The evolving roles of canonical WNT signaling in stem cells and tumorigenesis: Implications in targeted cancer therapies

Laboratory Investigation

Volumn 96, Issue 2, 2016, Pages 116-136

  Yang, Ke ^a,b,c   Wang, Xin ^b,d   Zhang, Hongmei ^a,b   Wang, Zhongliang ^a,b   Nan, Guoxin ^a,b   Li, Yasha ^a,b   Zhang, Fugui ^a,b   Mohammed, Maryam K ^b   Haydon, Rex C ^b   Luu, Hue H ^b   Bi, Yang ^a,b   He, Tong Chuan ^a,b  

^a CHONGQING MEDICAL UNIVERSITY   (China)

^b UNIVERSITY OF CHICAGO MEDICAL CENTER   (United States)

^c Chongqing Engineering Research Center of Stem Cell Therapy   (China)

^d SICHUAN UNIVERSITY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

BETA CATENIN; DISHEVELLED PROTEIN; GROWTH FACTOR; HHIPPO PROTEIN; NOTCH RECEPTOR; PORCUPINE (PROTEIN); PROTEIN; R SPONDIN; SONIC HEDGEHOG PROTEIN; T CELL FACTOR PROTEIN; TANKYRASE; TAZ PROTEIN; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG; WNT PROTEIN; YAP PROTEIN;

ARTICLE; CANCER STEM CELL; CANCER THERAPY; CARCINOGENESIS; CELL MEMBRANE; EMBRYONIC STEM CELL; HAIR FOLLICLE STEM CELL; HEMATOPOIETIC STEM CELL; HUMAN; INTESTINAL STEM CELL; MESENCHYMAL STEM CELL; METASTASIS; MOLECULAR INTERACTION; MOLECULARLY TARGETED THERAPY; NONHUMAN; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; PROTEIN PROTEIN INTERACTION; PROTEIN TARGETING; STEM CELL; STEM CELL SELF-RENEWAL; WNT SIGNALING PATHWAY; ANIMAL; DRUG DEVELOPMENT; MOUSE; NEOPLASMS;

ANIMALS; CARCINOGENESIS; DRUG DISCOVERY; HUMANS; MICE; NEOPLASMS; STEM CELLS; WNT PROTEINS; WNT SIGNALING PATHWAY;

EID: 84955564630     PISSN: 00236837     EISSN: 15300307     Source Type: Journal    
DOI: 10.1038/labinvest.2015.144     Document Type: Article

References (346)

1. Nusse R, Varmus HE. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 1982;31:99-109.
2. Nusse R, Varmus H. Three decades of Wnts: a personal perspective on how a scientific field developed. Embo J 2012;31:2670-2684.
3. Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature 1980;287:795-801.
4. Rijsewijk F, Schuermann M, Wagenaar E et al. The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless. Cell 1987;50:649-657.
5. Noordermeer J, Klingensmith J, Perrimon N et al. Dishevelled and armadillo act in the wingless signalling pathway in Drosophila. Nature 1994;367:80-83.
6. Peifer M, McCrea PD, Green KJ et al. The vertebrate adhesive junction proteins beta-catenin and plakoglobin and the Drosophila segment polarity gene armadillo form a multigene family with similar properties. J Cell Biol 1992;118:681-691.
7. Siegfried E, Chou TB, Perrimon N. wingless signaling acts through zeste-white 3, the Drosophila homolog of glycogen synthase kinase-3, to regulate engrailed and establish cell fate. Cell 1992;71: 1167-1179.
8. Siegfried E, Wilder EL, Perrimon N. Components of wingless signalling in Drosophila. Nature 1994;367:76-80.
9. Behrens J, von Kries JP, Kuhl M et al. Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 1996;382: 638-642.
10. Molenaar M, van de Wetering M, Oosterwegel M et al. XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell 1996;86:391-399.
11. Bhanot P, Brink M, Samos CH et al. A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature 1996;382:225-230.
12. Wehrli M, Dougan ST, Caldwell K et al. Arrow encodes an LDL-receptor-related protein essential for Wingless signalling. Nature 2000;407:527-530.
13. Kinzler KW, Nilbert MC, Su LK et al. Identification of FAP locus genes from chromosome 5q21. Science 1991;253:661-665.
14. Nishisho I, Nakamura Y, Miyoshi Y et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 1991;253: 665-669.
15. Rubinfeld B, Souza B, Albert I et al. Association of the APC gene product with beta-catenin. Science 1993;262:1731-1734.
16. Su LK, Vogelstein B, Kinzler KW. Association of the APC tumor suppressor protein with catenins. Science 1993;262:1734-1737.
17. Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 2004;20:781-810.
18. Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature 2005;434:843-850.
19. Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer 2008;8:387-398.
20. MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 2009;17:9-26.
21. Luo J, Chen J, Deng ZL et al. Wnt signaling and human diseases: what are the therapeutic implications? Lab Invest 2007;87:97-103.
22. Wagner ER, Zhu G, Zhang BQ et al. The therapeutic potential of the Wnt signaling pathway in bone disorders. Curr Mol Pharmacol 2011;4: 14-25.
23. Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell 2012;149:1192-1205.
24. Gough NR. Focus issue: Wnt and beta-catenin signaling in development and disease. Sci Signal 2012;5:eg2.
25. Niehrs C. The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol 2012;13:767-779.
26. Anastas JN, Moon RT. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer 2013;13:11-26.
27. Clevers H, Loh KM, Nusse R. Stem cell signaling. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. Science 2014;346:1248012.
28. Willert K, Brown JD, Danenberg E et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 2003;423: 448-452.
29. Janda CY, Waghray D, Levin AM et al. Structural basis of Wnt recognition by Frizzled. Science 2012;337:59-64.
30. Franch-Marro X, Wendler F, Griffith J et al. In vivo role of lipid adducts on Wingless. J Cell Sci 2008;121(Pt 10):1587-1592.
31. Kurayoshi M, Yamamoto H, Izumi S et al. Post-translational palmitoylation and glycosylation of Wnt-5a are necessary for its signalling. Biochem J 2007;402:515-523.
32. Hofmann K. A superfamily of membrane-bound O-acyltransferases with implications for wnt signaling. Trends Biochem Sci 2000;25: 111-112.
33. Kadowaki T, Wilder E, Klingensmith J et al. The segment polarity gene porcupine encodes a putative multitransmembrane protein involved in Wingless processing. Genes Dev 1996;10:3116-3128.
34. Takada R, Satomi Y, Kurata T et al. Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion. Dev Cell 2006;11:791-801.
35. Banziger C, Soldini D, Schutt C et al. Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells. Cell 2006;125:509-522.
36. Fu J, Jiang M, Mirando AJ et al. Reciprocal regulation of Wnt and Gpr177/mouse Wntless is required for embryonic axis formation. Proc Natl Acad Sci USA 2009;106:18598-18603.
37. Port F, Basler K. Wnt trafficking: new insights into Wnt maturation, secretion and spreading. Traffic 2010;11:1265-1271.
38. Yu J, Chia J, Canning CA et al. WLS retrograde transport to the endoplasmic reticulum during Wnt secretion. Dev Cell 2014;29: 277-291.
