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Can we safely target the WNT pathway?

Key Points

  • WNT signalling is a complex cascade and there is extensive crosstalk with other pathways.

  • WNT signalling has crucial roles in both normal homeostasis and disease, and thereby there has been considerable difficulty in safely targeting the WNT pathway, thus hampering development to date.

  • There are multiple points of intervention in the WNT signalling cascade that have been investigated; however, many of them may be limited from the standpoint of therapeutic efficacy owing to on-target side effects.

  • WNT signalling has crucial roles in stem cells — both normal and cancer stem cells — in both the maintenance of potency and initiation of differentiation.

  • Currently, several specific inhibitors and modulators of WNT signalling have entered clinical trials. Preliminary results and future prospects are discussed.

Abstract

WNT–β-catenin signalling is involved in a multitude of developmental processes and the maintenance of adult tissue homeostasis by regulating cell proliferation, differentiation, migration, genetic stability and apoptosis, as well as by maintaining adult stem cells in a pluripotent state. Not surprisingly, aberrant regulation of this pathway is therefore associated with a variety of diseases, including cancer, fibrosis and neurodegeneration. Despite this knowledge, therapeutic agents specifically targeting the WNT pathway have only recently entered clinical trials and none has yet been approved. This Review examines the problems and potential solutions to this vexing situation and attempts to bring them into perspective.

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Figure 1: A simplified representation of the canonical WNT–β-catenin signalling cascade.
Figure 2: WNT signalling in stem cells.
Figure 3: Modes of stem cell division.

References

  1. Nusse, R. & Varmus, H. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 31, 99–109 (1982).

    Article  CAS  PubMed  Google Scholar 

  2. Baker, N. E. Molecular cloning of sequences from wingless, a segment polarity gene in Drosophila: the spatial distribution of a transcript in embryos. EMBO J. 6, 1765–1773 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. McMahon, A. P. & Moon, R. T. Ectopic expression of the proto-oncogene int-1 in Xenopus embryos leads to duplication of the embryonic axis. Cell 58, 1075–1084 (1989).

    Article  CAS  PubMed  Google Scholar 

  4. Logan, C. Y. & Nusse, R. The Wnt signaling pathway in development and disease. Annu. Rev. Cell Dev. Biol. 20, 781–810 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. van Amerongen, R. & Nusse, R. Towards an integrated view of Wnt signaling in development. Development 136, 3205–3214 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Alonso, L. & Fuchs, E. Stem cells in the skin: waste not, Wnt not. Genes Dev. 17, 1189–1200 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Pinto, D. & Clevers, H. Wnt control of stem cells and differentiation in the intestinal epithelium. Exp. Cell Res. 306, 357–363 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Nemeth, M. J., Mak, K. K., Yang, Y. & Bodine, D. M. β-catenin expression in the bone marrow microenvironment is required for long-term maintenance of primitive hematopoietic cells. Stem Cells 27, 1109–1119 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Malhotra, S. & Kincade, P. W. Wnt-related molecules and signaling pathway equilibrium in hematopoiesis. Cell Stem Cell 4, 27–36 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Monga, S. P. Role of Wnt/β-catenin signaling in liver metabolism and cancer. Int. J. Biochem. Cell Biol. 43, 1021–1029 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Beers, M. F. & Morrisey, E. E. The three R's of lung health and disease: repair, remodeling, and regeneration. J. Clin. Invest. 121, 2065–2073 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Whyte, J. L., Smith, A. A. & Helms, J. A. Wnt signaling and injury repair. Cold Spring Harb. Perspect. Biol. 4, a008078 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Inestrosa, N. C. & Arenas, E. Emerging roles of Wnts in the adult nervous system. Nature Rev. Neurosci. 11, 77–86 (2010).

    Article  CAS  Google Scholar 

  14. Cisternas, P., Henriquez, J. P., Brandan, E. & Inestrosa, N. C. Wnt signaling in skeletal muscle dynamics: myogenesis, neuromuscular synapse and fibrosis. Mol. Neurobiol. 49, 574–589 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. Webster, M. R. & Weeraratna, A. T. A. Wnt-er migration: the confusing role of β-catenin in melanoma metastasis. Sci. Signal. 6, e11 (2013).

    Article  CAS  Google Scholar 

  16. Hoffmeyer, K. et al. Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells. Science 336, 1549–1554 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Rawson, J. B. et al. Promoter methylation of Wnt5a is associated with microsatellite instability and BRAF V600E mutation in two large populations of colorectal cancer patients. Br. J. Cancer 104, 1906–1912 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Alberici, P. & Fodde, R. The role of the APC tumor suppressor in chromosomal instability. Genome Dyn. 1, 149–170 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Frisch, S. M., Schaller, M. & Cieply, B. Mechanisms that link the oncogenic epithelial-mesenchymal transition to suppression of anoikis. J. Cell Sci. 126, 21–29 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pecinas-Slaus, N. Wnt signal transduction pathway and apoptosis: a review. Cancer Cell. Int. 10, 22 (2010).

    Article  CAS  Google Scholar 

  21. Porfiri, E. et al. Induction of a β-catenin-LEF-1 complex by wnt-1 and transforming mutants of β-catenin. Oncogene 15, 2833–2839 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. de La Coste, A. et al. Somatic mutations of the β-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc. Natl Acad. Sci. USA 95, 8847–8851 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Anastas, J. N. & Moon, R. T. WNT signalling pathways as therapeutic targets in cancer. Nature Rev. Cancer 13, 11–26 (2013).

    Article  CAS  Google Scholar 

  24. Dees, C. & Distler, J. H. Canonical Wnt signaling as a key-regulator of fibrogenesis — implications for targeted therapies? Exp. Dermatol. 22, 710–713 (2013).

    Article  PubMed  Google Scholar 

  25. Chilosi, M. et al. Aberrant Wnt/β-catenin pathway activation in idiopathic pulmonary fibrosis. Am. J. Pathol. 162, 1495–1502 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Schinner, S. Wnt-signalling and the metabolic syndrome. Horm. Metab. Res. 41, 159–163 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Inestrosa, N. C., Montecinos-Oliva, C. & Fuenzalida, M. Wnt signaling: role in Alzheimer disease and schizophrenia. J. Neuroimmune Pharmacol. 7, 788–807 (2012).

    Article  PubMed  Google Scholar 

  28. Berwick, D. C. & Harvey, K. The importance of Wnt signalling for neurodegeneration in Parkinson's disease. Biochem. Soc. Trans. 40, 1123–1128 (2012).

    Article  CAS  PubMed  Google Scholar 

  29. Okerlund, N. D. & Cheyette, B. N. Synaptic Wnt signaling — a contributor to major psychiatric disorders? J. Neurodev. Disord. 3, 162–174 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Niehrs, C. The complex world of WNT receptor signalling. Nature Rev. Mol. Cell. Biol. 13, 767–779 (2012).

    Article  CAS  Google Scholar 

  31. Veeman, M. T., Axelrod, J. & Moon, R. T. A second canon. Functions and mechanisms of β-catenin-independent Wnt signaling. Dev. Cell 5, 367–377 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Angers, S. & Moon, R. T. Proximal events in Wnt signal transduction. Nature Rev. Mol. Cell. Biol. 10, 468–477 (2009).

