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20 pages, 3651 KiB

Open AccessArticle

Impact of Wnt/β-Catenin Inhibition on Cell Proliferation through CDC25A Downregulation in Soft Tissue Sarcomas

by Esther Martinez-Font, Marina Pérez-Capó, Rafael Ramos, Irene Felipe, Carmen Garcías, Pablo Luna, Josefa Terrasa, Javier Martín-Broto, Oliver Vögler, Regina Alemany and Antònia Obrador-Hevia

Cancers 2020, 12(9), 2556; https://doi.org/10.3390/cancers12092556 - 8 Sep 2020

Cited by 15 | Viewed by 3376

Abstract

The Wnt signaling pathway is an important cellular mechanism for regulating differentiation processes as well as cell cycle events, and different inhibitors of this pathway, for example, PRI-724, are showing promising results in clinical trials for treatment of advanced pancreatic adenocarcinoma or ovarian [...] Read more.

The Wnt signaling pathway is an important cellular mechanism for regulating differentiation processes as well as cell cycle events, and different inhibitors of this pathway, for example, PRI-724, are showing promising results in clinical trials for treatment of advanced pancreatic adenocarcinoma or ovarian cancer. Growing evidence suggests that Wnt signaling may also be crucial for tumorigenesis and progression of soft tissue sarcomas (STS), a malignant neoplasm with few therapeutic options at an advanced state. Our study with several STS cell lines and primary cultures shows that inhibition of Wnt/β-catenin signaling with PRI-724 is able to suppress cell viability/proliferation and to increase cell death rates. TCF/β-catenin-mediated transcriptional activity is decreased in treated cells, leading to downregulation of its target genes CCND1 and CDC25A. The latter was critical because its downregulation via siRNA was able to mimic the effect of PRI-724 on cell cycle arrest and cell death induction. An evaluation of NCBI/GenBank data confirmed that CDC25A mRNA is elevated in STS patients. Importantly, PRI-724 in combination with standard STS chemotherapeutics doxorubicin or trabectedin enhanced their antitumoral effect in a synergistic manner according to isobolographic analysis, suggesting that Wnt inhibition through PRI-724 could be a beneficial combination regime in patients with advanced STS. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer)

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22 pages, 3623 KiB

Open AccessArticle

Inhibiting WNT Ligand Production for Improved Immune Recognition in the Ovarian Tumor Microenvironment

by Whitney N. Goldsberry, Selene Meza-Perez, Angelina I. Londoño, Ashwini A. Katre, Bryan T. Mott, Brandon M. Roane, Nidhi Goel, Jaclyn A. Wall, Sara J. Cooper, Lyse A. Norian, Troy D. Randall, Michael J. Birrer and Rebecca C. Arend

Cancers 2020, 12(3), 766; https://doi.org/10.3390/cancers12030766 - 24 Mar 2020

Cited by 19 | Viewed by 4940

Abstract

In ovarian cancer, upregulation of the Wnt/β–catenin pathway leads to chemoresistance and correlates with T cell exclusion from the tumor microenvironment (TME). Our objectives were to validate these findings in an independent cohort of ovarian cancer subjects and determine whether inhibiting the Wnt [...] Read more.

In ovarian cancer, upregulation of the Wnt/β–catenin pathway leads to chemoresistance and correlates with T cell exclusion from the tumor microenvironment (TME). Our objectives were to validate these findings in an independent cohort of ovarian cancer subjects and determine whether inhibiting the Wnt pathway in a syngeneic ovarian cancer murine model could create a more T-cell-inflamed TME, which would lead to decreased tumor growth and improved survival. We preformed RNA sequencing in a cohort of human high grade serous ovarian carcinoma subjects. We used CGX1321, an inhibitor to the porcupine (PORCN) enzyme that is necessary for secretion of WNT ligand, in mice with established ID8 tumors, a murine ovarian cancer cell line. In order to investigate the effect of decreased Wnt/β–catenin pathway activity in the dendritic cells (DCs), we injected ID8 cells in mice that lacked β–catenin specifically in DCs. Furthermore, to understand how much the effects of blocking the Wnt/β–catenin pathway are dependent on CD8⁺ T cells, we injected ID8 cells into mice with CD8⁺ T cell depletion. We confirmed a negative correlation between Wnt activity and T cell signature in our cohort. Decreasing WNT ligand production resulted in increases in T cell, macrophage and dendritic cell functions, decreased tumor burden and improved survival. Reduced tumor growth was found in mice that lacked β–catenin specifically in DCs. When CD8⁺ T cells were depleted, CGX1321 treatment did not have the same magnitude of effect on tumor growth. Our investigation confirmed an increase in Wnt activity correlated with a decreased T-cell-inflamed environment; a relationship that was further supported in our pre-clinical model that suggests inhibiting the Wnt/β–catenin pathway was associated with decreased tumor growth and improved survival via a partial dependence on CD8⁺ T cells. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer)