39. Jiang M, Ku WY, Fu J et al. Gpr177 regulates pulmonary vasculature development. Development 2013;140:3589-3594.
40. Yamamoto H, Awada C, Hanaki H et al. The apical and basolateral secretion of Wnt11 and Wnt3a in polarized epithelial cells is regulated by different mechanisms. J Cell Sci 2013;126(Pt 13):2931-2943.
41. Zhong Z, Zylstra-Diegel CR, Schumacher CA et al. Wntless functions in mature osteoblasts to regulate bone mass. Proc Natl Acad Sci USA 2012;109:E2197-E2204.
42. Zhu X, Zhu H, Zhang L et al. Wls-mediated Wnts differentially regulate distal limb patterning and tissue morphogenesis. Dev Biol 2012;365: 328-338.
43. Fu J, Ivy Yu HM, Maruyama T et al. Gpr177/mouse Wntless is essential for Wnt-mediated craniofacial and brain development. Dev Dyn 2011;240:365-371.
44. Galli LM, Szabo LA, Li L et al. Concentration-dependent effects of WNTLESS on WNT1/3A signaling. Dev Dyn 2014;243:1095-1105.
45. Cavallo RA, Cox RT, Moline MM et al. Drosophila Tcf and Groucho interact to repress Wingless signalling activity. Nature 1998;395: 604-608.
46. Roose J, Molenaar M, Peterson J et al. The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors. Nature 1998;395:608-612.
47. Arce L, Pate KT, Waterman ML. Groucho binds two conserved regions of LEF-1 for HDAC-dependent repression. BMC Cancer 2009;9:159.
48. Bilic J, Huang YL, Davidson G et al. Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation. Science 2007;316:1619-1622.
49. Zeng X, Huang H, Tamai K et al. Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions. Development 2008;135:367-375.
50. Metcalfe C, Mendoza-Topaz C, Mieszczanek J et al. Stability elements in the LRP6 cytoplasmic tail confer efficient signalling upon DIX-dependent polymerization. J Cell Sci 2010;123(Pt 9): 1588-1599.
51. Kramps T, Peter O, Brunner E et al. Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex. Cell 2002;109:47-60.
52. Li J, Sutter C, Parker DS et al. CBP/p300 are bimodal regulators of Wnt signaling. EMBO J 2007;26:2284-2294.
53. He TC, Chan TA, Vogelstein B et al. PPARdelta is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell 1999;99:335-345.
54. He TC, Sparks AB, Rago C et al. Identification of c-MYC as a target of the APC pathway. Science 1998;281:1509-1512.
55. Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 1999;398:422-426.
56. Shtutman M, Zhurinsky J, Simcha I et al. The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci USA 1999;96: 5522-5527.
57. Yan D, Wiesmann M, Rohan M et al. Elevated expression of axin2 and hnkd mRNA provides evidence that Wnt/beta-catenin signaling is activated in human colon tumors. Proc Natl Acad Sci USA 2001;98: 14973-14978.
58. Lustig B, Jerchow B, Sachs M et al. Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol Cell Biol 2002;22:1184-1193.
59. Jho EH, Zhang T, Domon C et al. Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol Cell Biol 2002;22:1172-1183.
60. Willert J, Epping M, Pollack JR et al. A transcriptional response to Wnt protein in human embryonic carcinoma cells. BMC. Dev Biol 2002;2:8.
61. Kikuchi A, Yamamoto H, Sato A et al. New insights into the mechanism of Wnt signaling pathway activation. Int Rev Cell Mol Biol 2011;291:21-71.
62. Gan XQ, Wang JY, Xi Y et al. Nuclear Dvl, c-Jun, beta-catenin, and TCF form a complex leading to stabilization of beta-catenin-TCF interaction. J Cell Biol 2008;180:1087-1100.
63. Louie SH, Yang XY, Conrad WH et al. Modulation of the beta-catenin signaling pathway by the dishevelled-associated protein Hipk1. PLoS One 2009;4:e4310.
64. Wang W, Li X, Lee M et al. FOXKs promote Wnt/beta-catenin signaling by translocating DVL into the nucleus. Dev Cell 2015;32:707-718.
65. Teo JL, Ma H, Nguyen C et al. Specific inhibition of CBP/beta-catenin interaction rescues defects in neuronal differentiation caused by a presenilin-1 mutation. Proc Natl Acad Sci USA 2005;102: 12171-12176.
66. Sasaki T, Hwang H, Nguyen C et al. The small molecule Wnt signaling modulator ICG-001 improves contractile function in chronically infarcted rat myocardium. PLoS One 2013;8:e75010.
67. Wolf D, Rodova M, Miska EA et al. Acetylation of beta-catenin by CREB-binding protein (CBP). J Biol Chem 2002;277:25562-25567.
68. Levy L, Wei Y, Labalette C et al. Acetylation of beta-catenin by p300 regulates beta-catenin-Tcf4 interaction. Mol Cell Biol 2004;24: 3404-3414.
69. Chocarro-Calvo A, Garcia-Martinez JM, Ardila-Gonzalez S et al. Glucose-induced beta-catenin acetylation enhances Wnt signaling in cancer. Mol Cell 2013;49:474-486.
70. Kessler R, Hausmann G, Basler K. The PHD domain is required to link Drosophila Pygopus to Legless/beta-catenin and not to histone H3. Mech Dev 2009;126:752-759.
71. Miller TC, Rutherford TJ, Johnson CM et al. Allosteric remodelling of the histone H3 binding pocket in the Pygo2 PHD finger triggered by its binding to the B9L/BCL9 co-factor. J Mol Biol 2010;401: 969-984.
72. van den Bosch MH, Blom AB, van Lent PL et al. Canonical Wnt signaling skews TGF-beta signaling in chondrocytes towards signaling via ALK1 and Smad 1/5/8. Cell Signal 2014;26:951-958.
73. Funa NS, Schachter KA, Lerdrup M et al. Beta-catenin regulates primitive streak induction through collaborative interactions with SMAD2/SMAD3 and OCT4. Cell Stem Cell 2015;16:639-652.
74. Zhang N, Wei P, Gong A et al. FoxM1 promotes beta-catenin nuclear localization and controls Wnt target-gene expression and glioma tumorigenesis. Cancer Cell 2011;20:427-442.
75. Kim KA, Zhao J, Andarmani S et al. R-Spondin proteins: a novel link to beta-catenin activation. Cell Cycle 2006;5:23-26.
76. Nam JS, Turcotte TJ, Smith PF et al. Mouse cristin/R-spondin family proteins are novel ligands for the Frizzled 8 and LRP6 receptors and activate beta-catenin-dependent gene expression. J Biol Chem 2006;281:13247-13257.
77. Kazanskaya O, Glinka A, del Barco Barrantes I et al. R-Spondin2 is a secreted activator of Wnt/beta-catenin signaling and is required for Xenopus myogenesis. Dev Cell 2004;7:525-534.
78. Kim KA, Wagle M, Tran K et al. R-Spondin family members regulate the Wnt pathway by a common mechanism. Mol Biol Cell 2008;19: 2588-2596.
79. Wei Q, Yokota C, Semenov MV et al. R-spondin1 is a high affinity ligand for LRP6 and induces LRP6 phosphorylation and beta-catenin signaling. J Biol Chem 2007;282:15903-15911.
80. Carmon KS, Gong X, Lin Q et al. R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta-catenin signaling. Proc Natl Acad Sci USA 2011;108:11452-11457.