    Article  CAS  Google Scholar 

  33. Nusse, R. & Varmus, H. Three decades of Wnts: a personal perspective on how a scientific field developed. EMBO J. 31, 2670–2684 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fagotto, F. Looking beyond the Wnt pathway for the deep nature of β-catenin. EMBO Rep. 14, 422–433 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Miller, R. K., Hong, J. Y., Muñoz, W. A. & McCrea, P. D. β-catenin versus the other armadillo catenins: assessing our current view of canonical Wnt signaling. Prog. Mol. Biol. Transl. Sci. 116, 387–407 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Brembeck, F. H., Rosário, M. & Birchmeier, W. Balancing cell adhesion and Wnt signaling, the key role of β-catenin. Curr. Opin. Genet. Dev. 16, 51–59 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. van Veelen, W. et al. β-catenin tyrosine 654 phosphorylation increases Wnt signalling and intestinal tumorigenesis. Gut 60, 1204–1212 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. Kawabata, A. Prostaglandin E2 and pain — an update. Biol. Pharm. Bull. 34, 1170–1173 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Gumbiner, B. M. Carcinogenesis: a balance between β-catenin and APC. Curr. Biol. 7, R444–R446 (1997).

    Article  Google Scholar 

  40. Rubinfeld, B. et al. Binding of GSK3β to the APC-β-catenin complex and regulation of complex assembly. Science 272, 1023–1026 (1996).

    Article  CAS  PubMed  Google Scholar 

  41. Brunner, E., Peter, O., Schweizer, L. & Basler, K. Pangolin encodes a Lef-1 homologue that acts downstream of Armadillo to transduce the Wingless signal in Drosophila. Nature 385, 829–833 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. van de Wetering, M. et al. Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF. Cell 88, 789–799 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Takemaru, K. I. & Moon, R. T. The transcriptional coactivator CBP interacts with β-catenin to activate gene expression. J. Cell Biol. 149, 249–254 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hecht, A., Vleminckx, K., Stemmler, M. P., van Roy, F. & Kemler, R. The p300/CBP acetyltransferases function as transcriptional coactivators of β-catenin in vertebrates. EMBO J. 19, 1839–1850 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Rasola, A. et al. A positive feedback loop between hepatocyte growth factor receptor and β-catenin sustains colorectal cancer cell invasive growth. Oncogene 26, 1078–1087 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Coluccia, A. M. et al. Bcr-Abl stabilizes β-catenin in chronic myeloid leukemia through its tyrosine phosphorylation. EMBO J. 26, 1456–1466 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kim, Y. M. et al. The γ catenin/CBP complex maintains survivin transcription in β-catenin deficient/depleted cancer cells. Curr. Cancer Drug Targets 11, 213–225 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Maeda, O. et al. Plakoglobin (γ-catenin) has TCF/LEF family-dependent transcriptional activity in β-catenin-deficient cell line. Oncogene 23, 964–972 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Jeannet, G. et al. Long-term, multilineage hematopoiesis occurs in the combined absence of β-catenin and γ-catenin. Blood 111, 142–149 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Le, N. H., Franken, P. & Fodde, R. Tumour-stroma interactions in colorectal cancer: converging on β-catenin activation and cancer stemness. Br. J. Cancer 98, 1886–1893 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Polakis, P. Drugging Wnt signalling in cancer. EMBO J. 31, 2737–2746 (2012); erratum 31, 3375 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zimmerman, Z. F., Moon, R. T. & Chien, A. J. Targeting Wnt pathways in disease. Cold Spring Harb. Perspect. Biol. 4, a008086 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Herr, P., Hausmann, G. & Basler, K. WNT secretion and signalling in human disease. Trends Mol. Med. 18, 483–493 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. Clevers, H. & Nusse, R. Wnt/β-catenin signaling and disease. Cell 149, 1192–1205 (2012).

    Article  CAS  PubMed  Google Scholar 

  55. Groden, J. et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66, 589–600 (1991).

    Article  CAS  PubMed  Google Scholar 

  56. Kinzler, K. W. et al. Identification of FAP locus genes from chromosome 5q21. Science 253, 661–665 (1991).

    Article  CAS  PubMed  Google Scholar 

  57. Bodmer, W. F. Cancer genetics: colorectal cancer as a model. J. Hum. Genet. 51, 391–396 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Polakis, P. The many ways of Wnt in cancer. Curr. Opin. Genet. Dev. 17, 45–51 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Lengauer, C., Kinzler, K. W. & Vogelstein, B. Genetic instabilities in human cancers. Nature 396, 643–649 (1998).

    Article  CAS  PubMed  Google Scholar 

  60. Clements, W. M., Lowy, A. M. & Groden, J. Adenomatous polyposis coli/β-catenin interaction and downstream targets: altered gene expression in gastrointestinal tumors. Clin. Colorectal Cancer 3, 113–120 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Drier, Y. et al. Somatic rearrangements across cancer reveal classes of samples with distinct patterns of DNA breakage and rearrangement-induced hypermutability. Genome Res. 23, 228–235 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Rubinfeld, B. et al. Stabilization of β-catenin by genetic defects in melanoma cell lines. Science 275, 1790–1792 (1997).

    Article  CAS  PubMed  Google Scholar 

  63. Han, Z. G. Functional genomic studies: insights into the pathogenesis of liver cancer. Annu. Rev. Genom. Hum. Genet. 13, 171–205 (2012).

    Article  CAS  Google Scholar 

  64. Sastre-Perona, A. & Santisteban, P. Role of the wnt pathway in thyroid cancer. Front. Endocrinol. 3, 31 (2012).

    Article  CAS  Google Scholar 

  65. Gatcliffe, T. A., Monk, B. J., Planutis, K. & Holcombe, R. F. Wnt signaling in ovarian tumorigenesis. Int. J. Gynecol. Cancer 18, 954–962 (2008).

    Article  CAS  PubMed  Google Scholar 

  66. Caldwell, G. M. et al. The Wnt antagonist sFRP1 in colorectal tumorigenesis. Cancer Res. 64, 883–888 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Lee, A. Y. et al. Expression of the secreted frizzled-related protein gene family is downregulated in human mesothelioma. Oncogene 23, 6672–6676 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Suzuki, H. et al. Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nature Genet. 36, 417–422 (2004). This study describes the discovery of a causal link between epigenetic inactivation of WNT antagonists (SFRP) and constitutive WNT signalling activity in colon cancers.

    Article  CAS  PubMed  Google Scholar 

  69. Fukui, T. et al. Transcriptional silencing of secreted frizzled related protein 1 (SFRP 1) by promoter hypermethylation in non-small-cell lung cancer. Oncogene 24, 6323–6327 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Zou, H. et al. Aberrant methylation of secreted frizzled-related protein genes in esophageal adenocarcinoma and Barrett's esophagus. Int. J. Cancer 116, 584–591 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Rhee, C. et al. Wnt and frizzled receptors as potential targets for immunotherapy in head and neck squamous cell carcinomas. Oncogene 21, 6598–6605 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Wong, S. C. et al. Expression of frizzled-related protein and Wnt-signalling molecules in invasive human breast tumours. J. Pathol. 196, 145–153 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Milovanovic, T. et al. Expression of Wnt genes and frizzled 1 and 2 receptors in normal breast epithelium and infiltrating breast carcinoma. Int. J. Oncol. 25, 1337–1342 (2004).

    CAS  PubMed  Google Scholar 

  74. Okino, K. et al. Up-regulation and overproduction of DVL-1, the human counterpart of the Drosophila dishevelled gene, in cervical squamous cell carcinoma. Oncol. Rep. 10, 1219–1223 (2003).

    CAS  PubMed  Google Scholar 

  75. Uematsu, K. et al. Wnt pathway activation in mesothelioma: evidence of Dishevelled overexpression and transcriptional activity of β-catenin. Cancer Res. 63, 4547–4551 (2003).