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18 pages, 4749 KiB

Open AccessArticle

Simultaneous Multi-Organ Metastases from Chemo-Resistant Triple-Negative Breast Cancer Are Prevented by Interfering with WNT-Signaling

by Iram Fatima, Ikbale El-Ayachi, Hilaire C. Playa, Jackelyn A. Alva-Ornelas, Aysha B. Khalid, William L. Kuenzinger, Peter Wend, Jackelyn C. Pence, Lauren Brakefield, Raisa I. Krutilina, Daniel L. Johnson, Ruth M. O’Regan, Victoria Seewaldt, Tiffany N. Seagroves, Susan A. Krum and Gustavo A. Miranda-Carboni

Cancers 2019, 11(12), 2039; https://doi.org/10.3390/cancers11122039 - 17 Dec 2019

Cited by 28 | Viewed by 4360

Abstract

Triple-negative breast cancers (TNBCs), which lack specific targeted therapy options, evolve into highly chemo-resistant tumors that metastasize to multiple organs simultaneously. We have previously shown that TNBCs maintain an activated WNT10B-driven network that drives metastasis. Pharmacologic inhibition by ICG-001 decreases β-catenin-mediated proliferation of [...] Read more.

Triple-negative breast cancers (TNBCs), which lack specific targeted therapy options, evolve into highly chemo-resistant tumors that metastasize to multiple organs simultaneously. We have previously shown that TNBCs maintain an activated WNT10B-driven network that drives metastasis. Pharmacologic inhibition by ICG-001 decreases β-catenin-mediated proliferation of multiple TNBC cell lines and TNBC patient-derived xenograft (PDX)-derived cell lines. In vitro, ICG-001 was effective in combination with the conventional cytotoxic chemotherapeutics, cisplatin and doxorubicin, to decrease the proliferation of MDA-MB-231 cells. In contrast, in TNBC PDX-derived cells doxorubicin plus ICG-001 was synergistic, while pairing with cisplatin was not as effective. Mechanistically, cytotoxicity induced by doxorubicin, but not cisplatin, with ICG-001 was associated with increased cleavage of PARP-1 in the PDX cells only. In vivo, MDA-MB-231 and TNBC PDX orthotopic primary tumors initiated de novo simultaneous multi-organ metastases, including bone metastases. WNT monotherapy blocked multi-organ metastases as measured by luciferase imaging and histology. The loss of expression of the WNT10B/β-catenin direct targets HMGA2, EZH2, AXIN2, MYC, PCNA, CCND1, transcriptionally active β-catenin, SNAIL and vimentin both in vitro and in vivo in the primary tumors mechanistically explains loss of multi-organ metastases. WNT monotherapy induced VEGFA expression in both tumor model systems, whereas increased CD31 was observed only in the MDA-MB-231 tumors. Moreover, WNT-inhibition sensitized the anticancer response of the TNBC PDX model to doxorubicin, preventing simultaneous metastases to the liver and ovaries, as well as to bone. Our data demonstrate that WNT-inhibition sensitizes TNBC to anthracyclines and treats multi-organ metastases of TNBC. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer)

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19 pages, 10627 KiB

Open AccessArticle

Novel Thienopyrimidine Derivative, RP-010, Induces β-Catenin Fragmentation and Is Efficacious against Prostate Cancer Cells

by Haneen Amawi, Noor Hussein, Sai H. S. Boddu, Chandrabose Karthikeyan, Frederick E. Williams, Charles R. Ashby, Jr., Dayanidhi Raman, Piyush Trivedi and Amit K. Tiwari