81. de Lau W, Barker N, Low TY et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature 2011;476: 293-297.
82. Hao HX, Xie Y, Zhang Y et al. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature 2012;485:195-200.
83. Koo BK, Spit M, Jordens I et al. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature 2012;488:665-669.
84. de Lau WB, Snel B, Clevers HC. The R-spondin protein family. Genome Biol 2012;13:242.
85. Finch PW, He X, Kelley MJ et al. Purification and molecular cloning of a secreted, Frizzled-related antagonist of Wnt action. Proc Natl Acad Sci USA 1997;94:6770-6775.
86. Kawano Y, Kypta R. Secreted antagonists of the Wnt signalling pathway. J Cell Sci 2003;116(Pt 13):2627-2634.
87. Ladher RK, Church VL, Allen S et al. Cloning and expression of the Wnt antagonists Sfrp-2 and Frzb during chick development. Dev Biol 2000;218:183-198.
88. Hsieh JC, Kodjabachian L, Rebbert ML et al. A new secreted protein that binds to Wnt proteins and inhibits their activities. Nature 1999;398:431-436.
89. Glinka A, Wu W, Delius H et al. Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature 1998;391:357-362.
90. Mao B, Wu W, Davidson G et al. Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. Nature 2002;417:664-667.
91. Ellwanger K, Saito H, Clement-Lacroix P et al. Targeted disruption of the Wnt regulator Kremen induces limb defects and high bone density. Mol Cell Biol 2008;28:4875-4882.
92. Semenov MV, Zhang X, He X. DKK1 antagonizes Wnt signaling without promotion of LRP6 internalization and degradation. J Biol Chem 2008;283:21427-21432.
93. Wang K, Zhang Y, Li X et al. Characterization of the Kremen-binding site on Dkk1 and elucidation of the role of Kremen in Dkk-mediated Wnt antagonism. J Biol Chem 2008;283:23371-23375.
94. Itasaki N, Jones CM, Mercurio S et al. Wise, a context-dependent activator and inhibitor of Wnt signalling. Development 2003;130: 4295-4305.
95. Li X, Zhang Y, Kang H et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 2005;280:19883-19887.
96. Semenov M, Tamai K, He X. SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. J Biol Chem 2005;280:26770-26775.
97. Johnson ML, Harnish K, Nusse R et al. LRP5 and Wnt signaling: a union made for bone. J Bone Miner Res 2004;19:1749-1757.
98. Kim JH, Liu X, Wang J et al. Wnt signaling in bone formation and its therapeutic potential for bone diseases. Ther Adv Musculoskelet Dis 2013;5:13-31.
99. Apte U, Zeng G, Muller P et al. Activation of Wnt/beta-catenin pathway during hepatocyte growth factor-induced hepatomegaly in mice. Hepatology 2006;44:992-1002.
100. Monga SP, Mars WM, Pediaditakis P et al. Hepatocyte growth factor induces Wnt-independent nuclear translocation of beta-catenin after Met-beta-catenin dissociation in hepatocytes. Cancer Res 2002;62: 2064-2071.
101. Nakopoulou L, Gakiopoulou H, Keramopoulos A et al. c-met tyrosine kinase receptor expression is associated with abnormal beta-catenin expression and favourable prognostic factors in invasive breast carcinoma. Histopathology 2000;36:313-325.
102. Rasola A, Fassetta M, De Bacco F et al. A positive feedback loop between hepatocyte growth factor receptor and beta-catenin sustains colorectal cancer cell invasive growth. Oncogene 2007;26: 1078-1087.
103. Ji H, Wang J, Nika H et al. EGF-induced ERK activation promotes CK2-mediated disassociation of alpha-Catenin from beta-Catenin and transactivation of beta-Catenin. Mol Cell 2009;36:547-559.
104. Ochiai A, Akimoto S, Kanai Y et al. c-erbB-2 gene product associates with catenins in human cancer cells. Biochem Biophys Res Commun 1994;205:73-78.
105. Yang W, Xia Y, Ji H et al. Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation. Nature 2011;480:118-122.
106. Bommer GT, Feng Y, Iura A et al. IRS1 regulation by Wnt/beta-catenin signaling and varied contribution of IRS1 to the neoplastic phenotype. J Biol Chem 2010;285:1928-1938.
107. Desbois-Mouthon C, Cadoret A, Blivet-Van Eggelpoel MJ et al. Insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades involving GSK-3beta inhibition and Ras activation. Oncogene 2001;20:252-259.
108. Longato L, de la Monte S, Kuzushita N et al. Overexpression of insulin receptor substrate-1 and hepatitis Bx genes causes premalignant alterations in the liver. Hepatology 2009;49:1935-1943.
109. Ramocki NM, Wilkins HR, Magness ST et al. Insulin receptor substrate-1 deficiency promotes apoptosis in the putative intestinal crypt stem cell region, limits Apcmin/+ tumors, and regulates Sox9. Endocrinology 2008;149:261-267.
110. Satyamoorthy K, Li G, Vaidya B et al. Insulin-like growth factor-1 induces survival and growth of biologically early melanoma cells through both the mitogen-activated protein kinase and beta-catenin pathways. Cancer Res 2001;61:7318-7324.
111. Verras M, Sun Z. Beta-catenin is involved in insulin-like growth factor 1-mediated transactivation of the androgen receptor. Mol Endocrinol 2005;19:391-398.
112. Birdsey GM, Shah AV, Dufton N et al. The endothelial transcription factor ERG promotes vascular stability and growth through Wnt/beta-catenin signaling. Dev Cell 2015;32:82-96.
113. Naik S, Dothager RS, Marasa J et al. Vascular endothelial growth factor receptor-1 is synthetic lethal to aberrant {beta}-catenin activation in colon cancer. Clin Cancer Res 2009;15:7529-7537.
114. Clausse N, Baines D, Moore R et al. Activation of both Wnt-1 and Fgf-3 by insertion of mouse mammary tumor virus downstream in the reverse orientation: a reappraisal of the enhancer insertion model. Virology 1993;194:157-165.
115. Katoh M, Katoh M. Cross-talk of WNT and FGF signaling pathways at GSK3beta to regulate beta-catenin and SNAIL signaling cascades. Cancer Biol Ther 2006;5:1059-1064.
116. Lee FS, Lane TF, Kuo A et al. Insertional mutagenesis identifies a member of the Wnt gene family as a candidate oncogene in the mammary epithelium of int-2/Fgf-3 transgenic mice. Proc Natl Acad Sci USA 1995;92:2268-2272.
117. Nicholes K, Guillet S, Tomlinson E et al. A mouse model of hepato-cellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am J Pathol 2002;160: 2295-2307.
118. Pai R, Dunlap D, Qing J et al. Inhibition of fibroblast growth factor 19 reduces tumor growth by modulating beta-catenin signaling. Cancer Res 2008;68:5086-5095.
119. Shackleford GM, MacArthur CA, Kwan HC et al. Mouse mammary tumor virus infection accelerates mammary carcinogenesis in Wnt-1 transgenic mice by insertional activation of int-2/Fgf-3 and hst/Fgf-4. Proc Natl Acad Sci USA 1993;90:740-744.
120. Li Y, Zhang X, Polakiewicz RD et al. HDAC6 is required for epidermal growth factor-induced beta-catenin nuclear localization. J Biol Chem 2008;283:12686-12690.