    CAS  PubMed  Google Scholar 

  76. Uematsu, K. et al. Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression. Oncogene 22, 7218–7221 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Kikuchi, A. & Yamamoto, H. Tumor formation due to abnormalities in the β-catenin-independent pathway of Wnt signaling. Cancer Sci. 99, 202–208 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Cao, X., Eu, K. W., Seow-Choen, F., Zao, Y. & Cheah, P. Y. APC mutation and phenotypic spectrum of Singapore familial adenomatous polyposis patients. Eur. J. Hum. Genet. 8, 42–48 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Takada, T. et al. Methylation-associated silencing of the Wnt antagonist SFRP1 gene in human ovarian cancers. Cancer Sci. 95, 741–744 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Lugli, A. et al. Prognostic significance of the wnt signalling pathway molecules APC, β-catenin and E-cadherin in colorectal cancer: a tissue microarray-based analysis. Histopathology 50, 453–464 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Kageshita, T. et al. Loss of β-catenin expression associated with disease progression in malignant melanoma. Br. J. Dermatol. 145, 210–216 (2001).

    Article  CAS  PubMed  Google Scholar 

  82. Maelandsmo, G. M., Holm, R., Nesland, J. M., Fodstad, Ø. & Flørenes, V. A. Reduced β-catenin expression in the cytoplasm of advanced-stage superficial spreading malignant melanoma. Clin. Cancer Res. 9, 3383–3388 (2003).

    CAS  PubMed  Google Scholar 

  83. Bachmann, I. M., Straume, O., Puntervoll, H. E., Kalvenes, M. B. & Akslen, L. A. Importance of P-cadherin, β-catenin, and Wnt5a/frizzled for progression of melanocytic tumors and prognosis in cutaneous melanoma. Clin. Cancer Res. 11, 8606–8614 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Chien, A. J. et al. Activated Wnt/β-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model. Proc. Natl Acad. Sci. USA 106, 1193–1198 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Bakker, E. R. et al. β-catenin signaling dosage dictates tissue-specific tumor predisposition in Apc-driven cancer. Oncogene 32, 4579–4585 (2013).

    Article  CAS  PubMed  Google Scholar 

  86. Salinas, P. C. & Zou, Y. Wnt signaling in neural circuit assembly. Annu. Rev. Neurosci. 31, 339–354 (2008).

    Article  CAS  PubMed  Google Scholar 

  87. Freese, J. L., Pino, D. & Pleasure, S. J. Wnt signaling in development and disease. Neurobiol. Dis. 38, 148–153 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Millar, J. K., Christie, S., Semple, C. A. & Porteous, D. J. Chromosomal location and genomic structure of the human translin-associated factor X gene (TRAX; TSNAX) revealed by intergenic splicing to DISC1, a gene disrupted by a translocation segregating with schizophrenia. Genomics 67, 69–77 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Blackwood, D. H. et al. Schizophrenia and affective disorders — cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am. J. Hum. Genet. 69, 428–433 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Mao, Y. et al. Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3β/β-catenin signaling. Cell 136, 1017–1031 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Courchesne, E. et al. Unusual brain growth patterns in early life in patients with autistic disorder: an MRI study. Neurology 57, 245–254 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. Courchesne, E., Carper, R. & Akshoomoff, N. Evidence of brain overgrowth in the first year of life in autism. J. Am. Med. Assoc. 290, 337–344 (2003).

    Article  Google Scholar 

  93. Sparks, B. F. et al. Brain structural abnormalities in young children with autism spectrum disorder. Neurology 59, 184–192 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Schumann, C. M. et al. The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages. J. Neurosci. 24, 6392–6401 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Chenn, A. & Walsh, C. A. Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 297, 365–369 (2002). This article highlights the importance of β-catenin in neuronal stem cells and neuronal development.

    Article  CAS  PubMed  Google Scholar 

  96. Chenn, A. & Walsh, C. A. Increased neuronal production, enlarged forebrains and cytoarchitectural distortions in β-catenin overexpressing transgenic mice. Cereb. Cortex 13, 599–606 (2003).

    Article  PubMed  Google Scholar 

  97. Kalkman, H. O. A review of the evidence for the canonical Wnt pathway in autism spectrum disorders. Mol. Autism 3, 10 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kang, D. E. et al. Presenilin couples the paired phosphorylation of β-catenin independent of axin: implications for β-catenin activation in tumorigenesis. Cell 110, 751–762 (2002).

    Article  CAS  PubMed  Google Scholar 

  99. De Ferrari, G. V. et al. Common genetic variation within the low-density lipoprotein receptor-related protein 6 and late-onset Alzheimer's disease. Proc. Natl Acad. Sci. USA 104, 9434–9439 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Wang, R., Dineley, K. T., Sweatt, J. D. & Zheng, H. Presenilin 1 familial Alzheimer's disease mutation leads to defective associative learning and impaired adult neurogenesis. Neuroscience 126, 305–312 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Teo, J. L., Ma, H., Nguyen, C., Lam, C. & Kahn, M. Specific inhibition of CBP/β-catenin interaction rescues defects in neuronal differentiation caused by a presenilin-1 mutation. Proc. Natl Acad. Sci. USA 102, 12171–12176 (2005). This is the first publication that describes the model for differential usage of coactivators in WNT–β-catenin signalling to explain the divergent outcomes — that is, proliferation versus differentiation via activation of the WNT signalling cascade.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Crews, L., Patrick, C., Adame, A., Rockenstein, E. & Masliah, E. Modulation of aberrant CDK5 signaling rescues impaired neurogenesis in models of Alzheimer's disease. Cell Death Dis. 2, e120 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Liebner, S. & Plate, K. H. Differentiation of the brain vasculature: the answer came blowing by the Wnt. J. Angiogenes. Res. 2, 1 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Dickins, E. M. & Salinas, P. C. Wnts in action: from synapse formation to synaptic maintenance. Front. Cell Neurosci. 7, 162 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Li, B. et al. WNT5A signaling contributes to Aβ-induced neuroinflammation and neurotoxicity. PLoS ONE 6, e22920 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Hackam, A. S. The Wnt signaling pathway in retinal degenerations. IUBMB Life 57, 381–388 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. L'episcopo, F. et al. A Wnt1 regulated Frizzled-1/β-catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: therapeutical relevance for neuron survival and neuroprotection. Mol. Neurodegener. 6, 49 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hamblet, N. S. et al. Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation and neural tube closure. Development 129, 5827–5838 (2002).

    Article  CAS  PubMed  Google Scholar 

  109. Zeng, L. et al. The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation. Cell 90, 181–192 (1997).

    Article  CAS  PubMed  Google Scholar 

  110. Carter, M. et al. Crooked tail (Cd) model of human folate-responsive neural tube defects is mutated in Wnt coreceptor lipoprotein receptor-related protein 6. Proc. Natl Acad. Sci. USA 102, 12843–12848 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Kokubu, C. et al. Skeletal defects in ringelschwanz mutant mice reveal that Lrp6 is required for proper somitogenesis and osteogenesis. Development 131, 5469–5480 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. Pinson, K. I., Brennan, J., Monkley, S., Avery, B. J. & Skarnes, W. C. An LDL-receptor-related protein mediates Wnt signalling in mice. Nature 407, 535–538 (2000).

    Article  CAS  PubMed  Google Scholar 

  113. Bellugi, U., Lichtenberger, L., Mills, D., Galaburda, A. & Korenberg, J. R. Bridging cognition, the brain and molecular genetics: evidence from Williams syndrome. Trends Neurosci. 22, 197–207 (1999).

    Article  CAS  PubMed  Google Scholar 

  114. Doyle, T. F., Bellugi, U., Korenberg, J. R. & Graham, J. “Everybody in the world is my friend” hypersociability in young children with Williams syndrome. Am. J. Med. Genet. A 124A, 263–273 (2004).

