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17 pages, 2321 KiB

Open AccessArticle

Methylation Patterns of DKK1, DKK3 and GSK3β Are Accompanied with Different Expression Levels in Human Astrocytoma

by Anja Kafka, Anja Bukovac, Emilija Brglez, Ana-Marija Jarmek, Karolina Poljak, Petar Brlek, Kamelija Žarković, Niko Njirić and Nives Pećina-Šlaus

Cancers 2021, 13(11), 2530; https://doi.org/10.3390/cancers13112530 - 21 May 2021

Cited by 5 | Viewed by 3495

Abstract

In the present study, we investigated genetic and epigenetic changes and protein expression levels of negative regulators of Wnt signaling, DKK1, DKK3, and APC as well as glycogen synthase kinase 3 (GSK3β) and β-catenin in 64 human astrocytomas of grades II–IV. [...] Read more.

In the present study, we investigated genetic and epigenetic changes and protein expression levels of negative regulators of Wnt signaling, DKK1, DKK3, and APC as well as glycogen synthase kinase 3 (GSK3β) and β-catenin in 64 human astrocytomas of grades II–IV. Methylation-specific PCR revealed promoter methylation of DKK1, DKK3, and GSK3β in 38%, 43%, and 18% of samples, respectively. Grade IV comprised the lowest number of methylated GSK3β cases and highest of DKK3. Evaluation of the immunostaining using H-score was performed for β-catenin, both total and unphosphorylated (active) forms. Additionally, active (pY216) and inactive (pS9) forms of GSK3β protein were also analyzed. Spearman’s correlation confirmed the prevalence of β-catenin’s active form (r_s = 0.634, p < 0.001) in astrocytoma tumor cells. The Wilcoxon test revealed that astrocytoma with higher levels of the active pGSK3β-Y216 form had lower expression levels of its inactive form (p < 0.0001, Z = −5.332). Changes in APC’s exon 11 were observed in 44.44% of samples by PCR/RFLP. Astrocytomas with changes of APC had higher H-score values of total β-catenin compared to the group without genetic changes (t = −2.264, p = 0.038). Furthermore, a positive correlation between samples with methylated DKK3 promoter and the expression of active pGSK3β-Y216 (r_s = 0.356, p = 0.011) was established. Our results emphasize the importance of methylation for the regulation of Wnt signaling. Large deletions of the APC gene associated with increased β-catenin levels, together with oncogenic effects of both β-catenin and GSK3β, are clearly involved in astrocytoma evolution. Our findings contribute to a better understanding of the etiology of gliomas. Further studies should elucidate the clinical and therapeutic relevance of the observed molecular alterations. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer: Opportunities Abound If We Can Avoid the Sword of Damocles)

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22 pages, 3113 KiB

Open AccessArticle

p300 Serine 89: A Critical Signaling Integrator and Its Effects on Intestinal Homeostasis and Repair

by Keane K. Y. Lai, Xiaohui Hu, Keisuke Chosa, Cu Nguyen, David P. Lin, Keith K. Lai, Nobuo Kato, Yusuke Higuchi, Sarah K. Highlander, Elizabeth Melendez, Yoshihiro Eriguchi, Patrick T. Fueger, Andre J. Ouellette, Nyam-Osor Chimge, Masaya Ono and Michael Kahn

Cancers 2021, 13(6), 1288; https://doi.org/10.3390/cancers13061288 - 14 Mar 2021

Cited by 11 | Viewed by 3417

Abstract

Differential usage of Kat3 coactivators, CBP and p300, by β-catenin is a fundamental regulatory mechanism in stem cell maintenance and initiation of differentiation and repair. Based upon our earlier pharmacologic studies, p300 serine 89 (S89) is critical for controlling differential coactivator usage by [...] Read more.