121. Chen D, Zhao M, Mundy GR. Bone morphogenetic proteins. Growth Factors 2004;22:233-241.
122. Dumont N, Arteaga CL. Targeting the TGF beta signaling network in human neoplasia. Cancer Cell 2003;3:531-536.
123. Yingling JM, Blanchard KL, Sawyer JS. Development of TGF-beta signalling inhibitors for cancer therapy. Nat Rev Drug Discov 2004;3: 1011-1022.
124. Wang RN, Green J, Wang Z et al. Bone morphogenetic protein (BMP) signaling in development and human diseases. Genes Dis 2014;1: 87-105.
125. Luther G, Wagner ER, Zhu G et al. BMP-9 induced osteogenic differentiation of mesenchymal stem cells: molecular mechanism and therapeutic potential. Curr Gene Ther 2011;11:229-240.
126. Lamplot JD, Qin J, Nan G et al. BMP9 signaling in stem cell differentiation and osteogenesis. Am J Stem Cells 2013;2:1-21.
127. Kim JS, Crooks H, Dracheva T et al. Oncogenic beta-catenin is required for bone morphogenetic protein 4 expression in human cancer cells. Cancer Res 2002;62:2744-2748.
128. Hoppler S, Moon RT. BMP-2/-4 and Wnt-8 cooperatively pattern the Xenopus mesoderm. Mech Dev 1998;71:119-129.
129. Labbe E, Letamendia A, Attisano L. Association of Smads with lymphoid enhancer binding factor 1/T cell-specific factor mediates cooperative signaling by the transforming growth factor-beta and wnt pathways. Proc Natl Acad Sci USA 2000;97:8358-8363.
130. Nishita M, Hashimoto MK, Ogata S et al. Interaction between Wnt and TGF-beta signalling pathways during formation of Spemann's organizer. Nature 2000;403:781-785.
131. Szeto DP, Kimelman D. Combinatorial gene regulation by Bmp and Wnt in zebrafish posterior mesoderm formation. Development 2004;131:3751-3760.
132. Hussein SM, Duff EK, Sirard C. Smad4 and beta-catenin co-activators functionally interact with lymphoid-enhancing factor to regulate graded expression of Msx2. J Biol Chem 2003;278:48805-48814.
133. Letamendia A, Labbe E, Attisano L. Transcriptional regulation by Smads: cross-talk between the TGF-beta and Wnt pathways. J Bone Joint Surg Am 2001;83-A Suppl 1(Pt 1):S31-S39.
134. Theil T, Aydin S, Koch S et al. Wnt and Bmp signalling cooperatively regulate graded Emx2 expression in the dorsal telencephalon. Development 2002;129:3045-3054.
135. Sakai D, Tanaka Y, Endo Y et al. Regulation of Slug transcription in embryonic ectoderm by beta-catenin-Lef/Tcf and BMP-Smad signaling. Dev Growth Differ 2005;47:471-482.
136. Hu MC, Rosenblum ND. Smad1, beta-catenin and Tcf4 associate in a molecular complex with the Myc promoter in dysplastic renal tissue and cooperate to control Myc transcription. Development 2005;132: 215-225.
137. Bhowmick NA, Chytil A, Plieth D et al. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 2004;303:848-851.
138. Li X, Placencio V, Iturregui JM et al. Prostate tumor progression is mediated by a paracrine TGF-beta/Wnt3a signaling axis. Oncogene 2008;27:7118-7130.
139. Han G, Li AG, Liang YY et al. Smad7-induced beta-catenin degradation alters epidermal appendage development. Dev Cell 2006;11:301-312.
140. Edlund S, Lee SY, Grimsby S et al. Interaction between Smad7 and beta-catenin: importance for transforming growth factor beta-induced apoptosis. Mol Cell Biol 2005;25:1475-1488.
141. Tang Y, Liu Z, Zhao L et al. Smad7 stabilizes beta-catenin binding to E-cadherin complex and promotes cell-cell adhesion. J Biol Chem 2008;283:23956-23963.
142. Song J, McColl J, Camp E et al. Smad1 transcription factor integrates BMP2 and Wnt3a signals in migrating cardiac progenitor cells. Proc Natl Acad Sci USA 2014;111:7337-7342.
143. Itasaki N, Hoppler S. Cross-talk between Wnt and bone morphogenic protein signaling: a turbulent relationship. Dev Dyn 2010;239:16-33.
144. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science 1999;284: 770-776.
145. Fortini ME. Notch signaling: the core pathway and its posttrans-lational regulation. Dev Cell 2009;16:633-647.
146. Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 2009;137:216-233.
147. Duncan AW, Rattis FM, DiMascio LN et al. Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance. Nat Immunol 2005;6:314-322.
148. Galceran J, Sustmann C, Hsu SC et al. LEF1-mediated regulation of Delta-like1 links Wnt and Notch signaling in somitogenesis. Genes Dev 2004;18:2718-2723.
149. Nakamura T, Tsuchiya K, Watanabe M. Cross-talk between Wnt and Notch signaling in intestinal epithelial cell fate decision. J Gastroenterol 2007;42:705-710.
150. Collu GM, Hidalgo-Sastre A, Brennan K. Wnt-Notch signalling cross-talk in development and disease. Cell Mol Life Sci 2014;71:3553-3567.
151. Munoz-Descalzo S, de Navascues J, Arias AM. Wnt-Notch signalling: an integrated mechanism regulating transitions between cell states. Bioessays 2012;34:110-118.
152. Hayward P, Brennan K, Sanders P et al. Notch modulates Wnt signalling by associating with Armadillo/beta-catenin and regulating its transcriptional activity. Development 2005;132:1819-1830.
153. Axelrod JD, Matsuno K, Artavanis-Tsakonas S et al. Interaction between Wingless and Notch signaling pathways mediated by dishevelled. Science 1996;271:1826-1832.
154. Nicolas M, Wolfer A, Raj K et al. Notch1 functions as a tumor suppressor in mouse skin. Nat Genet 2003;33:416-421.
155. Revet I, Huizenga G, Koster J et al. MSX1 induces the Wnt pathway antagonist genes DKK1, DKK2, DKK3, and SFRP1 in neuroblastoma cells, but does not block Wnt3 and Wnt5A signalling to DVL3. Cancer Lett 2010;289:195-207.
156. Duan L, Yao J, Wu X et al. Growth suppression induced by Notch1 activation involves Wnt-beta-catenin down-regulation in human tongue carcinoma cells. Biol Cell 2006;98:479-490.
157. Fre S, Pallavi SK, Huyghe M et al. Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestine. Proc Natl Acad Sci USA 2009;106:6309-6314.
158. Lopez-Terrada D, Gunaratne PH, Adesina AM et al. Histologic subtypes of hepatoblastoma are characterized by differential canonical Wnt and Notch pathway activation in DLK+ precursors. Hum Pathol 2009;40:783-794.
159. Moreno CS. The Sex-determining region Y-box 4 and homeobox C6 transcriptional networks in prostate cancer progression: cros-stalk with the Wnt, Notch, and PI3K pathways. Am J Pathol 2010;176: 518-527.
160. Collu GM, Brennan K. Cooperation between Wnt and Notch signalling in human breast cancer. Breast Cancer Res 2007;9:105.