    Article  PubMed  Google Scholar 

  115. Zhao, C. et al. Hippocampal and visuospatial learning defects in mice with a deletion of frizzled 9, a gene in the Williams syndrome deletion interval. Development 132, 2917–2927 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Gong, Y. et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107, 513–523 (2001). In conjunction with reference 125, this paper demonstrates the importance of WNT–β-catenin signalling in bone development and the therapeutic possibility that WNT signalling can be manipulated safely to increase bone density.

    Article  CAS  PubMed  Google Scholar 

  117. Boyden, L. M. et al. High bone density due to a mutation in LDL-receptor-related protein 5. N. Engl. J. Med. 346, 1513–1521 (2002).

    Article  CAS  PubMed  Google Scholar 

  118. Day, T. F., Guo, X., Garrett-Beal, L. & Yang, Y. Wnt/β-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev. Cell 8, 739–750 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. Rodda, S. J. & McMahon, A. P. Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors. Development 133, 3231–3244 (2006).

    Article  CAS  PubMed  Google Scholar 

  120. Glass, D. A. et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev. Cell 8, 751–764 (2005).

    Article  CAS  PubMed  Google Scholar 

  121. Holmen, S. L. et al. Essential role of β-catenin in postnatal bone acquisition. J. Biol. Chem. 280, 21162–21168 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Li, X. et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J. Biol. Chem. 280, 19883–19887 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Semënov, M., Tamai, K. & He, X. SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J. Biol. Chem. 280, 26770–26775 (2005).

    Article  CAS  PubMed  Google Scholar 

  124. Li, X. et al. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J. Bone Miner. Res. 24, 578–588 (2009).

    Article  CAS  PubMed  Google Scholar 

  125. Little, R. D., Recker, R. R. & Johnson, M. L. High bone density due to a mutation in LDL-receptor-related protein 5. N. Engl. J. Med. 347, 943–944 (2002). In conjunction with reference 116, this paper demonstrates the importance of WNT–β-catenin signalling in bone development and the therapeutic possibility that WNT signalling can be manipulated safely to increase bone density.

    Article  PubMed  Google Scholar 

  126. Ellies, D. L. et al. Bone density ligand, sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity. J. Bone Miner. Res. 21, 1738–1749 (2006).

    Article  CAS  PubMed  Google Scholar 

  127. Semënov, M. & He, X. LRP5 mutations linked to high bone mass diseases cause reduced LRP5 binding and inhibition by SOST. J. Biol. Chem. 281, 38276–38284 (2006).

    Article  CAS  PubMed  Google Scholar 

  128. Hoeppner, L. H., Secreto, F. J. & Westendorf, J. J. Wnt signaling as a therapeutic target for bone diseases. Expert Opin. Ther. Targets 13, 485–496 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Zaidan, M. et al. Increased risk of solid renal tumors in lithium-treated patients. Kidney Int. http://dx.doi.org/10.1038/ki.2014.2 (2014).

  130. Gabrielli, A., Avvedimento, E. V. & Krieg, T. Scleroderma. N. Engl. J. Med. 360, 1989–2003 (2009).

    Article  CAS  PubMed  Google Scholar 

  131. Surendran, K., Schiavi, S. & Hruska, K. A. Wnt-dependent β-catenin signaling is activated after unilateral ureteral obstruction, and recombinant secreted frizzled-related protein 4 alters the progression of renal fibrosis J. Am. Soc. Nephrol. 16, 2373–2384 (2005).

    Article  CAS  PubMed  Google Scholar 

  132. Myung, S. J. et al. Wnt signaling enhances the activation and survival of human hepatic stellate cells. FEBS Lett. 581, 2954–2958 (2007).

    Article  CAS  PubMed  Google Scholar 

  133. Königshoff, M. et al. Functional Wnt signaling is increased in idiopathic pulmonary fibrosis. PLoS ONE 3, e2142 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Henderson, W. R. Jr. et al. Inhibition of Wnt/β-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis. Proc. Natl Acad. Sci. USA 107, 14309–14314 (2010). This study first demonstrates that idiopathic pulmonary fibrosis may be pharmacologically reversible via modulation of WNT–β-catenin signalling.

    Article  PubMed  PubMed Central  Google Scholar 

  135. Hao, S. et al. Targeted inhibition of β-catenin/CBP signaling ameliorates renal interstitial fibrosis. J. Am. Soc. Nephrol. 22, 1642–1653 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Konigshoff, M. et al. WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis. J. Clin. Invest. 119, 772–787 (2009).

    PubMed  PubMed Central  Google Scholar 

  137. Flozak, A. S. et al. β-catenin/T-cell factor signaling is activated during lung injury and promotes the survival and migration of alveolar epithelial cells. J. Biol. Chem. 285, 3157–3167 (2010).

    Article  CAS  PubMed  Google Scholar 

  138. Ulsamer, A. et al. Axin pathway activity regulates in vivo pY654-β-catenin accumulation and pulmonary fibrosis. J. Biol. Chem. 287, 5164–5172 (2012).

    Article  CAS  PubMed  Google Scholar 

  139. Akhmetshina, A. et al. Activation of canonical Wnt signalling is required for TGF-β mediated fibrosis. Nature Commun. 3, 735 (2012).

    Article  CAS  Google Scholar 

  140. Tanjore, H. et al. β-catenin in the alveolar epithelium protects from lung fibrosis after intratracheal bleomycin. Am. J. Respir. Crit. Care Med. 187, 630–639 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Gottardi, C. J. & Königshoff, M. Considerations for targeting β-catenin signaling in fibrosis. Am. J. Respir. Crit. Care Med. 187, 566–568 (2013).

    Article  CAS  PubMed  Google Scholar 

  142. Dravid, G. et al. Defining the role of Wnt/β-catenin signaling in the survival, proliferation, and self-renewal of human embryonic stem cells. Stem Cells 23, 1489–1501 (2005).

    Article  CAS  PubMed  Google Scholar 

  143. Qyang, Y. et al. The renewal and differentiation of Isl1+ cardiovascular progenitors are controlled by a Wnt/β-catenin pathway. Cell Stem Cell 1, 165–179 (2007).

    Article  CAS  PubMed  Google Scholar 

  144. Saraswati, S. et al. Pyrvinium, a potent small molecule Wnt inhibitor, promotes wound repair and post-MI cardiac remodeling. PLoS ONE 5, e15521 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Sasaki, T., Hwang, H., Nguyen, C., Kloner, R. A. & Kahn, M. The small molecule Wnt signaling modulator ICG-001 improves contractile function in chronically infarcted rat myocardium. PLoS ONE 8, e75010 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. de Lau, W., Peng, W. C., Gros, P. & Clevers, H. The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength. Genes Dev. 28, 305–316 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. de Lau, W. B. M., Snel, B. & Clevers, H. C. The R-spondin protein family. Genome Biol. 13, 242 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Zhao, J. et al. R-spondin1, a novel intestinotrophic mitogen, ameliorates experimental colitis in mice. Gastroenterology 132, 1331–1343 (2007).

    Article  CAS  PubMed  Google Scholar 

  149. Bhanja, P. et al. Protective role of R-spondin1, an intestinal stem cell growth factor, against radiation-induced gastrointestinal syndrome in mice. PLoS ONE 4, e8014 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Zhou, W. J., Geng, Z. H., Spence, J. R. & Geng, J. G. Induction of intestinal stem cells by R-spondin 1 and Slit2 augments chemoradioprotection. Nature 50, 107–111 (2013).

