Wnt signaling in cancer

Zhan, Tianzuo; Rindtorff, Niklas; Boutros, Michael

doi:10.1038/onc.2016.304

Cited by 2,153 publications

(1,936 citation statements)

References 204 publications

(216 reference statements)

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“…A better understanding of the mechanisms underlying Wnt signaling therefore might lay the foundation for novel therapeutic approaches. Blocking Wnt secretion with the Porcn inhibitor LGK974 induced regression of multiple tumor models in vivo (Liu et al , 2013) and is currently being investigated in clinical studies (Lum & Chen, 2015; Zhan et al , 2017). Despite the high relevance of secreted Wnt ligands in different cancers and the reported additional Wnt‐independent functions of Porcn (Covey et al , 2012; Erlenhardt et al , 2016), inhibition of Porcn is to date the only pharmacological approach to inhibit Wnt secretion.…”

Section: Discussionmentioning

confidence: 99%

ERAD‐dependent control of the Wnt secretory factor Evi

et al. 2018

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Active regulation of protein abundance is an essential strategy to modulate cellular signaling pathways. Within the Wnt signaling cascade, regulated degradation of β‐catenin by the ubiquitin‐proteasome system (UPS) affects the outcome of canonical Wnt signaling. Here, we found that abundance of the Wnt cargo receptor Evi (Wls/GPR177), which is required for Wnt protein secretion, is also regulated by the UPS through endoplasmic reticulum (ER)‐associated degradation (ERAD). In the absence of Wnt ligands, Evi is ubiquitinated and targeted for ERAD in a VCP‐dependent manner. Ubiquitination of Evi involves the E2‐conjugating enzyme UBE2J2 and the E3‐ligase CGRRF1. Furthermore, we show that a triaging complex of Porcn and VCP determines whether Evi enters the secretory or the ERAD pathway. In this way, ERAD‐dependent control of Evi availability impacts the scale of Wnt protein secretion by adjusting the amount of Evi to meet the requirement of Wnt protein export. As Wnt and Evi protein levels are often dysregulated in cancer, targeting regulatory ERAD components might be a useful approach for therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

ERAD‐dependent control of the Wnt secretory factor Evi

et al. 2018

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“…Inhibiting a soluble Wnt antagonist may increase local Wnt signaling and promote tumor growth. 52 Although Wnt signaling has been shown to stimulate myeloma cell proliferation in vitro, 53 treatment with anti-sclerostin antibody had no effect on myeloma burden in the skeleton or spleen of the 5TGM1-eGFP, 5T2MM, or MM1.S models. The absence of effect across multiple models suggests that sclerostin does not regulate pathways that control tumor growth.…”

Section: Discussionmentioning

confidence: 99%

“…Wnt signaling promotes tumor growth, 51,52 and aberrant Wnt signaling has been reported to increase myeloma cell proliferation. 53 Soluble Wnt antagonists inhibit endogenous Wnt signaling and therefore the antisclerostin antibody might promote tumor proliferation by stopping Wnt suppression in the local bone microenvironment.…”

Section: Additive Effects Of Anti-sclerostin Antibody and Zamentioning

confidence: 99%

Inhibiting the osteocyte-specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma

McDonald

Reagan

Youlten

et al. 2017

Blood

168

161

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Multiple myeloma (MM) is a plasma cell cancer that develops in the skeleton causing profound bone destruction and fractures. The bone disease is mediated by increased osteoclastic bone resorption and suppressed bone formation. Bisphosphonates used for treatment inhibit bone resorption and prevent bone loss but fail to influence bone formation and do not replace lost bone, so patients continue to fracture. Stimulating bone formation to increase bone mass and fracture resistance is a priority; however, targeting tumor-derived modulators of bone formation has had limited success. Sclerostin is an osteocyte-specific Wnt antagonist that inhibits bone formation. We hypothesized that inhibiting sclerostin would prevent development of bone disease and increase resistance to fracture in MM. Sclerostin was expressed in osteocytes from bones from naive and myeloma-bearing mice. In contrast, sclerostin was not expressed by plasma cells from 630 patients with myeloma or 54 myeloma cell lines. Mice injected with 5TGM1-eGFP, 5T2MM, or MM1.S myeloma cells demonstrated significant bone loss, which was associated with a decrease in fracture resistance in the vertebrae. Treatment with anti-sclerostin antibody increased osteoblast numbers and bone formation rate but did not inhibit bone resorption or reduce tumor burden. Treatment with anti-sclerostin antibody prevented myeloma-induced bone loss, reduced osteolytic bone lesions, and increased fracture resistance. Treatment with anti-sclerostin antibody and zoledronic acid combined increased bone mass and fracture resistance when compared with treatment with zoledronic acid alone. This study defines a therapeutic strategy superior to the current standard of care that will reduce fractures for patients with MM

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“…Additionally, the β-catenin-independent Wnt pathway has been demonstrated to be upregulated in the CTCs of prostate carcinoma cell lines that demonstrate resistance to androgen receptor inhibition (45). In summary, increasing evidence has revealed that β-catenin-dependent and -independent Wnt signaling may promote tumorigenesis in a tissue-specific manner (46). Furthermore, the proliferation of glioma cells may be inhibited by targeting specific molecules using Wnt2 and β-catenin small interfering RNAs (18,47,48).…”

Section: Discussionmentioning

confidence: 99%

Expression profile and clinical significance of Wnt signaling in human gliomas

Zhang

Geng

et al. 2017

Oncol Lett

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Abstract. Wnt signaling has been identified as a critical regulator of human tumor development in vitro. However, there remains a lack of studies systematically examining the expression pattern and clinical relevance of the core molecules of Wnt signaling in glioma tissues. In the present study, it was identified that the mRNA expression levels of Wnt3a and 5a, and their receptors frizzled 2, 6 and 7 increased, whereas Wnt7b was markedly decreased in glioma relative to non-tumor tissue. The mRNA levels of β-catenin, adenomatous polyposis coli gene product, glycogen synthase kinase 3β (GSK3β) and AXIN1 and its target genes cyclin D1 and AXIN2 did not differ. Similarly, the protein levels of Wnt2b, 3a and 5a were increased in gliomas, while β-catenin, GSK3β and cyclin D1 were not. Furthermore, based on data from the R2: Genomics Analysis and Visualization Platform, the expression of Wnt2b and 5a, and frizzled 2, 6 and 7 were highly associated with the prognosis of patients with glioma. Taken together, the results of the present study demonstrate that β-catenin is not upregulated in gliomas and that the Wnt signaling pathway may promote glioma development via noncanonical or alternative pathways.

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Wnt signaling in cancer

Cited by 2,153 publications

References 204 publications

ERAD‐dependent control of the Wnt secretory factor Evi

ERAD‐dependent control of the Wnt secretory factor Evi

Inhibiting the osteocyte-specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma

Expression profile and clinical significance of Wnt signaling in human gliomas

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