161. Ayyanan A, Civenni G, Ciarloni L et al. Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch-dependent mechanism. Proc Natl Acad Sci USA 2006;103: 3799-3804.
162. Estrach S, Ambler CA, Lo Celso C et al. Jagged 1 is a beta-catenin target gene required for ectopic hair follicle formation in adult epidermis. Development 2006;133:4427-4438.
163. Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev 2001;15:3059-3087.
164. van Den Heuvel M. Fat hedgehogs, slower or richer? Sci STKE 2001;2001:pe31.
165. Taipale J, Beachy PA. The Hedgehog and Wnt signalling pathways in cancer. Nature 2001;411:349-354.
166. Hooper JE, Scott MP. Communicating with Hedgehogs. Nat Rev Mol Cell Biol 2005;6:306-317.
167. Bonifas JM, Pennypacker S, Chuang PT et al. Activation of expression of hedgehog target genes in basal cell carcinomas. J Invest Dermatol 2001;116:739-742.
168. Yang SH, Andl T, Grachtchouk V et al. Pathological responses to oncogenic Hedgehog signaling in skin are dependent on canonical Wnt/beta3-catenin signaling. Nat Genet 2008;40:1130-1135.
169. Liao X, Siu MK, Au CW et al. Aberrant activation of hedgehog signaling pathway contributes to endometrial carcinogenesis through beta-catenin. Mod Pathol 2009;22:839-847.
170. Noubissi FK, Goswami S, Sanek NA et al. Wnt signaling stimulates transcriptional outcome of the Hedgehog pathway by stabilizing GLI1 mRNA. Cancer Res 2009;69:8572-8578.
171. Varnat F, Zacchetti G, Ruiz i Altaba A. Hedgehog pathway activity is required for the lethality and intestinal phenotypes of mice with hyperactive Wnt signaling. Mech Dev 2010;127:73-81.
172. Kim BM, Choi MY. New insights into the role of Hedgehog signaling in gastrointestinal development and cancer. Gastroenterology 2009;137:422-424.
173. Arimura S, Matsunaga A, Kitamura T et al. Reduced level of smoothened suppresses intestinal tumorigenesis by down-regulation of Wnt signaling. Gastroenterology 2009;137:629-638.
174. Pasca di Magliano M, Biankin AV, Heiser PW et al. Common activation of canonical Wnt signaling in pancreatic adenocarcinoma. PLoS One 2007;2:e1155.
175. van den Brink GR, Bleuming SA, Hardwick JC et al. Indian Hedgehog is an antagonist of Wnt signaling in colonic epithelial cell differentiation. Nat Genet 2004;36:277-282.
176. Yanai K, Nakamura M, Akiyoshi T et al. Cross-talk of hedgehog and Wnt pathways in gastric cancer. Cancer Lett 2008;263:145-156.
177. Dong J, Feldmann G, Huang J et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 2007;130: 1120-1133.
178. Varelas X. The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease. Development 2014;141:1614-1626.
179. Hansen CG, Moroishi T, Guan KL. YAP and TAZ: a nexus for Hippo signaling and beyond. Trends Cell Biol 2015;25:499-513.
180. Piccolo S, Dupont S, Cordenonsi M. The biology of YAP/TAZ: hippo signaling and beyond. Physiol Rev 2014;94:1287-1312.
181. Wang Z, Ye J, Deng Y et al. Wnt Hippo: A balanced act or dynamic duo? Genes Dis 2014;1:127-128.
182. Ramos A, Camargo FD. The Hippo signaling pathway and stem cell biology. Trends Cell Biol 2012;22:339-346.
183. Barry ER, Morikawa T, Butler BL et al. Restriction of intestinal stem cell expansion and the regenerative response by YAP. Nature 2013;493: 106-110.
184. Heallen T, Zhang M, Wang J et al. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 2011;332:458-461.
185. Azzolin L, Panciera T, Soligo S et al. YAP/TAZ incorporation in the beta-catenin destruction complex orchestrates the Wnt response. Cell 2014;158:157-170.
186. Cai J, Maitra A, Anders RA et al. beta-Catenin destruction complex-independent regulation of Hippo-YAP signaling by APC in intestinal tumorigenesis. Genes Dev 2015;29:1493-1506.
187. Park HW, Kim YC, Yu B et al. Alternative Wnt signaling activates YAP/TAZ. Cell 2015;162:780-794.
188. Holland JD, Klaus A, Garratt AN et al. Wnt signaling in stem and cancer stem cells. Curr Opin Cell Biol 2013;25:254-264.
189. Hanna J, Markoulaki S, Mitalipova M et al. Metastable pluripotent states in NOD-mouse-derived ESCs. Cell Stem Cell 2009;4:513-524.
190. Merrill BJ. Wnt pathway regulation of embryonic stem cell self-renewal. Cold Spring Harb Perspect Biol 2012;4:a007971.
191. Sato N, Meijer L, Skaltsounis L et al. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 2004;10:55-63.
192. Abu-Remaileh M, Gerson A, Farago M et al. Oct-3/4 regulates stem cell identity and cell fate decisions by modulating Wnt/beta-catenin signalling. EMBO J 2010;29:3236-3248.
193. Lluis F, Pedone E, Pepe S et al. Periodic activation of Wnt/beta-catenin signaling enhances somatic cell reprogramming mediated by cell fusion. Cell Stem Cell 2008;3:493-507.
194. Zhang P, Chang WH, Fong B et al. Regulation of induced pluripotent stem (iPS) cell induction by Wnt/beta-catenin signaling. J Biol Chem 2014;289:9221-9232.
195. Rastegar F, Shenaq D, Huang J et al. Mesenchymal stem cells: Molecular characteristics and clinical applications. World J. Stem Cells 2010;2:67-80.
196. Day TF, Guo X, Garrett-Beal L et al. Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell 2005;8: 739-750.
197. Luo Q, Kang Q, Si W et al. Connective tissue growth factor (CTGF) is regulated by Wnt and bone morphogenetic proteins signaling in osteoblast differentiation of mesenchymal stem cells. J Biol Chem 2004;279:55958-55968.
198. Si W, Kang Q, Luu HH et al. CCN1/Cyr61 is regulated by the canonical Wnt signal and plays an important role in Wnt3A-induced osteoblast differentiation of mesenchymal stem cells. Mol Cell Biol 2006;26: 2955-2964.
199. Tang N, Song WX, Luo J et al. BMP-9-induced osteogenic differentiation of mesenchymal progenitors requires functional canonical Wnt/beta-catenin signalling. J Cell Mol Med 2009;13:2448-2464.
200. Wang J, Zhang H, Zhang W et al. Bone morphogenetic protein-9 effectively induces osteo/odontoblastic differentiation of the rever-sibly immortalized stem cells of dental apical papilla. Stem Cells Dev 2014;23:1405-1416.
201. Zhang H, Wang J, Deng F et al. Canonical Wnt signaling acts synergistically on BMP9-induced osteo/odontoblastic differentiation of stem cells of dental apical papilla (SCAPs). Biomaterials 2015;39: 145-154.
202. Liu J, Farmer SR. Regulating the balance between peroxisome proliferator-activated receptor gamma and beta-catenin signaling during adipogenesis. A glycogen synthase kinase 3beta phos-phorylation-defective mutant of beta-catenin inhibits expression of a subset of adipogenic genes. J Biol Chem 2004;279:45020-45027.