Cancers 2019, 11(5), 711; https://doi.org/10.3390/cancers11050711 - 23 May 2019

Cited by 17 | Viewed by 4589

Abstract

Thienopyrimidines containing a thiophene ring fused to pyrimidine are reported to have a wide-spectrum of anticancer efficacy in vitro. Here, we report for the first time that thieno[3,2-d]pyrimidine-based compounds, also known as the RP series, have efficacy in prostate cancer cells. [...] Read more.

Thienopyrimidines containing a thiophene ring fused to pyrimidine are reported to have a wide-spectrum of anticancer efficacy in vitro. Here, we report for the first time that thieno[3,2-d]pyrimidine-based compounds, also known as the RP series, have efficacy in prostate cancer cells. The compound RP-010 was efficacious against both PC-3 and DU145 prostate cancer (PC) cells (IC₅₀ < 1 µM). The cytotoxicity of RP-010 was significantly lower in non-PC, CHO, and CRL-1459 cell lines. RP-010 (0.5, 1, 2, and 4 µM) arrested prostate cancer cells in G2 phase of the cell cycle, and induced mitotic catastrophe and apoptosis in both PC cell lines. Mechanistic studies suggested that RP-010 (1 and 2 µM) affected the wingless-type MMTV (Wnt)/β-catenin signaling pathway, in association with β-catenin fragmentation, while also downregulating important proteins in the pathway, including LRP-6, DVL3, and c-Myc. Interestingly, RP-010 (1 and 2 µM) induced nuclear translocation of the negative feedback proteins, Naked 1 and Naked 2, in the Wnt pathway. In addition, RP-010 (0.5, 1, 2 and 4 µM) significantly decreased the migration of PC cells in vitro. Finally, RP-010 did not produce significant toxic effects in zebrafish at concentrations of up to 6 µM. In conclusion, RP-010 may be an efficacious and relatively nontoxic anticancer compound for prostate cancer. Future mechanistic and in vivo efficacy studies are needed to optimize the hit compound RP-010 for lead optimization and clinical use. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer)

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19 pages, 24736 KiB

Open AccessArticle

Modulating PKCα Activity to Target Wnt/β-Catenin Signaling in Colon Cancer

by Sébastien Dupasquier, Philippe Blache, Laurence Picque Lasorsa, Han Zhao, Jean-Daniel Abraham, Jody J. Haigh, Marc Ychou and Corinne Prévostel

Cancers 2019, 11(5), 693; https://doi.org/10.3390/cancers11050693 - 18 May 2019

Cited by 23 | Viewed by 4135

Abstract

Inactivating mutations of the tumor suppressor Adenomatosis Polyposis Coli (APC), which are found in familial adenomatosis polyposis and in 80% of sporadic colorectal cancers (CRC), result in constitutive activation of the Wnt/β-catenin pathway and tumor development in the intestine. These mutations disconnect the [...] Read more.

Inactivating mutations of the tumor suppressor Adenomatosis Polyposis Coli (APC), which are found in familial adenomatosis polyposis and in 80% of sporadic colorectal cancers (CRC), result in constitutive activation of the Wnt/β-catenin pathway and tumor development in the intestine. These mutations disconnect the Wnt/β-catenin pathway from its Wnt extracellular signal by inactivating the APC/GSK3-β/axin destruction complex of β-catenin. This results in sustained nuclear accumulation of β-catenin, followed by β-catenin-dependent co-transcriptional activation of Wnt/β-catenin target genes. Thus, mechanisms acting downstream of APC, such as those controlling β-catenin stability and/or co-transcriptional activity, are attractive targets for CRC treatment. Protein Kinase C-α (PKCα) phosphorylates the orphan receptor RORα that then inhibits β-catenin co-transcriptional activity. PKCα also phosphorylates β-catenin, leading to its degradation by the proteasome. Here, using both in vitro (DLD-1 cells) and in vivo (C57BL/6J mice) PKCα knock-in models, we investigated whether enhancing PKCα function could be beneficial in CRC treatment. We found that PKCα is infrequently mutated in CRC samples, and that inducing PKCα function is not deleterious for the normal intestinal epithelium. Conversely, di-terpene ester-induced PKCα activity triggers CRC cell death. Together, these data indicate that PKCα is a relevant drug target for CRC treatment. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer)