    Article  CAS  Google Scholar 

  151. Yu, Q., Sharma, A. & Sen, J. M. TCF1 and β-catenin regulate T cell development and function. Immunol. Res. 47, 45–55 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Gattinoni, L. et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nature Med. 15, 808–813 (2009).

    Article  CAS  PubMed  Google Scholar 

  153. Jeannet, G. et al. Essential role of the Wnt pathway effector Tcf-1 for the establishment of functional CD8 T cell memory. Proc. Natl Acad. Sci. USA 107, 9777–9782 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Zhao, D. M. et al. Constitutive activation of Wnt signaling favors generation of memory CD8 T cells. J. Immun. 184, 1191–11989 (2010).

    Article  CAS  PubMed  Google Scholar 

  155. Zhou, X. et al. Differentiation and persistence of memory CD8+ T cells depend on T cell factor 1. Immunity 33, 229–240 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Notani, D. et al. Global regulator SATB1 recruits β-catenin and regulates TH2 differentiation in Wnt-dependent manner. PLoS Biol. 8, e1000296 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Ding, Y., Shen, S., Lino, A. C., Curotto de Lafaille, M. A. & Lafaille, J. J. β-catenin stabilization extends regulatory T cell survival and induces anergy in nonregulatory T cells. Nature Med. 14, 162–169 (2008).

    Article  CAS  PubMed  Google Scholar 

  158. Sen, M. et al. Expression and function of wingless and frizzled homologs in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 97, 2791–2796 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Nakamura, Y., Nawata, M. & Wakitani, S. Expression profiles and functional analyses of Wnt-related genes in human joint disorders. Am. J. Pathol. 167, 97–105 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Keerthivasan, S. et al. β-catenin promotes colitis and colon cancer through imprinting of proinflammatory properties in T Cells. Sci. Transl. Med. 6, 225ra28 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Otero, K. et al. Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and β-catenin. Nature Immunol. 10, 734–743 (2009).

    Article  CAS  Google Scholar 

  162. Wood, L. D. et al. The genomic landscapes of human breast and colorectal cancers. Science 318, 1108–1113 (2007).

    Article  CAS  PubMed  Google Scholar 

  163. García-Jiménez, C. Wnt and incretin connections. Vitam. Horm. 84, 355–387 (2010).

    Article  PubMed  Google Scholar 

  164. Abiola, M. et al. Activation of Wnt/β-catenin signaling increases insulin sensitivity through a reciprocal regulation of Wnt10b and SREBP-1c in skeletal muscle cells. PLoS ONE 4, e8509 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Welters, H. J. & Kulkarni, R. N. Wnt signaling: relevance to β-cell biology and diabetes. Trends Endocrinol. Metab. 19, 349–355 (2008).

    Article  CAS  PubMed  Google Scholar 

  166. Grant, S. F. et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nature Genet. 38, 320–323 (2006). This study shows that TCF7L2 (also known as TCF4 ) human polymorphisms are associated with an increased risk of type 2 diabetes. This has been subsequently validated in a number of studies in diverse populations.

    Article  CAS  PubMed  Google Scholar 

  167. Takamoto, I. et al. TCF7L2 in mouse pancreatic β cells plays a crucial role in glucose homeostasis by regulating β cell mass. Diabetologia 57, 542–553 (2014).

    Article  CAS  PubMed  Google Scholar 

  168. Aly, H. et al. A novel strategy to increase the proliferative potential of adult human β-cells while maintaining their differentiated phenotype. PLoS ONE 8, e66131 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Rando, T. A. Stem cells, ageing and the quest for immortality. Nature 441, 1080–1086 (2006).

    Article  CAS  PubMed  Google Scholar 

  170. Hernandez, L. et al. Functional coupling between the extracellular matrix and nuclear lamina by Wnt signaling in progeria. Dev. Cell 19, 413–425 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Liu, H. et al. Augmented Wnt signaling in a mammalian model of accelerated aging. Science 317, 803–806 (2007).

    Article  CAS  PubMed  Google Scholar 

  172. Brack, A. S. et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807–810 (2007). References 170–172 demonstrate that increased WNT signalling is associated with ageing.

    Article  CAS  PubMed  Google Scholar 

  173. Bernard, P. & Harley, V. R. Wnt4 action in gonadal development and sex determination. Int. J. Biochem. Cell Biol. 39, 31–43 (2007).

    Article  CAS  PubMed  Google Scholar 

  174. Lear, J. T. Oral hedgehog-pathway inhibitors for basal-cell carcinoma. N. Engl. J. Med. 366, 2225–2226 (2012).

    Article  CAS  PubMed  Google Scholar 

  175. Sakata, T. & Chen, J. K. Chemical 'Jekyll and Hyde's: small-molecule inhibitors of developmental signaling pathways. Chem. Soc. Rev. 40, 4318–4331 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. White, B. D. et al. β-catenin signaling increases in proliferating NG2+ progenitors and astrocytes during post-traumatic gliogenesis in the adult brain. Stem Cells 28, 297–307 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Fancy, S. P. et al. Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination. Nature Neurosci. 14, 1009–1016 (2011).

    Article  CAS  PubMed  Google Scholar 

  178. Previdi, S. et al. Interaction between human-breast cancer metastasis and bone microenvironment through activated hepatocyte growth factor/Met and β-catenin/Wnt pathways. Eur. J. Cancer 46, 1679–1691 (2010).

    Article  CAS  PubMed  Google Scholar 

  179. Kajiguchi, T. et al. FLT3 regulates β-catenin tyrosine phosphorylation, nuclear localization, and transcriptional activity in acute myeloid leukemia cells. Leukemia 21, 2476–2484 (2007).

    Article  CAS  PubMed  Google Scholar 

  180. Kajiguchi, T. et al. Y654 of β-catenin is essential for FLT3/ITD-related tyrosine phosphorylation and nuclear localization of β-catenin. Eur. J. Haematol. 88, 314–320 (2012).

    Article  CAS  PubMed  Google Scholar 

  181. Zhou, L. et al. Tyrosine kinase inhibitor STI-571/Gleevec down-regulates the β-catenin signaling activity. Cancer Lett. 193, 161–170 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Christensen, J. G. et al. A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res. 63, 7345–7355 (2003).

    CAS  PubMed  Google Scholar 

  183. Hayward, P. et al. Notch modulates Wnt signalling by associating with Armadillo/β-catenin and regulating its transcriptional activity. Development 132, 1819–1830 (2005).

    Article  CAS  PubMed  Google Scholar 

  184. Bertrand, F. E., Angus, C. W., Partis, W. J. & Sigounas, G. Developmental pathways in colon cancer: crosstalk between WNT, BMP, Hedgehog and Notch. Cell Cycle 11, 4344–4351 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Lukaszewicz, A. I., McMillan, M. K. & Kahn, M. Small molecules and stem cells. Potency and lineage commitment: the new quest for the fountain of youth. J. Med. Chem. 53, 3439–3453 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Yao, J. et al. Combination treatment of PD98059 and DAPT in gastric cancer through induction of apoptosis and downregulation of WNT/β-catenin. Cancer Biol. Ther. 14, 833–839 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Janssen, K. P. et al. APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression. Gastroenterology 131, 1096–1109 (2003).

    Article  CAS  Google Scholar 

  188. Sansom, O. J. et al. Loss of Apc allows phenotypic manifestation of the transforming properties of an endogenous K-ras oncogene in vivo. Proc. Natl Acad. Sci. USA 103, 14122–14127 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Harada, N. et al. Hepatocarcinogenesis in mice with β-catenin and Ha-Ras gene mutations. Cancer Res. 64, 48–54 (2004).