Differential usage of Kat3 coactivators, CBP and p300, by β-catenin is a fundamental regulatory mechanism in stem cell maintenance and initiation of differentiation and repair. Based upon our earlier pharmacologic studies, p300 serine 89 (S89) is critical for controlling differential coactivator usage by β-catenin via post-translational phosphorylation in stem/progenitor populations, and appears to be a target for a number of kinase cascades. To further investigate mechanisms of signal integration effected by this domain, we generated p300 S89A knock-in mice. We show that S89A mice are extremely sensitive to intestinal insult resulting in colitis, which is known to significantly increase the risk of developing colorectal cancer. We demonstrate cell intrinsic differences, and microbiome compositional differences and differential immune responses, in intestine of S89A versus wild type mice. Genomic and proteomic analyses reveal pathway differences, including lipid metabolism, oxidative stress response, mitochondrial function and oxidative phosphorylation. The diverse effects on fundamental processes including epithelial differentiation, metabolism, immune response and microbiome colonization, all brought about by a single amino acid modification S89A, highlights the critical role of this region in p300 as a signaling nexus and the rationale for conservation of this residue and surrounding region for hundreds of million years of vertebrate evolution. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer: Opportunities Abound If We Can Avoid the Sword of Damocles)

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16 pages, 2410 KiB

Open AccessArticle

Small Molecule Inhibitors of Microenvironmental Wnt/β-Catenin Signaling Enhance the Chemosensitivity of Acute Myeloid Leukemia

by Paul Takam Kamga, Giada Dal Collo, Adriana Cassaro, Riccardo Bazzoni, Pietro Delfino, Annalisa Adamo, Alice Bonato, Carmine Carbone, Ilaria Tanasi, Massimiliano Bonifacio and Mauro Krampera

Cancers 2020, 12(9), 2696; https://doi.org/10.3390/cancers12092696 - 21 Sep 2020

Cited by 15 | Viewed by 3312

Abstract

Wnt/β-catenin signaling has been reported in Acute Myeloid leukemia, but little is known about its significance as a prognostic biomarker and drug target. In this study, we first evaluated the correlation between expression levels of Wnt molecules and clinical outcome. Then, we studied—in [...] Read more.

Wnt/β-catenin signaling has been reported in Acute Myeloid leukemia, but little is known about its significance as a prognostic biomarker and drug target. In this study, we first evaluated the correlation between expression levels of Wnt molecules and clinical outcome. Then, we studied—in vitro and in vivo—the anti-leukemic value of combinatorial treatment between Wnt inhibitors and classic anti-leukemia drugs. Higher levels of β-catenin, Ser675-phospho-β-catenin and GSK-3α (total and Ser 9) were found in AML cells from intermediate or poor risk patients; nevertheless, patients presenting high activity of Wnt/β-catenin displayed shorter progression-free survival (PFS) according to univariate analysis. In vitro, many pharmacological inhibitors of Wnt signalling, i.e., LRP6 (Niclosamide), GSK-3 (LiCl, AR-A014418), and TCF/LEF (PNU-74654) but not Porcupine (IWP-2), significantly reduced proliferation and improved the drug sensitivity of AML cells cultured alone or in the presence of bone marrow stromal cells. In vivo, PNU-74654, Niclosamide and LiCl administration significantly reduced the bone marrow leukemic burden acting synergistically with Ara-C, thus improving mouse survival. Overall, our study demonstrates the antileukemic role of Wnt/β-catenin inhibition that may represent a potential new therapeutics strategy in AML. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer: Opportunities Abound If We Can Avoid the Sword of Damocles)

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18 pages, 4839 KiB

Open AccessArticle

Identification and Validation of an Aspergillus nidulans Secondary Metabolite Derivative as an Inhibitor of the Musashi-RNA Interaction

by Lan Lan, Jiajun Liu, Minli Xing, Amber R. Smith, Jinan Wang, Xiaoqing Wu, Carl Appelman, Ke Li, Anuradha Roy, Ragul Gowthaman, John Karanicolas, Amber D. Somoza, Clay C. C. Wang, Yinglong Miao, Roberto De Guzman, Berl R. Oakley, Kristi L. Neufeld and Liang Xu

Cancers 2020, 12(8), 2221; https://doi.org/10.3390/cancers12082221 - 8 Aug 2020

Cited by 13 | Viewed by 3614

Abstract

RNA-binding protein Musashi-1 (MSI1) is a key regulator of several stem cell populations. MSI1 is involved in tumor proliferation and maintenance, and it regulates target mRNAs at the translational level. The known mRNA targets of MSI1 include Numb, APC, and P21 [...] Read more.