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16 pages, 5861 KiB

Open AccessArticle

YC-1 Antagonizes Wnt/β-Catenin Signaling Through the EBP1 p42 Isoform in Hepatocellular Carcinoma

by Ju-Yun Wu, Yu-Lueng Shih, Shih-Ping Lin, Tsai-Yuan Hsieh and Ya-Wen Lin

Cancers 2019, 11(5), 661; https://doi.org/10.3390/cancers11050661 - 13 May 2019

Cited by 8 | Viewed by 4050

Abstract

Novel drugs targeting Wnt signaling are gradually being developed for hepatocellular carcinoma (HCC) treatment. In this study, we used a Wnt-responsive Super-TOPflash (STF) luciferase reporter assay to screen a new compound targeting Wnt signaling. 3-(5′-Hydroxymethyl-2′-furyl)-1-benzylindazole (YC-1) was identified as a small molecule inhibitor [...] Read more.

Novel drugs targeting Wnt signaling are gradually being developed for hepatocellular carcinoma (HCC) treatment. In this study, we used a Wnt-responsive Super-TOPflash (STF) luciferase reporter assay to screen a new compound targeting Wnt signaling. 3-(5′-Hydroxymethyl-2′-furyl)-1-benzylindazole (YC-1) was identified as a small molecule inhibitor of the Wnt/β-catenin pathway. Our coimmunoprecipitation (co-IP) data showed that YC-1 did not affect the β-catenin/TCF interaction. Then, by mass spectrometry, we identified the ErbB3 receptor-binding protein 1 (EBP1) interaction with the β-catenin/TCF complex upon YC-1 treatment. EBP1 encodes two splice isoforms, p42 and p48. We further demonstrated that YC-1 enhances p42 isoform binding to the β-catenin/TCF complex and reduces the transcriptional activity of the complex. The suppression of colony formation by YC-1 was significantly reversed after knockdown of both isoforms (p48 and p42); however, the inhibition of colony formation was maintained when only EBP1 p48 was silenced. Taken together, these results suggest that YC-1 treatment results in a reduction in Wnt-regulated transcription through EBP1 p42 and leads to the inhibition of tumor cell proliferation. These data imply that YC-1 is a drug that antagonizes Wnt/β-catenin signaling in HCC. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer)

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Review

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22 pages, 1760 KiB

Open AccessReview

Wnt Signaling Pathways in Keratinocyte Carcinomas

by Christopher M. R. Lang, Chim Kei Chan, Anthony Veltri and Wen-Hui Lien

Cancers 2019, 11(9), 1216; https://doi.org/10.3390/cancers11091216 - 21 Aug 2019

Cited by 29 | Viewed by 5801

Abstract

The skin functions as a barrier between the organism and the surrounding environment. Direct exposure to external stimuli and the accumulation of genetic mutations may lead to abnormal cell growth, irreversible tissue damage and potentially favor skin malignancy. Skin homeostasis is coordinated by [...] Read more.

The skin functions as a barrier between the organism and the surrounding environment. Direct exposure to external stimuli and the accumulation of genetic mutations may lead to abnormal cell growth, irreversible tissue damage and potentially favor skin malignancy. Skin homeostasis is coordinated by an intricate signaling network, and its dysregulation has been implicated in the development of skin cancers. Wnt signaling is one such regulatory pathway orchestrating skin development, homeostasis, and stem cell activation. Aberrant regulation of Wnt signaling cascades not only gives rise to tumor initiation, progression and invasion, but also maintains cancer stem cells which contribute to tumor recurrence. In this review, we summarize recent studies highlighting functional evidence of Wnt-related oncology in keratinocyte carcinomas, as well as discussing preclinical and clinical approaches that target oncogenic Wnt signaling to treat cancers. Our review provides valuable insight into the significance of Wnt signaling for future interventions against keratinocyte carcinomas. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer)

