Giles RH, van Es JH, Clevers H.. Caught in a Wnt storm: Wnt signaling in cancer. Biophys Biochim Acta 1653: 1-24

Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 07/2003; 1653(1):1-24. DOI: 10.1016/S0304-419X(03)00005-2
Source: PubMed


The Wnt signaling pathway, named for its most upstream ligands, the Wnts, is involved in various differentiation events during embryonic development and leads to tumor formation when aberrantly activated. Molecular studies have pinpointed activating mutations of the Wnt signaling pathway as the cause of approximately 90% of colorectal cancer (CRC), and somewhat less frequently in cancers at other sites, such as hepatocellular carcinoma (HCC). Ironically, Wnts themselves are only rarely involved in the activation of the pathway during carcinogenesis. Mutations mimicking Wnt stimulation-generally inactivating APC mutations or activating beta-catenin mutations-result in nuclear accumulation of beta-catenin which subsequently complexes with T-cell factor/lymphoid enhancing factor (TCF/LEF) transcription factors to activate gene transcription. Recent data identifying target genes has revealed a genetic program regulated by beta-catenin/TCF controlling the transcription of a suite of genes promoting cellular proliferation and repressing differentiation during embryogenesis, carcinogenesis, and in the post-embryonic regulation of cell positioning in the intestinal crypts. This review considers the spectra of tumors arising from active Wnt signaling and attempts to place perspective on recent data that begin to elucidate the mechanisms prompting uncontrolled cell growth following induction of Wnt signaling.

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Available from: Rachel H Giles
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    • "Wnt signaling is initiated when Wnt ligands engage their cognate Received 23 October 2014; Accepted 12 February 2015 receptor complex. The central player of Wnt signaling is the cytoplasmic protein β-catenin, which accumulates in the cell cytoplasm, translocates into the nucleus and functions as a cofactor for transcription factors of the T-cell factor/lymphoid enhancing factor (TCF/LEF) family (Giles et al., 2003). When Wnt receptors are not engaged, β-catenin is destabilized (Reya and Clevers, 2005). "
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    ABSTRACT: Tumor repopulation after radiotherapy is a big obstacle for clinical cancer therapy. The molecular mechanisms of tumor cell repopulation after radiotherapy remain unclear. This study investigated the role of sonic hedgehog (SHH) and Wnt signaling pathways in tumor repopulation after radiotherapy in an in vitro repopulation model. In this model, irradiated dying tumor cells functioned as feeder cells, while luciferase-labeled living tumor cells acted as reporter cells. Proliferation of reporter cells was measured by bioluminescence imaging. Results showed that irradiated dying HT29 and Panc1 cells significantly stimulated the repopulation of their living cells. In HT29 and Panc1 cells, radiation significantly inhibited Wnt activity. In the irradiated dying HT29 and Panc1 cells, the activated nuclear β-catenin was significantly decreased. Wnt agonist 68166 significantly decreased, whereas Wnt antagonist significantly increased repopulation in HT29 and Panc1 tumor cells in a dose dependent manner. β-catenin shRNA significantly promoted tumor cell repopulation. The level of secreted frizzled related protein-1, hedgehog, and Gli1 were increased in irradiated cells. Our results highlighted the interaction between Wnt and SHH signaling pathways in dying tumor cells and suggested that downregulation of Wnt signaling after SHH activation is negatively associated with tumor repopulation.
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    • "Colorectal cancer is one of the most common malignancies worldwide, with >1,000,000 cases reported annually (1). Several developmental signaling pathways that are involved in the carcinogenesis of colorectal cancer, including the Wnt/β-catenin (2), TGF-β/Smad (3) Notch (4) and receptor tyrosine kinase (5) pathways, have been widely investigated. However, the role of hedgehog (Hh)-glioma-associated oncogene homolog (GLI) signaling in colorectal cancer remains controversial (6,7), and certain studies have indicated that Hh signaling is inactive in colorectal cancer (8–10). "
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    • "Phosphorylated STATs form homodimers, shuttle to the nucleus, and participate in transcriptional regulation of a variety of genes. mutations in b-catenin are also found in 48% of small intestinal adenocarcinomas and 64% of gastric polyps (Giles et al., 2003). The Wnt signaling pathway is classified as canonical, which signals via b-catenin, or non-canonical, which operates in a b-catenin-independent manner (Davis and Zur Nieden, 2008). "
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