RNA-binding protein Musashi-1 (MSI1) is a key regulator of several stem cell populations. MSI1 is involved in tumor proliferation and maintenance, and it regulates target mRNAs at the translational level. The known mRNA targets of MSI1 include Numb, APC, and P21^WAF-1, key regulators of Notch/Wnt signaling and cell cycle progression, respectively. In this study, we aim to identify small molecule inhibitors of MSI1–mRNA interactions, which could block the growth of cancer cells with high levels of MSI1. Using a fluorescence polarization (FP) assay, we screened small molecules from several chemical libraries for those that disrupt the binding of MSI1 to its consensus RNA. One cluster of hit compounds is the derivatives of secondary metabolites from Aspergillus nidulans. One of the top hits, Aza-9, from this cluster was further validated by surface plasmon resonance and nuclear magnetic resonance spectroscopy, which demonstrated that Aza-9 binds directly to MSI1, and the binding is at the RNA binding pocket. We also show that Aza-9 binds to Musashi-2 (MSI2) as well. To test whether Aza-9 has anti-cancer potential, we used liposomes to facilitate Aza-9 cellular uptake. Aza-9-liposome inhibits proliferation, induces apoptosis and autophagy, and down-regulates Notch and Wnt signaling in colon cancer cell lines. In conclusion, we identified a series of potential lead compounds for inhibiting MSI1/2 function, while establishing a framework for identifying small molecule inhibitors of RNA binding proteins using FP-based screening methodology. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer: Opportunities Abound If We Can Avoid the Sword of Damocles)

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17 pages, 1638 KiB

Open AccessArticle

Oncogenic Serine 45-Deleted β-Catenin Remains Susceptible to Wnt Stimulation and APC Regulation in Human Colonocytes

by Taybor W. Parker, Aaron J. Rudeen and Kristi L. Neufeld

Cancers 2020, 12(8), 2114; https://doi.org/10.3390/cancers12082114 - 30 Jul 2020

Cited by 5 | Viewed by 3748

Abstract

The Wnt/β-catenin signaling pathway is deregulated in nearly all colorectal cancers (CRCs), predominantly through mutation of the tumor suppressor Adenomatous Polyposis Coli (APC). APC mutation is thought to allow a “just-right” amount of Wnt pathway activation by fine-tuning β-catenin levels. While [...] Read more.

The Wnt/β-catenin signaling pathway is deregulated in nearly all colorectal cancers (CRCs), predominantly through mutation of the tumor suppressor Adenomatous Polyposis Coli (APC). APC mutation is thought to allow a “just-right” amount of Wnt pathway activation by fine-tuning β-catenin levels. While at a much lower frequency, mutations that result in a β-catenin that is compromised for degradation occur in a subset of human CRCs. Here, we investigate whether one such “stabilized” β-catenin responds to regulatory stimuli, thus allowing β-catenin levels conducive for tumor formation. We utilize cells harboring a single mutant allele encoding Ser45-deleted β-catenin (β-catΔS45) to test the effects of Wnt3a treatment or APC-depletion on β-catΔS45 regulation and activity. We find that APC and β-catΔS45 retain interaction with Wnt receptors. Unexpectedly, β-catΔS45 accumulates and activates TOPflash reporter upon Wnt treatment or APC-depletion, but only accumulates in the nucleus upon APC loss. Finally, we find that β-catenin phosphorylation at GSK-3β sites and proteasomal degradation continue to occur in the absence of Ser45. Our results expand the current understanding of Wnt/β-catenin signaling and provide an example of a β-catenin mutation that maintains some ability to respond to Wnt, a possible key to establishing β-catenin activity that is “just-right” for tumorigenesis. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer: Opportunities Abound If We Can Avoid the Sword of Damocles)