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23 pages, 2129 KiB

Open AccessReview

A Role for the WNT Co-Receptor LRP6 in Pathogenesis and Therapy of Epithelial Cancers

by Jennifer Raisch, Anthony Côté-Biron and Nathalie Rivard

Cancers 2019, 11(8), 1162; https://doi.org/10.3390/cancers11081162 - 13 Aug 2019

Cited by 47 | Viewed by 6944

Abstract

The WNT/β-catenin signaling pathway controls stem and progenitor cell proliferation, survival and differentiation in epithelial tissues. Aberrant stimulation of this pathway is therefore frequently observed in cancers from epithelial origin. For instance, colorectal and hepatic cancers display activating mutations in the CTNNB1 gene [...] Read more.

The WNT/β-catenin signaling pathway controls stem and progenitor cell proliferation, survival and differentiation in epithelial tissues. Aberrant stimulation of this pathway is therefore frequently observed in cancers from epithelial origin. For instance, colorectal and hepatic cancers display activating mutations in the CTNNB1 gene encoding β-catenin, or inactivating APC and AXIN gene mutations. However, these mutations are uncommon in breast and pancreatic cancers despite nuclear β-catenin localization, indicative of pathway activation. Notably, the low-density lipoprotein receptor-related protein 6 (LRP6), an indispensable co-receptor for WNT, is frequently overexpressed in colorectal, liver, breast and pancreatic adenocarcinomas in association with increased WNT/β -catenin signaling. Moreover, LRP6 is hyperphosphorylated in KRAS-mutated cells and in patient-derived colorectal tumours. Polymorphisms in the LRP6 gene are also associated with different susceptibility to developing specific types of lung, bladder and colorectal cancers. Additionally, recent observations suggest that LRP6 dysfunction may be involved in carcinogenesis. Indeed, reducing LRP6 expression and/or activity inhibits cancer cell proliferation and delays tumour growth in vivo. This review summarizes current knowledge regarding the biological function and regulation of LRP6 in the development of epithelial cancers—especially colorectal, liver, breast and pancreatic cancers. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer)

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15 pages, 1969 KiB

Open AccessReview

WNT Signaling in Neuroblastoma

by Juergen Becker and Joerg Wilting

Cancers 2019, 11(7), 1013; https://doi.org/10.3390/cancers11071013 - 19 Jul 2019

Cited by 24 | Viewed by 6078

Abstract

The term WNT (wingless-type MMTV integration site family) signaling comprises a complex molecular pathway consisting of ligands, receptors, coreceptors, signal transducers and transcriptional modulators with crucial functions during embryonic development, including all aspects of proliferation, morphogenesis and differentiation. Its involvement in cancer biology [...] Read more.

The term WNT (wingless-type MMTV integration site family) signaling comprises a complex molecular pathway consisting of ligands, receptors, coreceptors, signal transducers and transcriptional modulators with crucial functions during embryonic development, including all aspects of proliferation, morphogenesis and differentiation. Its involvement in cancer biology is well documented. Even though WNT signaling has been divided into mainly three distinct branches in the past, increasing evidence shows that some molecular hubs can act in various branches by exchanging interaction partners. Here we discuss developmental and clinical aspects of WNT signaling in neuroblastoma (NB), an embryonic tumor with an extremely broad clinical spectrum, ranging from spontaneous differentiation to fatal outcome. We discuss implications of WNT molecules in NB onset, progression, and relapse due to chemoresistance. In the light of the still too high number of NB deaths, new pathways must be considered. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer)

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16 pages, 1351 KiB

Open AccessReview

Wnt Signaling in Cancer Metabolism and Immunity

by Sara El-Sahli, Ying Xie, Lisheng Wang and Sheng Liu

Cancers 2019, 11(7), 904; https://doi.org/10.3390/cancers11070904 - 28 Jun 2019

Cited by 92 | Viewed by 10603

Abstract

The Wingless (Wnt)/β-catenin pathway has long been associated with tumorigenesis, tumor plasticity, and tumor-initiating cells called cancer stem cells (CSCs). Wnt signaling has recently been implicated in the metabolic reprogramming of cancer cells. Aberrant Wnt signaling is considered to be a driver of [...] Read more.

