC) accounts for 90% of all kidney cancers. Due to poor diagnosis, high resistance to the systemic therapies and the fact that most RCC cases occur sporadically, current research switched its focus on studying the molecular mechanisms underlying RCC. The [...] Read more.
Renal cell carcinoma (RCC) accounts for 90% of all kidney cancers. Due to poor diagnosis, high resistance to the systemic therapies and the fact that most RCC cases occur sporadically, current research switched its focus on studying the molecular mechanisms underlying RCC. The aim is the discovery of new effective and less toxic anti-cancer drugs and novel diagnostic markers. Besides the PI3K/Akt/mTOR, HGF/Met and VHL/hypoxia cellular signaling pathways, the involvement of the Wnt/β-catenin pathway in RCC is commonly studied. Wnt signaling and its targeted genes are known to actively participate in different biological processes during embryonic development and renal cancer. Recently, studies have shown that targeting this pathway by alternating/inhibiting its intracellular signal transduction can reduce cancer cells viability and inhibit their growth. The targets and drugs identified show promising potential to serve as novel RCC therapeutics and prognostic markers. This review aims to summarize the current status quo regarding recent research on RCC focusing on the involvement of the Wnt/β-catenin pathway and how its understanding could facilitate the identification of potential therapeutic targets, new drugs and diagnostic biomarkers. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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Open AccessReview Control of Wnt Receptor Turnover by R-spondin-ZNRF3/RNF43 Signaling Module and Its Dysregulation in Cancer
Received: 30 March 2016 / Revised: 23 May 2016 / Accepted: 2 June 2016 / Published: 8 June 2016
Cited by 20 | PDF Full-text (539 KB) | HTML Full-text | XML Full-text
Abstract
Aberrant activation of the Wnt/β-catenin pathway is frequently found in various cancers, often through mutations of downstream components. Inhibiting β-catenin signaling in tumors with downstream pathway mutations remains challenging, due to a lack of favorable targets. On the other hand, targeting upstream components [...] Read more.
Aberrant activation of the Wnt/β-catenin pathway is frequently found in various cancers, often through mutations of downstream components. Inhibiting β-catenin signaling in tumors with downstream pathway mutations remains challenging, due to a lack of favorable targets. On the other hand, targeting upstream components of the Wnt pathway is rather straightforward. However, it is difficult to identify tumors addicted to autocrine or paracrine Wnt signaling. Discovery of the R-spondin-ZNRF3/RNF43 signaling module and its genetic alterations in cancers represents a breakthrough in this area. Membrane E3 ligase ZNRF3 and RNF43 are critical negative feedback regulators of the Wnt pathway, which function through promoting ubiquitination and degradation of Wnt receptors. R-spondin proteins (RSPO1-4) serve as natural antagonists of ZNRF3/RNF43. To maintain strong and sustained Wnt/β-catenin signaling, cancers need to overcome ZNRF3/RNF43-mediated feedback inhibition. Indeed, mutations of RNF43/ZNRF3 and recurrent translocations of RSPO2/RSPO3 have recently been identified in various cancers. Significantly, genetic alterations in RNF43/ZNRF3/RSPO2/RSPO3 have shown promise as predictive biomarkers in pre-clinical models for the efficacy of upstream Wnt inhibitors. In this review, we will discuss the biology of the R-spondin-ZNRF3/RNF43 signaling module, cancer-associated alterations of this signaling module, and their value as biomarkers to identify Wnt-addicted tumors. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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Open AccessReview Frizzled7: A Promising Achilles’ Heel for Targeting the Wnt Receptor Complex to Treat Cancer
Received: 31 March 2016 / Revised: 3 May 2016 / Accepted: 9 May 2016 / Published: 17 May 2016
Cited by 22 | PDF Full-text (795 KB) | HTML Full-text | XML Full-text
Abstract
Frizzled7 is arguably the most studied member of the Frizzled family, which are the cognate Wnt receptors. Frizzled7 is highly conserved through evolution, from Hydra through to humans, and is expressed in diverse organisms, tissues and human disease contexts. Frizzled receptors can homo- [...] Read more.
Frizzled7 is arguably the most studied member of the Frizzled family, which are the cognate Wnt receptors. Frizzled7 is highly conserved through evolution, from Hydra through to humans, and is expressed in diverse organisms, tissues and human disease contexts. Frizzled receptors can homo- or hetero-polymerise and associate with several co-receptors to transmit Wnt signalling. Notably, Frizzled7 can transmit signalling via multiple Wnt transduction pathways and bind to several different Wnt ligands, Frizzled receptors and co-receptors. These promiscuous binding and functional properties are thought to underlie the pivotal role Frizzled7 plays in embryonic developmental and stem cell function. Recent studies have identified that Frizzled7 is upregulated in diverse human cancers, and promotes proliferation, progression and invasion, and orchestrates cellular transitions that underscore cancer metastasis. Importantly, Frizzled7 is able to regulate Wnt signalling activity even in cancer cells which have mutations to down-stream signal transducers. In this review we discuss the various aspects of Frizzled7 signalling and function, and the implications these have for therapeutic targeting of Frizzled7 in cancer. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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Open AccessReview The Wnt Target Gene L1 in Colon Cancer Invasion and Metastasis
Received: 17 March 2016 / Revised: 26 April 2016 / Accepted: 6 May 2016 / Published: 11 May 2016
Cited by 5 | PDF Full-text (2565 KB) | HTML Full-text | XML Full-text
Abstract
The Wnt-β-catenin signaling pathway is highly conserved during evolution and determines normal tissue homeostasis. Hyperactivation of Wnt-β-catenin signaling is a characteristic feature of colorectal cancer (CRC) development. β-catenin is a major transducer of the Wnt signal from the cytoplasm into the nucleus where [...] Read more.
The Wnt-β-catenin signaling pathway is highly conserved during evolution and determines normal tissue homeostasis. Hyperactivation of Wnt-β-catenin signaling is a characteristic feature of colorectal cancer (CRC) development. β-catenin is a major transducer of the Wnt signal from the cytoplasm into the nucleus where it acts as a co-transcriptional activator of β-catenin-TCF target genes. β-catenin is also required for linking cadherin type cell-cell adhesion receptors to the cytoskeleton, and consequently Wnt-β-catenin signaling is an attractive system for investigating the role of adhesion-mediated signaling in both normal intestinal tissue homeostasis and CRC development. In this review, we summarize our studies on one Wnt-β-catenin target gene, L1, a member of the immunoglobulin-like cell adhesion transmembrane receptor family. We describe the mechanisms of L1-mediated signaling in CRC cells, its exclusive localization in invasive areas of CRC tissue, and its ability to increase cell motility and confer metastasis to the liver. We discuss the activation (by L1) of genes via an ezrin-NF-κB pathway and the induction of genes also found in the intestinal stem cell signature. By studying L1 (adhesion)-mediated signaling, we expect to learn about mechanisms regulating both normal intestinal homeostasis and CRC development. Full article
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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Cancers EISSN 2072-6694 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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