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14 pages, 2832 KiB

Open AccessCommunication

Targeting the CBP/β-Catenin Interaction to Suppress Activation of Cancer-Promoting Pancreatic Stellate Cells

by Mingtian Che, Soo-Mi Kweon, Jia-Ling Teo, Yate-Ching Yuan, Laleh G. Melstrom, Richard T. Waldron, Aurelia Lugea, Raul A. Urrutia, Stephen J. Pandol and Keane K. Y. Lai

Cancers 2020, 12(6), 1476; https://doi.org/10.3390/cancers12061476 - 5 Jun 2020

Cited by 14 | Viewed by 3558

Abstract

Background: Although cyclic AMP-response element binding protein-binding protein (CBP)/β-catenin signaling is known to promote proliferation and fibrosis in various organ systems, its role in the activation of pancreatic stellate cells (PSCs), the key effector cells of desmoplasia in pancreatic cancer and fibrosis in [...] Read more.

Background: Although cyclic AMP-response element binding protein-binding protein (CBP)/β-catenin signaling is known to promote proliferation and fibrosis in various organ systems, its role in the activation of pancreatic stellate cells (PSCs), the key effector cells of desmoplasia in pancreatic cancer and fibrosis in chronic pancreatitis, is largely unknown. Methods: To investigate the role of the CBP/β-catenin signaling pathway in the activation of PSCs, we have treated mouse and human PSCs with the small molecule specific CBP/β-catenin antagonist ICG-001 and examined the effects of treatment on parameters of activation. Results: We report for the first time that CBP/β-catenin antagonism suppresses activation of PSCs as evidenced by their decreased proliferation, down-regulation of “activation” markers, e.g., α-smooth muscle actin (α-SMA/Acta2), collagen type I alpha 1 (Col1a1), Prolyl 4-hydroxylase, and Survivin, up-regulation of peroxisome proliferator activated receptor gamma (Ppar-γ) which is associated with quiescence, and reduced migration; additionally, CBP/β-catenin antagonism also suppresses PSC-induced migration of cancer cells. Conclusion: CBP/β-catenin antagonism represents a novel therapeutic strategy for suppressing PSC activation and may be effective at countering PSC promotion of pancreatic cancer. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer: Opportunities Abound If We Can Avoid the Sword of Damocles)

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14 pages, 1299 KiB

Open AccessArticle

The Hepatitis B Virus Pre-Core Protein p22 Activates Wnt Signaling

by Bang Manh Tran, Dustin James Flanagan, Gregor Ebert, Nadia Warner, Hoanh Tran, Theodora Fifis, Georgios Kastrappis, Christopher Christophi, Marc Pellegrini, Joseph Torresi, Toby James Phesse and Elizabeth Vincan

Cancers 2020, 12(6), 1435; https://doi.org/10.3390/cancers12061435 - 31 May 2020

Cited by 16 | Viewed by 3872

Abstract

An emerging theme for Wnt-addicted cancers is that the pathway is regulated at multiple steps via various mechanisms. Infection with hepatitis B virus (HBV) is a major risk factor for liver cancer, as is deregulated Wnt signaling, however, the interaction between these two [...] Read more.