    Article  CAS  PubMed  Google Scholar 

  190. Kerkhoff, E. et al. Regulation of c-myc expression by Ras/Raf signalling. Oncogene 16, 211–216 (1998).

    Article  CAS  PubMed  Google Scholar 

  191. Araki, Y. et al. Regulation of cyclooxygenase-2 expression by the Wnt and Ras pathways. Cancer Res. 63, 728–734 (2003).

    CAS  PubMed  Google Scholar 

  192. Masckauchán, T. N., Shawber, C. J., Funahashi, Y., Li, C. M. & Kitajewski, J. Wnt/β-catenin signaling induces proliferation, survival and interleukin-8 in human endothelial cells. Angiogenesis 8, 43–51 (2005).

    Article  CAS  PubMed  Google Scholar 

  193. Radtke, F. & Clevers, H. Self-renewal and cancer of the gut: two sides of a coin. Science 307, 1904–1909 (2005).

    Article  CAS  PubMed  Google Scholar 

  194. Corada, M. et al. The Wnt/β-catenin pathway modulates vascular remodeling and specification by upregulating Dll4/Notch signaling. Dev. Cell 18, 938–949 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Aulehla, A. et al. Wnt3a plays a major role in the segmentation clock controlling somitogenesis. Dev. Cell 4, 395–406 (2003).

    Article  CAS  PubMed  Google Scholar 

  196. Miyabayashi, T. et al. Wnt/β-catenin/CBP signaling maintains long-term murine embryonic stem cell pluripotency. Proc. Natl Acad. Sci. USA 104, 5668–5673 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Hasegawa, K. et al. Wnt signaling orchestration with a small molecule DYRK inhibitor provides long-term xeno-free human pluripotent cell expansion. Stem Cells Transl. Med. 1, 18–28 (2012). References 196 and 197 demonstrate that selective inhibition of WNT–β-catenin–p300 signalling maintains both mouse and human stem cell pluripotency.

    Article  CAS  PubMed  Google Scholar 

  198. Gupta, P. B. et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 138, 645–659 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Lu, D. et al. Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells. Proc. Natl Acad. Sci. USA 108, 13253–13257 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  200. Klein, P. S. & Melton, D. A. A molecular mechanism for the effect of lithium on development. Proc. Natl Acad. Sci. USA 93, 8455–8459 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Giardiello, F. M. et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N. Engl. J. Med. 328, 131–136 (1993).

    Article  Google Scholar 

  202. Schreinemachers, D. M. & Everson, R. B. Aspirin use and lung, colon, and breast cancer incidence in a prospective study. Epidemeology 5, 138–146 (1994).

    Article  CAS  Google Scholar 

  203. Dihlmann, S., Siermann, A. & von Knebel Doeberitz, M. The nonsteroidal anti-inflammatory drugs aspirin and indomethacin attenuate β-catenin/TCF-4 signaling. Oncogene 20, 645–653 (2001).

    Article  CAS  PubMed  Google Scholar 

  204. Thun, M. J., Henley, S. J. & Patrono, C. Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. J. Natl Cancer. Inst. 94, 252–266 (2002).

    Article  CAS  PubMed  Google Scholar 

  205. Sandler, R. S. et al. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N. Engl. J. Med. 348, 883–890 (2003).

    Article  CAS  PubMed  Google Scholar 

  206. Baron, J. A. et al. A randomized trial of aspirin to prevent colorectal adenomas. N. Engl. J. Med. 348, 891–899 (2003).

    Article  CAS  PubMed  Google Scholar 

  207. Boon, E. M. et al. Sulindac targets nuclear β-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines. Br. J. Cancer 90, 224–229 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Grösch, S., Tegeder, I., Niederberger, E., Bräutigam, L. & Geisslinger, G. COX-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib. FASEB J. 15, 2742–2744 (2001).

    Article  CAS  PubMed  Google Scholar 

  209. Maier, T. J., Janssen, A., Schmidt, R., Geisslinger, G. & Grösch, S. Targeting the β-catenin/APC pathway: a novel mechanism to explain the cyclooxygenase-2- independent anticarcinogenic effects of celecoxib in human colon carcinoma cells. FASEB J. 19, 1353–1355 (2005).

    Article  CAS  PubMed  Google Scholar 

  210. Phillips, R. K. et al. A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut 50, 857–860 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Shah, S., Hecht, A., Pestell, R. & Byers, S. W. Trans-repression of β-catenin activity by nuclear receptors. J. Biol. Chem. 278, 48137–48145 (2003).

    Article  CAS  PubMed  Google Scholar 

  212. Pálmer, H. G. et al. Vitamin D3 promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of β-catenin signaling. J. Cell Biol. 154, 369–387 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

  213. Pendás-Franco, N. et al. Vitamin D and Wnt/β-catenin pathway in colon cancer: role and regulation of DICKKOPF genes. Anticancer Res. 28, 2613–2623 (2008).

    PubMed  Google Scholar 

  214. Rao, C. V. et al. Chemoprevention of colon carcinogenesis by phenylethyl-3-methylcaffeate. Cancer Res. 55, 2310–2315 (1995).

    CAS  PubMed  Google Scholar 

  215. Jaiswal, A. S., Marlow, B. P., Gupta, N. & Narayan, S. β-catenin-mediated transactivation and cell-cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells. Oncogene 21, 8414–8427 (2002).

    Article  CAS  PubMed  Google Scholar 

  216. Park, C. H. et al. Quercetin, a potent inhibitor against β-catenin/Tcf signaling in SW480 colon cancer cells. Biochem. Biophys. Res. Commun. 328, 227–234 (2005).

    Article  CAS  PubMed  Google Scholar 

  217. Kim, J. et al. Suppression of Wnt signaling by the green tea compound (-)-epigallocatechin 3-gallate (EGCG) in invasive breast cancer cells. Requirement of the transcriptional repressor HBP1. J. Biol. Chem. 281, 10865–10875 (2006).

    Article  CAS  PubMed  Google Scholar 

  218. Roccaro, A. M. et al. Resveratrol exerts antiproliferative activity and induces apoptosis in Waldenström's macroglobulinemia. Clin. Cancer Res. 14, 1849–1858 (2008).

    Article  CAS  PubMed  Google Scholar 

  219. Funato, Y., Michiue, T., Asashima, M. & Miki, H. The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt-β-catenin signalling through dishevelled. Nature Cell. Biol. 8, 501–508 (2006).

    Article  CAS  PubMed  Google Scholar 

  220. Antelmann, H. & Helmann, J. D. Thiol-based redox switches and gene regulation. Antioxid. Redox. Signal. 14, 1049–1063 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Thorne, C. A. et al. Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α. Nature Chem. Biol. 6, 829–836 (2010).

    Article  CAS  Google Scholar 

  222. Lepourcelet, M. et al. Small-molecule antagonists of the oncogenic Tcf/β-catenin protein complex. Cancer Cell 5, 91–102 (2004). This publication reports the first identification of natural small-molecule inhibitors (although not truly selective) of TCF–β-catenin complexes using an ELISA-based high-throughput screen.

    Article  CAS  PubMed  Google Scholar 

  223. Gonsalves, F. C. et al. An. RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway. Proc. Natl Acad. Sci. USA 108, 5894–5863 (2011).

    Article  Google Scholar 

  224. Chen, Z. et al. 2,4-diamino-quinazolines as inhibitors of β-catenin/Tcf-4 pathway: potential treatment for colorectal cancer. Bioorg. Med. Chem. Lett. 19, 4980–4983 (2009).