203. Taipaleenmaki H, Abdallah BM, AlDahmash A et al. Wnt signalling mediates the cross-talk between bone marrow derived pre-adipocytic and pre-osteoblastic cell populations. Exp Cell Res 2011;317:745-756.
204. Gao Q, Guo M, Jiang X et al. A cocktail method for promoting cardiomyocyte differentiation from bone marrow-derived mesenchymal stem cells. Stem Cells Int 2014;2014:162024.
205. Alfaro MP, Pagni M, Vincent A et al. The Wnt modulator sFRP2 enhances mesenchymal stem cell engraftment, granulation tissue formation and myocardial repair. Proc Natl Acad Sci USA 2008;105: 18366-18371.
206. De Boer J, Wang HJ, Van Blitterswijk C. Effects of Wnt signaling on proliferation and differentiation of human mesenchymal stem cells. Tissue Eng 2004;10:393-401.
207. Clevers H. The intestinal crypt, a prototype stem cell compartment. Cell 2013;154:274-284.
208. Tian H, Biehs B, Warming S et al. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 2011;478:255-259.
209. Yan KS, Chia LA, Li X et al. The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations. Proc Natl Acad Sci USA 2012;109:466-471.
210. Gehart H, Clevers H. Repairing organs: lessons from intestine and liver. Trends Genet 2015;31:344-351.
211. Gregorieff A, Pinto D, Begthel H et al. Expression pattern of Wnt signaling components in the adult intestine. Gastroenterology 2005;129:626-638.
212. Li L, Clevers H. Coexistence of quiescent and active adult stem cells in mammals. Science 2010;327:542-545.
213. Bastide P, Darido C, Pannequin J et al. Sox9 regulates cell proliferation and is required for Paneth cell differentiation in the intestinal epithelium. J Cell Biol 2007;178:635-648.
214. van der Flier LG, van Gijn ME, Hatzis P et al. Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell 2009;136: 903-912.
215. Batlle E, Henderson JT, Beghtel H et al. Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell 2002;111:251-263.
216. Tian H, Biehs B, Chiu C et al. Opposing activities of Notch and Wnt signaling regulate intestinal stem cells and gut homeostasis. Cell Rep 2015;11:33-42.
217. Nostro MC, Cheng X, Keller GM et al. Wnt, activin, and BMP signaling regulate distinct stages in the developmental pathway from embryonic stem cells to blood. Cell Stem Cell 2008;2:60-71.
218. Luis TC, Weerkamp F, Naber BA et al. Wnt3a deficiency irreversibly impairs hematopoietic stem cell self-renewal and leads to defects in progenitor cell differentiation. Blood 2009;113:546-554.
219. Zhao C, Blum J, Chen A et al. Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell 2007;12:528-541.
220. Schaniel C, Sirabella D, Qiu J et al. Wnt-inhibitory factor 1 dysregulation of the bone marrow niche exhausts hematopoietic stem cells. Blood 2011;118:2420-2429.
221. Reya T, Duncan AW, Ailles L et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 2003;423:409-414.
222. Fukuda S, Pelus LM. Regulation of the inhibitor-of-apoptosis family member survivin in normal cord blood and bone marrow CD34(+) cells by hematopoietic growth factors: implication of survivin expression in normal hematopoiesis. Blood 2001;98: 2091-2100.
223. Gurbuxani S, Xu Y, Keerthivasan G et al. Differential requirements for survivin in hematopoietic cell development. Proc Natl Acad Sci USA 2005;102:11480-11485.
224. Clements WK, Kim AD, Ong KG et al. A somitic Wnt16/Notch pathway specifies haematopoietic stem cells. Nature 2011;474:220-224.
225. Loeffler D, Kokkaliaris KD, Schroeder T. Wnt to notch relay signaling induces definitive hematopoiesis. Cell Stem Cell 2011;9:2-4.
226. Singbrant S, Karlsson G, Ehinger M et al. Canonical BMP signaling is dispensable for hematopoietic stem cell function in both adult and fetal liver hematopoiesis, but essential to preserve colon architecture. Blood 2010;115:4689-4698.
227. Fuchs E. Scratching the surface of skin development. Nature 2007;445:834-842.
228. Lim X, Nusse R. Wnt signaling in skin development, homeostasis, and disease. Cold Spring Harb Perspect Biol 2013;5:pii: a008029.
229. DasGupta R, Fuchs E. Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development 1999;126:4557-4568.
230. Huelsken J, Vogel R, Erdmann B et al. beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 2001;105:533-545.
231. Nguyen H, Merrill BJ, Polak L et al. Tcf3 and Tcf4 are essential for long-term homeostasis of skin epithelia. Nat Genet 2009;41:1068-1075.
232. Lien WH, Polak L, Lin M et al. In vivo transcriptional governance of hair follicle stem cells by canonical Wnt regulators. Nat Cell Biol 2014;16:179-190.
233. Sun P, Watanabe K, Fallahi M et al. Pygo2 regulates beta-catenin-induced activation of hair follicle stem/progenitor cells and skin hyperplasia. Proc Natl Acad Sci USA 2014;111:10215-10220.
234. Kandyba E, Leung Y, Chen YB et al. Competitive balance of intrabulge BMP/Wnt signaling reveals a robust gene network ruling stem cell homeostasis and cyclic activation. Proc Natl Acad Sci USA 2013;110: 1351-1356.
235. Kandyba E, Kobielak K. Wnt7b is an important intrinsic regulator of hair follicle stem cell homeostasis and hair follicle cycling. Stem Cells 2014;32:886-901.
236. Nusse R, van Ooyen A, Cox D et al. Mode of proviral activation of a putative mammary oncogene (int-1) on mouse chromosome 15. Nature 1984;307:131-136.
237. Korinek V, Barker N, Morin PJ et al. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/-colon carcinoma. Science 1997;275:1784-1787.
238. Morin PJ, Sparks AB, Korinek V et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 1997;275:1787-1790.
239. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996;87:159-170.
240. Kinzler KW, Vogelstein B. Landscaping the cancer terrain. Science 1998;280:1036-1037.
241. Clements WM, Lowy AM, Groden J. Adenomatous polyposis coli/beta-catenin interaction and downstream targets: altered gene expression in gastrointestinal tumors. Clin Colorectal Cancer 2003;3:113-120.
242. Su LK, Kinzler KW, Vogelstein B et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 1992;256:668-670.
243. Miyoshi Y, Iwao K, Nagasawa Y et al. Activation of the beta-catenin gene in primary hepatocellular carcinomas by somatic alterations involving exon 3. Cancer Res 1998;58:2524-2527.
244. Satoh S, Daigo Y, Furukawa Y et al. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet 2000;24:245-250.
245. Polakis P. The many ways of Wnt in cancer. Curr Opin Genet Dev 2007;17:45-51.
246. Zhang Y, Morris JPt, Yan W et al. Canonical wnt signaling is required for pancreatic carcinogenesis. Cancer Res 2013;73:4909-4922.
247. Xie D, Xie K. Pancreatic cancer stromal biology and therapy. Genes Dis 2015;2:133-143.
248. Yu M, Ting DT, Stott SL et al. RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis. Nature 2012;487:510-513.
249. Haydon RC, Deyrup A, Ishikawa A et al. Cytoplasmic and/or nuclear accumulation of the beta-catenin protein is a frequent event in human osteosarcoma. Int J Cancer 2002;102:338-342.