An emerging theme for Wnt-addicted cancers is that the pathway is regulated at multiple steps via various mechanisms. Infection with hepatitis B virus (HBV) is a major risk factor for liver cancer, as is deregulated Wnt signaling, however, the interaction between these two causes is poorly understood. To investigate this interaction, we screened the effect of the various HBV proteins for their effect on Wnt/β-catenin signaling and identified the pre-core protein p22 as a novel and potent activator of TCF/β-catenin transcription. The effect of p22 on TCF/β-catenin transcription was dose dependent and inhibited by dominant-negative TCF4. HBV p22 activated synthetic and native Wnt target gene promoter reporters, and TCF/β-catenin target gene expression in vivo. Importantly, HBV p22 activated Wnt signaling on its own and in addition to Wnt or β-catenin induced Wnt signaling. Furthermore, HBV p22 elevated TCF/β-catenin transcription above constitutive activation in colon cancer cells due to mutations in downstream genes of the Wnt pathway, namely APC and CTNNB1. Collectively, our data identifies a previously unappreciated role for the HBV pre-core protein p22 in elevating Wnt signaling. Understanding the molecular mechanisms of p22 activity will provide insight into how Wnt signaling is fine-tuned in cancer. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer: Opportunities Abound If We Can Avoid the Sword of Damocles)

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17 pages, 3934 KiB

Open AccessArticle

Feasibility of Targeting Traf2-and-Nck-Interacting Kinase in Synovial Sarcoma

by Tetsuya Sekita, Tesshi Yamada, Eisuke Kobayashi, Akihiko Yoshida, Toru Hirozane, Akira Kawai, Yuko Uno, Hideki Moriyama, Masaaki Sawa, Yuichi Nagakawa, Akihiko Tsuchida, Morio Matsumoto, Masaya Nakamura, Robert Nakayama and Mari Masuda

Cancers 2020, 12(5), 1258; https://doi.org/10.3390/cancers12051258 - 16 May 2020

Cited by 16 | Viewed by 5579

Abstract

Background: The treatment of patients with metastatic synovial sarcoma is still challenging, and the development of new molecular therapeutics is desirable. Dysregulation of Wnt signaling has been implicated in synovial sarcoma. Traf2-and-Nck-interacting kinase (TNIK) is an essential transcriptional co-regulator of Wnt target genes. [...] Read more.

Background: The treatment of patients with metastatic synovial sarcoma is still challenging, and the development of new molecular therapeutics is desirable. Dysregulation of Wnt signaling has been implicated in synovial sarcoma. Traf2-and-Nck-interacting kinase (TNIK) is an essential transcriptional co-regulator of Wnt target genes. We examined the efficacy of a small interfering RNA (siRNA) to TNIK and a small-molecule TNIK inhibitor, NCB-0846, for synovial sarcoma. Methods: The expression of TNIK was determined in 20 clinical samples of synovial sarcoma. The efficacy of NCB-0846 was evaluated in four synovial sarcoma cell lines and a mouse xenograft model. Results: We found that synovial sarcoma cell lines with Wnt activation were highly dependent upon the expression of TNIK for proliferation and survival. NCB-0846 induced apoptotic cell death in synovial sarcoma cells through blocking of Wnt target genes including MYC, and oral administration of NCB-846 induced regression of xenografts established by inoculation of synovial sarcoma cells. Discussion: It has become evident that activation of Wnt signaling is causatively involved in the pathogenesis of synovial sarcoma, but no molecular therapeutics targeting the pathway have been approved. This study revealed for the first time the therapeutic potential of TNIK inhibition in synovial sarcoma. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer: Opportunities Abound If We Can Avoid the Sword of Damocles)

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Review

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15 pages, 1446 KiB

Open AccessReview

β-Catenin Activation in Hepatocellular Cancer: Implications in Biology and Therapy

by Yekaterina Krutsenko, Aatur D. Singhi and Satdarshan P. Monga

Cancers 2021, 13(8), 1830; https://doi.org/10.3390/cancers13081830 - 12 Apr 2021

Cited by 20 | Viewed by 3902

Abstract

Hepatocellular cancer (HCC), the most common primary liver tumor, has been gradually growing in incidence globally. The whole-genome and whole-exome sequencing of HCC has led to an improved understanding of the molecular drivers of this tumor type. Activation of the Wnt signaling pathway, [...] Read more.