The Wingless (Wnt)/β-catenin pathway has long been associated with tumorigenesis, tumor plasticity, and tumor-initiating cells called cancer stem cells (CSCs). Wnt signaling has recently been implicated in the metabolic reprogramming of cancer cells. Aberrant Wnt signaling is considered to be a driver of metabolic alterations of glycolysis, glutaminolysis, and lipogenesis, processes essential to the survival of bulk and CSC populations. Over the past decade, the Wnt pathway has also been shown to regulate the tumor microenvironment (TME) and anti-cancer immunity. Wnt ligands released by tumor cells in the TME facilitate the immune evasion of cancer cells and hamper immunotherapy. In this review, we illustrate the role of the canonical Wnt/β-catenin pathway in cancer metabolism and immunity to explore the potential therapeutic approach of targeting Wnt signaling from a metabolic and immunological perspective. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer)

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19 pages, 1294 KiB

Open AccessReview

A Review of the Role of Wnt in Cancer Immunomodulation

by Whitney N. Goldsberry, Angelina Londoño, Troy D. Randall, Lyse A. Norian and Rebecca C. Arend

Cancers 2019, 11(6), 771; https://doi.org/10.3390/cancers11060771 - 4 Jun 2019

Cited by 51 | Viewed by 7639

Abstract

Alterations in the Wnt signaling pathway are associated with the advancement of cancers; however, the exact mechanisms responsible remain largely unknown. It has recently been established that heightened intratumoral Wnt signaling correlates with tumor immunomodulation and immune suppression, which likely contribute to the [...] Read more.

Alterations in the Wnt signaling pathway are associated with the advancement of cancers; however, the exact mechanisms responsible remain largely unknown. It has recently been established that heightened intratumoral Wnt signaling correlates with tumor immunomodulation and immune suppression, which likely contribute to the decreased efficacy of multiple cancer therapeutics. Here, we review available literature pertaining to connections between Wnt pathway activation in the tumor microenvironment and local immunomodulation. We focus specifically on preclinical and clinical data supporting the hypothesis that strategies targeting Wnt signaling could act as adjuncts for cancer therapy, either in combination with chemotherapy or immunotherapy, in a variety of tumor types. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer)

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15 pages, 2243 KiB

Open AccessReview

Targeting Wnt Signaling via Notch in Intestinal Carcinogenesis

by Elke Kaemmerer, Min Kyung Jeon, Alexander Berndt, Christian Liedtke and Nikolaus Gassler

Cancers 2019, 11(4), 555; https://doi.org/10.3390/cancers11040555 - 18 Apr 2019

Cited by 29 | Viewed by 6554

Abstract

Proliferation and differentiation of intestinal epithelial cells is assisted by highly specialized and well-regulated signaling cascades. The Wnt pathway, which is one of the fundamental pathways in the intestine, contributes to the organization of proliferative intestinal crypts by positioning and cycling of intestinal [...] Read more.

Proliferation and differentiation of intestinal epithelial cells is assisted by highly specialized and well-regulated signaling cascades. The Wnt pathway, which is one of the fundamental pathways in the intestine, contributes to the organization of proliferative intestinal crypts by positioning and cycling of intestinal stem cells and their derivatives. The Wnt pathway promotes differentiation of intestinal secretory cell types along the crypt-plateau and crypt-villus axis. In contrast to the Wnt pathway, the intestinal Notch cascade participates in cellular differentiation and directs progenitor cells towards an absorptive fate with diminished numbers of Paneth and goblet cells. Opposing activities of Notch and Wnt signaling in the regulation of intestinal stem cells and the enterocytic cell fate have been elucidated recently. In fact, targeting Notch was able to overcome tumorigenesis of intestinal adenomas, prevented carcinogenesis, and counteracted Paneth cell death in the absence of caspase 8. At present, pharmacological Notch inhibition is considered as an interesting tool targeting the intrinsic Wnt pathway activities in intestinal non-neoplastic disease and carcinogenesis. Full article

(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer)

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