250. Hoffmeyer K, Raggioli A, Rudloff S et al. Wnt/beta-catenin signaling regulates telomerase in stem cells and cancer cells. Science 2012;336: 1549-1554.
251. Wissmann C, Wild PJ, Kaiser S et al. WIF1, a component of the Wnt pathway, is down-regulated in prostate, breast, lung, and bladder cancer. J Pathol 2003;201:204-212.
252. Kansara M, Tsang M, Kodjabachian L et al. Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice. J Clin Invest 2009;119:837-851.
253. Augustin I, Goidts V, Bongers A et al. The Wnt secretion protein Evi/Gpr177 promotes glioma tumourigenesis. EMBO Mol Med 2012;4:38-51.
254. Maruyama EO, Yu HM, Jiang M et al. Gpr177 deficiency impairs mammary development and prohibits Wnt-induced tumorigenesis. PLoS One 2013;8:e56644.
255. Voloshanenko O, Erdmann G, Dubash TD et al. Wnt secretion is required to maintain high levels of Wnt activity in colon cancer cells. Nat Commun 2013;4:2610.
256. Both J, Krijgsman O, Bras J et al. Focal chromosomal copy number aberrations identify CMTM8 and GPR177 as new candidate driver genes in osteosarcoma. PLoS One 2014;9:e115835.
257. Chiou SS, Wang LT, Huang SB et al. Wntless (GPR177) expression correlates with poor prognosis in B-cell precursor acute lympho-blastic leukemia via Wnt signaling. Carcinogenesis 2014;35: 2357-2364.
258. Stewart J, James J, McCluggage GW et al. Analysis of wntless (WLS) expression in gastric, ovarian, and breast cancers reveals a strong association with HER2 overexpression. Mod Pathol 2015;28: 428-436.
259. Mullighan CG, Zhang J, Kasper LH et al. CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature 2011;471:235-239.
260. Rosenbluh J, Nijhawan D, Cox AG et al. beta-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigen-esis. Cell 2012;151:1457-1473.
261. Mehlen P, Puisieux A. Metastasis: a question of life or death. Nat Rev Cancer 2006;6:449-458.
262. Coghlin C, Murray GI. Current and emerging concepts in tumour metastasis. J Pathol 2010;222:1-15.
263. Heuberger J, Birchmeier W. Interplay of cadherin-mediated cell adhesion and canonical Wnt signaling. Cold Spring Harb Perspect Biol 2010;2:a002915.
264. Cathcart J, Pulkoski-Gross A, Cao J. Targeting matrix metalloprotei-nases in cancer: bringing new life to old ideas. Genes Dis 2015;2: 26-34.
265. Vermeulen L, De Sousa EMF, van der Heijden M et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol 2010;12:468-476.
266. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 2014;15:178-196.
267. Gonzalez DM, Medici D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal 2014;7:re8.
268. Nguyen DX, Chiang AC, Zhang XH et al. WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell 2009;138:51-62.
269. Previdi S, Maroni P, Matteucci E et al. Interaction between human-breast cancer metastasis and bone microenvironment through activated hepatocyte growth factor/Met and beta-catenin/Wnt pathways. Eur J Cancer 2010;46:1679-1691.
270. Yang L, Tang H, Kong Y et al. LGR5 promotes breast cancer progression and maintains stem-like cells through activation of Wnt/beta-catenin signaling. Stem Cells 2015;33:2913-2924.
271. Kawaguchi-Ihara N, Murohashi I, Nara N et al. Promotion of the self-renewal capacity of human acute leukemia cells by Wnt3A. Anticancer Res 2008;28:2701-2704.
272. Bisson I, Prowse DM. WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics. Cell Res 2009;19:683-697.
273. Molejon MI, Tellechea JI, Moutardier V et al. Targeting CD44 as a novel therapeutic approach for treating pancreatic cancer recurrence. Oncoscience 2015;2:572-575.
274. Schulenburg A, Cech P, Herbacek I et al. CD44-positive colorectal adenoma cells express the potential stem cell markers musashi antigen (msi1) and ephrin B2 receptor (EphB2). J Pathol 2007;213: 152-160.
275. Verkaar F, Zaman GJ. New avenues to target Wnt/beta-catenin signaling. Drug Discov Today 2011;16:35-41.
276. Polakis P. Drugging Wnt signalling in cancer. Embo J 2012;31: 2737-2746.
277. Jamieson C, Sharma M, Henderson BR. Targeting the beta-catenin nuclear transport pathway in cancer. Semin Cancer Biol 2014;27: 20-29.
278. Kahn M. Can we safely target the WNT pathway? Nat Rev Drug Discov 2014;13:513-532.
279. Madan B, Virshup DM. Targeting Wnts at the source-new mechanisms, new biomarkers, new drugs. Mol Cancer Ther 2015;14:1087-1094.
280. Morin PJ, Vogelstein B, Kinzler KW. Apoptosis and APC in colorectal tumorigenesis. Proc Natl Acad Sci USA 1996;93:7950-7954.
281. Chen S, Guttridge DC, You Z et al. Wnt-1 signaling inhibits apoptosis by activating beta-catenin/T cell factor-mediated transcription. J Cell Biol 2001;152:87-96.
282. He B, You L, Uematsu K et al. A monoclonal antibody against Wnt-1 induces apoptosis in human cancer cells. Neoplasia 2004;6:7-14.
283. Mikami I, You L, He B et al. Efficacy of Wnt-1 monoclonal antibody in sarcoma cells. BMC Cancer 2005;5:53.
284. Wei W, Chua MS, Grepper S et al. Blockade of Wnt-1 signaling leads to anti-tumor effects in hepatocellular carcinoma cells. Mol Cancer 2009;8:76.
285. Lavergne E, Hendaoui I, Coulouarn C et al. Blocking Wnt signaling by SFRP-like molecules inhibits in vivo cell proliferation and tumor growth in cells carrying active beta-catenin. Oncogene 2011;30:423-433.
286. Rubin EM, Guo Y, Tu K et al. Wnt inhibitory factor 1 decreases tumorigenesis and metastasis in osteosarcoma. Mol Cancer Ther 2010;9:731-741.
287. Horvath LG, Henshall SM, Kench JG et al. Membranous expression of secreted frizzled-related protein 4 predicts for good prognosis in localized prostate cancer and inhibits PC3 cellular proliferation in vitro. Clin Cancer Res 2004;10:615-625.
288. Joesting MS, Perrin S, Elenbaas B et al. Identification of SFRP1 as a candidate mediator of stromal-to-epithelial signaling in prostate cancer. Cancer Res 2005;65:10423-10430.
289. DeAlmeida VI, Miao L, Ernst JA et al. The soluble wnt receptor Frizzled8CRD-hFc inhibits the growth of teratocarcinomas in vivo. Cancer Res 2007;67:5371-5379.
290. Wei W, Chua MS, Grepper S et al. Soluble Frizzled-7 receptor inhibits Wnt signaling and sensitizes hepatocellular carcinoma cells towards doxorubicin. Mol Cancer 2011;10:16.
291. Nambotin SB, Lefrancois L, Sainsily X et al. Pharmacological inhibition of Frizzled-7 displays anti-tumor properties in hepatocellular carcinoma. J Hepatol 2011;54:288-299.