Hepatocellular cancer (HCC), the most common primary liver tumor, has been gradually growing in incidence globally. The whole-genome and whole-exome sequencing of HCC has led to an improved understanding of the molecular drivers of this tumor type. Activation of the Wnt signaling pathway, mostly due to stabilizing missense mutations in its downstream effector β-catenin (encoded by CTNNB1) or loss-of-function mutations in AXIN1 (the gene which encodes for Axin-1, an essential protein for β-catenin degradation), are seen in a major subset of HCC. Because of the important role of β-catenin in liver pathobiology, its role in HCC has been extensively investigated. In fact, CTNNB1 mutations have been shown to have a trunk role. β-Catenin has been shown to play an important role in regulating tumor cell proliferation and survival and in tumor angiogenesis, due to a host of target genes regulated by the β-catenin transactivation of its transcriptional factor TCF. Proof-of-concept preclinical studies have shown β-catenin to be a highly relevant therapeutic target in CTNNB1-mutated HCCs. More recently, studies have revealed a unique role of β-catenin activation in regulating both tumor metabolism as well as the tumor immune microenvironment. Both these roles have notable implications for the development of novel therapies for HCC. Thus, β-catenin has a pertinent role in driving HCC development and maintenance of this tumor-type, and could be a highly relevant therapeutic target in a subset of HCC cases. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer: Opportunities Abound If We Can Avoid the Sword of Damocles)

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13 pages, 2116 KiB

Open AccessReview

Wnt/β-Catenin Signaling and Immunotherapy Resistance: Lessons for the Treatment of Urothelial Carcinoma

by Alexander Chehrazi-Raffle, Tanya B. Dorff, Sumanta K. Pal and Yung Lyou

Cancers 2021, 13(4), 889; https://doi.org/10.3390/cancers13040889 - 20 Feb 2021

Cited by 25 | Viewed by 5023

Abstract

Urothelial cell carcinoma (UCC) is a significant public health burden. It accounts for approximately 90 percent of all bladder cancers with an estimated 200,000 annual deaths globally. Platinum based cytotoxic chemotherapy combinations are the current standard of care in the frontline setting for [...] Read more.

Urothelial cell carcinoma (UCC) is a significant public health burden. It accounts for approximately 90 percent of all bladder cancers with an estimated 200,000 annual deaths globally. Platinum based cytotoxic chemotherapy combinations are the current standard of care in the frontline setting for metastatic UCC. Even with these treatments the median overall survival is estimated to be about 15 months. Recently, immune checkpoint inhibitors (ICIs) have demonstrated superior clinical benefits compared to second line chemotherapy in UCC treatment. However only a minority of patients (~20%) respond to ICIs, which highlights the need to better understand the mechanisms behind resistance. In this review, we (i) examine the pathophysiology of Wnt/β-catenin signaling, (ii) discuss pre-clinical evidence that supports the combination of Wnt/β-catenin inhibitors and ICI, and (iii) propose future combination treatments that could be investigated through clinical trials. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer: Opportunities Abound If We Can Avoid the Sword of Damocles)

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27 pages, 1510 KiB

Open AccessReview

Targeting Wnt Signaling for Gastrointestinal Cancer Therapy: Present and Evolving Views

by Moon Jong Kim, Yuanjian Huang and Jae-Il Park

Cancers 2020, 12(12), 3638; https://doi.org/10.3390/cancers12123638 - 4 Dec 2020

Cited by 26 | Viewed by 4274

Abstract

Wnt signaling governs tissue development, homeostasis, and regeneration. However, aberrant activation of Wnt promotes tumorigenesis. Despite the ongoing efforts to manipulate Wnt signaling, therapeutic targeting of Wnt signaling remains challenging. In this review, we provide an overview of current clinical trials to target [...] Read more.