    Article  CAS  PubMed  Google Scholar 

  225. Trosset, J. Y. et al. Inhibition of protein-protein interactions: the discovery of druglike β-catenin inhibitors by combining virtual and biophysical screening. Proteins 64, 60–67 (2006).

    Article  CAS  PubMed  Google Scholar 

  226. Tian, W. et al. Structure-based discovery of a novel inhibitor targeting the β-catenin/Tcf4 interaction. Biochemistry 51, 724–731 (2012).

    Article  CAS  PubMed  Google Scholar 

  227. Hahne, G. & Grossmann, T. N. Direct targeting of β-catenin: inhibition of protein-protein interactions for the inactivation of Wnt signaling. Bioorg. Med. Chem. 21, 4020–4026 (2013).

    Article  CAS  PubMed  Google Scholar 

  228. Takada, K. et al. Targeted disruption of the BCL9/β-catenin complex inhibits oncogenic Wnt signaling. Sci. Transl. Med. 4, 148ra117 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Grossmann, T. N. et al. Inhibition of oncogenic Wnt signaling through direct targeting of β-catenin. Proc. Natl Acad. Sci. USA 109, 17942–17947 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  230. Shan, J., Shi, D. L., Wang, J. & Zheng, J. Identification of a specific inhibitor of the dishevelled PDZ domain. Biochemistry 44, 15495–15503 (2005).

    Article  CAS  PubMed  Google Scholar 

  231. Fujii, N. et al. An antagonist of dishevelled protein-protein interaction suppresses β-catenin-dependent tumor cell growth. Cancer Res. 67, 573–579 (2007).

    Article  CAS  PubMed  Google Scholar 

  232. Grandy, D. et al. Discovery and characterization of a small molecule inhibitor of the PDZ domain of dishevelled. J. Biol. Chem. 284, 16256–16263 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Chen, B. et al. Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nature Chem. Biol. 5, 100–107 (2009).

    Article  CAS  Google Scholar 

  234. Huang, S. M. et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461, 614–620 (2009). This publication provides evidence for the role of tankyrase in WNT signalling and a rationale for developing specific tankyrase inhibitors to target the WNT pathway.

    Article  CAS  PubMed  Google Scholar 

  235. Lehtiö, L., Chi, N. W. & Krauss, S. Tankyrases as drug targets. FEBS J. 280, 3576–3593 (2013).

    Article  CAS  PubMed  Google Scholar 

  236. Lau, T. et al. A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth. Cancer Res. 73, 3132–3144 (2013).

    Article  CAS  PubMed  Google Scholar 

  237. Hao, H. X. et al. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature 485, 195–200 (2012).

    Article  CAS  PubMed  Google Scholar 

  238. Jacob, L. S. et al. Genome-wide RNAi screen reveals disease-associated genes that are common to Hedgehog and Wnt signaling. Sci. Signal. 4, ra4 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Koo, B. K. et al. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature 488, 665–669 (2012).

    Article  CAS  PubMed  Google Scholar 

  240. Jiang, X. et al. Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proc. Natl Acad. Sci. USA 110, 12649–12654 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  241. Li, X. et al. Prostate tumor progression is mediated by a paracrine TGF-β/Wnt3a signaling axis. Oncogene 27, 7118–7130 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Wei, W., Chua, M. S., Grepper, S. & So, S. K. Soluble Frizzled-7 receptor inhibits Wnt signaling and sensitizes hepatocellular carcinoma cells towards doxorubicin. Mol. Cancer 10, 16 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Pode-Shakked, N. et al. Resistance or sensitivity of Wilms' tumor to anti-FZD7 antibody highlights the Wnt pathway as a possible therapeutic target. Oncogene 30, 1664–1680 (2011).

    Article  CAS  PubMed  Google Scholar 

  244. Gurney, A. et al. Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc. Natl Acad. Sci. USA 109, 11717–11722 (2012). This manuscript describes preclinical studies utilizing the monoclonal antibody OMP-18R5, which is currently in Phase I clinical trials.

    Article  PubMed  PubMed Central  Google Scholar 

  245. Kung, A. L. et al. Gene dose-dependent control of hematopoiesis and hematologic tumor suppression by CBP. Genes Dev. 14, 272–277 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  246. Yamauchi, T. et al. Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice. Nature Genet. 30, 221–226 (2002).

    Article  CAS  PubMed  Google Scholar 

  247. Roth, J. F. et al. Differential role of p300 and CBP acetyltransferase during myogenesis: 300 acts upstream of MyoD and Myf5. EMBO J. 22, 5186–5196 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. McMillan, M. & Kahn, M. Investigating Wnt signaling: a chemogenomic safari. Drug Discov. Today 10, 1467–1474 (2005).

    Article  CAS  PubMed  Google Scholar 

  249. Emami, K. H. et al. A small molecule inhibitor of β-catenin/CREB-binding protein transcription [corrected]. Proc. Natl Acad. Sci. USA 101, 12682–12687 (2004). This study and subsequent studies utilizing specific small-molecule CBP antagonists (including those detailed in references 252 and 253) provided the rationale for the clinical development of the second-generation CBP–catenin antagonist PRI-724, which is currently in Phase I/II clinical trials.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Marson, A. et al. Wnt signaling promotes reprogramming of somatic cells to pluripotency. Cell Stem Cell 3, 132–135 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Schenke-Layland, K. et al. Recapitulation of the embryonic cardiovascular progenitor cell niche. Biomaterials 2, 2748–2756 (2011).

    Article  CAS  Google Scholar 

  252. Wend, P. et al. Wnt/β-catenin signalling induces MLL to create epigenetic changes in salivary gland tumours. EMBO J. 32, 1977–1989 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Gang, E. J. et al. Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia. Oncogene 33, 2169–2178 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. He, K. et al. Cancer cells acquire a drug resistant, highly tumorigenic, cancer stem-like phenotype through modulation of the PI3K/Akt/β-catenin/CBP pathway. Int. J. Cancer 134, 43–54 (2014).

    Article  CAS  PubMed  Google Scholar 

  255. Kahn, M. Symmetric division versus asymmetric division: a tale of two coactivators. Future Med. Chem. 3, 1745–1763 (2011). This article outlines the mechanism whereby selective CBP–catenin antagonists can safely eliminate cancer stem cells via forced differentiation without having deleterious effects on the normal somatic stem cell populations.

    Article  CAS  PubMed  Google Scholar 

  256. Takada, R. et al. Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion. Dev. Cell 11, 791–801 (2006).

    Article  CAS  PubMed  Google Scholar 

  257. Liu, J. et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc. Natl Acad. Sci. USA 110, 20224–20229 (2013). This study describes the discovery of the small-molecule Porcupine inhibitor LGK974, which is currently in Phase I clinical trials.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Smith, D. C. et al. First-in-human evaluation of the human monoclonal antibody vantictumab (OMP-18R5; anti-Frizzled) targeting the WNT pathway in a phase I study for patients with advanced solid tumors. J. Clin. Oncol. Abstr. 31, 2540 (2013).

    Article  Google Scholar 

  259. Morishita, E. C. et al. Crystal structures of the armadillo repeat domain of adenomatous polyposis coli and its complex with the tyrosine-rich domain of Sam68. Structure 19, 1496–1508 (2011).

    Article  CAS  PubMed  Google Scholar 

  260. Ma, H., Nguyen, C., Lee., K. S. & Kahn, M. Differential roles for the coactivators CBP and p300 on TCF/β-catenin-mediated survivin gene expression. Oncogene 24, 3619–3631 (2005).

    Article  CAS  PubMed  Google Scholar 

  261. el-Khoueiry, A. et al. A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors. J. Clin. Oncol. Abstr. 31, 2501 (2013).