Wnt signaling governs tissue development, homeostasis, and regeneration. However, aberrant activation of Wnt promotes tumorigenesis. Despite the ongoing efforts to manipulate Wnt signaling, therapeutic targeting of Wnt signaling remains challenging. In this review, we provide an overview of current clinical trials to target Wnt signaling, with a major focus on gastrointestinal cancers. In addition, we discuss the caveats and alternative strategies for therapeutically targeting Wnt signaling for cancer treatment. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer: Opportunities Abound If We Can Avoid the Sword of Damocles)

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40 pages, 1305 KiB

Open AccessReview

Angiogenesis-Related Functions of Wnt Signaling in Colorectal Carcinogenesis

by Aldona Kasprzak

Cancers 2020, 12(12), 3601; https://doi.org/10.3390/cancers12123601 - 2 Dec 2020

Cited by 39 | Viewed by 4292

Abstract

Aberrant activation of the Wnt/Fzd/β-catenin signaling pathway is one of the major molecular mechanisms of colorectal cancer (CRC) development and progression. On the other hand, one of the most common clinical CRC characteristics include high levels of angiogenesis, which is a key event [...] Read more.

Aberrant activation of the Wnt/Fzd/β-catenin signaling pathway is one of the major molecular mechanisms of colorectal cancer (CRC) development and progression. On the other hand, one of the most common clinical CRC characteristics include high levels of angiogenesis, which is a key event in cancer cell dissemination and distant metastasis. The canonical Wnt/β-catenin downstream signaling regulates the most important pro-angiogenic molecules including vascular endothelial growth factor (VEGF) family members, matrix metalloproteinases (MMPs), and chemokines. Furthermore, mutations of the β-catenin gene associated with nuclear localization of the protein have been mainly detected in microsatellite unstable CRC. Elevated nuclear β-catenin increases the expression of many genes involved in tumor angiogenesis. Factors regulating angiogenesis with the participation of Wnt/β-catenin signaling include different groups of biologically active molecules including Wnt pathway components (e.g., Wnt2, DKK, BCL9 proteins), and non-Wnt pathway factors (e.g., chemoattractant cytokines, enzymatic proteins, and bioactive compounds of plants). Several lines of evidence argue for the use of angiogenesis inhibition in the treatment of CRC. In the context of this paper, components of the Wnt pathway are among the most promising targets for CRC therapy. This review summarizes the current knowledge about the role of the Wnt/Fzd/β-catenin signaling pathway in the process of CRC angiogenesis, aiming to improve the understanding of the mechanisms of metastasis as well as improvements in the management of this cancer. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer: Opportunities Abound If We Can Avoid the Sword of Damocles)

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13 pages, 3774 KiB

Open AccessReview

Wnt/β-Catenin Target Genes in Colon Cancer Metastasis: The Special Case of L1CAM

by Sanith Cheriyamundath and Avri Ben-Ze’ev

Cancers 2020, 12(11), 3444; https://doi.org/10.3390/cancers12113444 - 19 Nov 2020

Cited by 23 | Viewed by 3822

Abstract

Cell adhesion to neighboring cells is a fundamental biological process in multicellular organisms that is required for tissue morphogenesis. A tight coordination between cell–cell adhesion, signaling, and gene expression is a characteristic feature of normal tissues. Changes, and often disruption of this coordination, [...] Read more.

Cell adhesion to neighboring cells is a fundamental biological process in multicellular organisms that is required for tissue morphogenesis. A tight coordination between cell–cell adhesion, signaling, and gene expression is a characteristic feature of normal tissues. Changes, and often disruption of this coordination, are common during invasive and metastatic cancer development. The Wnt/β-catenin signaling pathway is an excellent model for studying the role of adhesion-mediated signaling in colorectal cancer (CRC) invasion and metastasis, because β-catenin has a dual role in the cell; it is a major adhesion linker of cadherin transmembrane receptors to the cytoskeleton and, in addition, it is also a key transducer of Wnt signaling to the nucleus, where it acts as a co-transcriptional activator of Wnt target genes. Hyperactivation of Wnt/β-catenin signaling is a common feature in the majority of CRC patients. We found that the neural cell adhesion receptor L1CAM (L1) is a target gene of β-catenin signaling and is induced in carcinoma cells of CRC patients, where it plays an important role in CRC metastasis. In this review, we will discuss studies on β-catenin target genes activated during CRC development (in particular, L1), the signaling pathways affected by L1, and the role of downstream target genes activated by L1 overexpression, especially those that are also part of the intestinal stem cell gene signature. As intestinal stem cells are highly regulated by Wnt signaling and are believed to also play major roles in CRC progression, unravelling the mechanisms underlying the regulation of these genes will shed light on both normal intestinal homeostasis and the development of invasive and metastatic CRC. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer: Opportunities Abound If We Can Avoid the Sword of Damocles)

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19 pages, 976 KiB

Open AccessReview

Wnt and Vitamin D at the Crossroads in Solid Cancer

by José Manuel González-Sancho, María Jesús Larriba and Alberto Muñoz

Cancers 2020, 12(11), 3434; https://doi.org/10.3390/cancers12113434 - 19 Nov 2020

Cited by 23 | Viewed by 3894

Abstract

Abnormal activation of the Wnt/β-catenin pathway is common in many types of solid cancers. Likewise, a large proportion of cancer patients have vitamin D deficiency. In line with these observations, Wnt/β-catenin signaling and 1α,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), the active [...] Read more.

Abnormal activation of the Wnt/β-catenin pathway is common in many types of solid cancers. Likewise, a large proportion of cancer patients have vitamin D deficiency. In line with these observations, Wnt/β-catenin signaling and 1α,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), the active vitamin D metabolite, usually have opposite effects on cancer cell proliferation and phenotype. In recent years, an increasing number of studies performed in a variety of cancer types have revealed a complex crosstalk between Wnt/β-catenin signaling and 1,25(OH)₂D₃. Here we review the mechanisms by which 1,25(OH)₂D₃ inhibits Wnt/β-catenin signaling and, conversely, how the activated Wnt/β-catenin pathway may abrogate vitamin D action. The available data suggest that interaction between Wnt/β-catenin signaling and the vitamin D system is at the crossroads in solid cancers and may have therapeutic applications. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer: Opportunities Abound If We Can Avoid the Sword of Damocles)

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16 pages, 1642 KiB

Open AccessReview

Not All Wnt Activation Is Equal: Ligand-Dependent versus Ligand-Independent Wnt Activation in Colorectal Cancer

by Sam O. Kleeman and Simon J. Leedham

Cancers 2020, 12(11), 3355; https://doi.org/10.3390/cancers12113355 - 13 Nov 2020

Cited by 28 | Viewed by 4704

Abstract

Wnt signaling is ubiquitously activated in colorectal tumors and driver mutations are identified in genes such as APC, CTNNB1, RNF43 and R-spondin (RSPO2/3). Adenomatous polyposis coli (APC) and CTNNB1 mutations lead to downstream constitutive activation (ligand-independent), while RNF43 and RSPO mutations require exogenous [...] Read more.

Wnt signaling is ubiquitously activated in colorectal tumors and driver mutations are identified in genes such as APC, CTNNB1, RNF43 and R-spondin (RSPO2/3). Adenomatous polyposis coli (APC) and CTNNB1 mutations lead to downstream constitutive activation (ligand-independent), while RNF43 and RSPO mutations require exogenous Wnt ligand to activate signaling (ligand-dependent). Here, we present evidence that these mutations are not equivalent and that ligand-dependent and ligand-independent tumors differ in terms of underlying Wnt biology, molecular pathogenesis, morphology and prognosis. These non-overlapping characteristics can be harnessed to develop biomarkers and targeted treatments for ligand-dependent tumors, including porcupine inhibitors, anti-RSPO3 antibodies and asparaginase. There is emerging evidence that these therapies may synergize with immunotherapy in ligand-dependent tumors. In summary, we propose that ligand-dependent tumors are an underappreciated separate disease entity in colorectal cancer. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer: Opportunities Abound If We Can Avoid the Sword of Damocles)

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