    Google Scholar 

  262. Mahmoudi, T. et al. The kinase TNIK is an essential activator of Wnt target genes. EMBO J. 28, 3329–3340 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Shitashige, M. et al. Traf2- and Nck-interacting kinase is essential for Wnt signaling and colorectal cancer growth. Cancer Res. 70, 5024–5033 (2010).

    Article  CAS  PubMed  Google Scholar 

  264. Onder, T. T. et al. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res. 68, 3645–3654 (2008).

    Article  CAS  PubMed  Google Scholar 

  265. Kim, K., Daniels, K. J. & Hay, E. D. Tissue-specific expression of β-catenin in normal mesenchyme and uveal melanomas and its effect on invasiveness. Exp. Cell Res. 245, 79–90 (1998).

    Article  CAS  PubMed  Google Scholar 

  266. Valastyan, S. & Weinberg, R. A. Tumor metastasis: molecular insights and evolving paradigms. Cell 147, 275–292 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Wagh, P. K. et al. β-catenin is required for Ron receptor-induced mammary tumorigenesis. Oncogene 30, 3694–3704 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Coluccia, A. M. et al. SKI-606 decreases growth and motility of colorectal cancer cells by preventing pp60(c-Src)-dependent tyrosine phosphorylation of β-catenin and its nuclear signaling. Cancer Res. 66, 2279–2286 (2006).

    Article  CAS  PubMed  Google Scholar 

  270. Ress, A. & Moelling, K. Bcr interferes with β-catenin-Tcf1 interaction. FEBS Lett. 580, 1227–1230 (2006).

    Article  CAS  PubMed  Google Scholar 

  271. Fujino, H., West, K. A. & Regan, J. W. Phosphorylation of glycogen synthase kinase-3 and stimulation of T-cell factor signaling following activation of EP2 and EP4 prostanoid receptors by prostaglandin E2. J. Biol. Chem. 277, 2614–2619 (2002).

    Article  CAS  PubMed  Google Scholar 

  272. Fujino, H. & Regan, J. W. FP prostanoid receptor activation of a T-cell factor/β-catenin signaling pathway. J. Biol. Chem. 276, 12489–12492 (2001).

    Article  CAS  PubMed  Google Scholar 

  273. Liu, X., Rubin, J. S. & Kimmel, A. R. Rapid, Wnt-induced changes in GSK3β associations that regulate β-catenin stabilization are mediated by Gα proteins. Curr. Biol. 15, 1989–1997 (2005).

    Article  CAS  PubMed  Google Scholar 

  274. Meigs, T. E., Fields, T. A., McKee, D. D. & Casey, P. J. Interaction of Gα12 and Gα13 with the cytoplasmic domain of cadherin provides a mechanism for β-catenin release. Proc. Natl Acad. Sci. USA 98, 519–524 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  275. Mazumdar, J. et al. O2 regulates stem cells through Wnt/β-catenin signalling. Nature Cell Biol. 12, 1007–1013 (2010).

    Article  CAS  PubMed  Google Scholar 

  276. Chocarro-Calvo, A., García-Martínez, J. M., Ardila-González, S., De la Vieja, A. & García-Jiménez, C. Glucose-induced β-catenin acetylation enhances Wnt signaling in cancer. Mol. Cell 49, 474–486 (2013).

    Article  CAS  PubMed  Google Scholar 

  277. Gómez-Orte, E., Sáenz-Narciso, B., Moreno, S. & Cabello, J. Multiple functions of the noncanonical Wnt pathway. Trends Genet. 29, 545–553 (2013).

    Article  CAS  PubMed  Google Scholar 

  278. Tada, M. & Kai, M. Noncanonical Wnt/PCP signaling during vertebrate gastrulation. Zebrafish 6, 29–40 (2009).

    Article  CAS  PubMed  Google Scholar 

  279. Wang, Y. Wnt/planar cell polarity signaling: a new paradigm for cancer therapy. Mol. Cancer Ther. 8, 2103–2109 (2009).

    Article  CAS  PubMed  Google Scholar 

  280. Lai, S. L., Chien, A. J. & Moon, R. T. Wnt/Fz signaling and the cytoskeleton: potential roles in tumorigenesis. Cell Res. 19, 532–545 (2009).

    Article  CAS  PubMed  Google Scholar 

  281. Ginis, I. et al. Differences between human and mouse embryonic stem cells. Dev. Biol. 269, 360–380 (2004).

    Article  CAS  PubMed  Google Scholar 

  282. Sato, N., Meijer, L., Skaltsounis, L., Greengard, P. & Brivanlou, A. H. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nature Med. 10, 55–63 (2004).

    Article  CAS  PubMed  Google Scholar 

  283. Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).

    Article  CAS  PubMed  Google Scholar 

  284. Otero, J. J., Fu, W., Kan, L., Cuadra, A. E. & Kessler, J. A. β-catenin signaling is required for neural differentiation of embryonic stem cells. Development 131, 3545–3557 (2004).

    Article  CAS  PubMed  Google Scholar 

  285. Faunes, F. et al. A membrane-associated β-catenin/Oct4 complex correlates with ground-state pluripotency in mouse embryonic stem cells. Development 140, 1171–1183 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  286. Zechner, D. et al. β-catenin signals regulate cell growth and the balance between progenitor cell expansion and differentiation in the nervous system. Dev. Biol. 258, 406–418 (2003).

    Article  CAS  PubMed  Google Scholar 

  287. Hari, L. et al. Lineage-specific requirements of β-catenin in neural crest development. J. Cell Biol. 159, 867–880 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  288. Muroyama, Y., Kondoh, H. & Takada, S. Wnt proteins promote neuronal differentiation in neural stem cell culture. Biochem. Biophys. Res. Commun. 313, 915–921 (2004).

    Article  CAS  PubMed  Google Scholar 

  289. LaBarge, M. The difficulty of targeting cancer stem cell niches. Clin. Cancer Res. 16, 3121–3129 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  290. Merchan, A. A. & Matsui, W. Targeting Hedgehog — a cancer stem cell pathway. Clin. Cancer Res. 16, 3130–3140 (2010).

    Article  Google Scholar 

  291. Pannuti, A. et al. Targeting Notch to target cancer stem cells. Clin. Cancer Res. 16, 3141–3152 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  292. Holland, J. D., Klaus, A., Garratt, A. N. & Birchmeier, W. Wnt signaling in stem and cancer stem cells. Curr. Opin. Cell Biol. 25, 254–264 (2013). This is an excellent recent review on the role of WNT signalling in cancer stem cells.

    Article  CAS  PubMed  Google Scholar 

  293. Cicalese, A. et al. The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell 138, 1083–1095 (2009).

    Article  CAS  PubMed  Google Scholar 

  294. Takahashi-Yanaga, F. & Kahn, M. Targeting Wnt signaling: can we safely eradicate cancer stem cells? Clin. Cancer Res. 16, 3153–3162 (2010).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Support from the USC Norris Comprehensive Cancer Center (Support Grant P30 CA014089) and the US National Institutes of Health (NIH) grants 1R01CA166161-01A1, 1R21NS074392-01, 1R21AI105057-01 and NIH 1R01 HL112638-01 are gratefully acknowledged. I thank J.-L. Teo for critical review and assistance with preparation of this manuscript. As with any attempt to review a broad and dynamically changing field, this is a snapshot of the current status. I apologize for any unintended omissions and oversights.

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The author is a consultant and equity holder in Prism Pharma Co. Ltd.

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Kahn, M. Can we safely target the WNT pathway?. Nat Rev Drug Discov 13, 513–532 (2014). https://doi.org/10.1038/nrd4233

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