292. Shin H, Kim JH, Lee YS et al. Change in gene expression profiles of secreted frizzled-related proteins (SFRPs) by sodium butyrate in gastric cancers: induction of promoter demethylation and histone modification causing inhibition of Wnt signaling. Int J Oncol 2012;40: 1533-1542.
293. Shan J, Shi DL, Wang J et al. Identification of a specific inhibitor of the dishevelled PDZ domain. Biochemistry 2005;44:15495-15503.
294. Fujii N, You L, Xu Z et al. An antagonist of dishevelled protein-protein interaction suppresses beta-catenin-dependent tumor cell growth. Cancer Res 2007;67:573-579.
295. Grandy D, Shan J, Zhang X et al. Discovery and characterization of a small molecule inhibitor of the PDZ domain of dishevelled. J Biol Chem 2009;284:16256-16263.
296. Huang SM, Mishina YM, Liu S et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 2009;461:614-620.
297. Chen B, Dodge ME, Tang W et al. Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat Chem Biol 2009;5:100-107.
298. Waaler J, Machon O, Tumova L et al. A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice. Cancer Res 2012;72:2822-2832.
299. Lau T, Chan E, Callow M et al. A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth. Cancer Res 2013;73:3132-3144.
300. Lehtio L, Chi NW, Krauss S. Tankyrases as drug targets. FEBS J 2013;280:3576-3593.
301. Liu J, Pan S, Hsieh MH et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci USA 2013;110: 20224-20229.
302. Kabiri Z, Greicius G, Madan B et al. Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts. Development 2014;141: 2206-2215.
303. Lepourcelet M, Chen YN, France DS et al. Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell 2004;5:91-102.
304. Wei W, Chua MS, Grepper S et al. Small molecule antagonists of Tcf4/beta-catenin complex inhibit the growth of HCC cells in vitro and in vivo. Int J Cancer 2010;126:2426-2436.
305. Minke KS, Staib P, Puetter A et al. Small molecule inhibitors of WNT signaling effectively induce apoptosis in acute myeloid leukemia cells. Eur J Haematol 2009;82:165-175.
306. Chen Z, Venkatesan AM, Dehnhardt CM et al. 2, 4-Diamino-quinazolines as inhibitors of beta-catenin/Tcf-4 pathway: Potential treatment for colorectal cancer. Bioorg Med Chem Lett 2009;19: 4980-4983.
307. Gonsalves FC, Klein K, Carson BB et al. An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway. Proc Natl Acad Sci USA 2011;108: 5954-5963.
308. Trosset JY, Dalvit C, Knapp S et al. Inhibition of protein-protein interactions: the discovery of druglike beta-catenin inhibitors by combining virtual and biophysical screening. Proteins 2006;64:60-67.
309. Tian W, Han X, Yan M et al. Structure-based discovery of a novel inhibitor targeting the beta-catenin/Tcf4 interaction. Biochemistry 2012;51:724-731.
310. Yao H, Ashihara E, Strovel JW et al. AV-65, a novel Wnt/beta-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model. Blood Cancer J 2011;1:e43.
311. Takada K, Zhu D, Bird GH et al. Targeted disruption of the BCL9/beta-catenin complex inhibits oncogenic Wnt signaling. Sci Transl Med 2012;4:148ra117.
312. Grossmann TN, Yeh JT, Bowman BR et al. Inhibition of oncogenic Wnt signaling through direct targeting of beta-catenin. Proc Natl Acad Sci USA 2012;109:17942-17947.
313. Emami KH, Nguyen C, Ma H et al. A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. Proc Natl Acad Sci USA 2004;101:12682-12687.
314. Eguchi M, Nguyen C, Lee SC et al. ICG-001, a novel small molecule regulator of TCF/beta-catenin transcription. Med Chem 2005;1: 467-472.
315. Miyabayashi T, Teo JL, Yamamoto M et al. Wnt/beta-catenin/CBP signaling maintains long-term murine embryonic stem cell pluripo-tency. Proc Natl Acad Sci USA 2007;104:5668-5673.
316. Hasegawa K, Yasuda SY, Teo JL et al. Wnt signaling orchestration with a small molecule DYRK inhibitor provides long-term xeno-free human pluripotent cell expansion. Stem Cells Transl Med 2012;1: 18-28.
317. Marson A, Foreman R, Chevalier B et al. Wnt signaling promotes reprogramming of somatic cells to pluripotency. Cell Stem Cell 2008;3:132-135.
318. Wend P, Fang L, Zhu Q et al. Wnt/beta-catenin signalling induces MLL to create epigenetic changes in salivary gland tumours. EMBO J 2013;32:1977-1989.
319. Gang EJ, Hsieh YT, Pham J et al. Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia. Oncogene 2014;33:2169-2178.
320. He K, Xu T, Xu Y et al. Cancer cells acquire a drug resistant, highly tumorigenic, cancer stem-like phenotype through modulation of the PI3K/Akt/beta-catenin/CBP pathway. Int J Cancer 2014;134: 43-54.
321. Lenz HJ, Kahn M. Safely targeting cancer stem cells via selective catenin coactivator antagonism. Cancer Sci 2014;105:1087-1092.
322. Smith ML, Hawcroft G, Hull MA. The effect of non-steroidal anti-inflammatory drugs on human colorectal cancer cells: evidence of different mechanisms of action. Eur J Cancer 2000;36:664-674.
323. Dihlmann S, Siermann A, von Knebel Doeberitz M. The nonsteroidal anti-inflammatory drugs aspirin and indomethacin attenuate beta-catenin/TCF-4 signaling. Oncogene 2001;20:645-653.
324. Zhou L, An N, Haydon RC et al. Tyrosine kinase inhibitor STI-571/Gleevec down-regulates the beta-catenin signaling activity. Cancer Lett 2003;193:161-170.
325. Christensen JG, Schreck R, Burrows J 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 2003;63:7345-7355.
326. Baryawno N, Sveinbjornsson B, Eksborg S et al. Small-molecule inhibitors of phosphatidylinositol 3-kinase/Akt signaling inhibit Wnt/beta-catenin pathway cross-talk and suppress medulloblastoma growth. Cancer Res 2010;70:266-276.
327. Pendas-Franco N, Aguilera O, Pereira F et al. Vitamin D and Wnt/beta-catenin pathway in colon cancer: role and regulation of DICKKOPF genes. Anticancer Res 2008;28:2613-2623.
328. Jaiswal AS, Marlow BP, Gupta N et al. Beta-catenin-mediated transactivation and cell-cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells. Oncogene 2002;21:8414-8427.
329. Kim J, Zhang X, Rieger-Christ KM 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 2006;281:10865-10875.
330. Park CH, Chang JY, Hahm ER et al. Quercetin, a potent inhibitor against beta-catenin/Tcf signaling in SW480 colon cancer cells. Biochem Biophys Res Commun 2005;328:227-234.
331. Roccaro AM, Leleu X, Sacco A et al. Resveratrol exerts antiproliferative activity and induces apoptosis in Waldenstrom's macroglobulinemia. Clin Cancer Res 2008;14:1849-1858.
332. He BC, Gao JL, Luo X et al. Ginsenoside Rg3 inhibits colorectal tumor growth through the down-regulation of Wnt/ss-catenin signaling. Int J Oncol 2011;38:437-445.
333. He BC, Gao JL, Zhang BQ et al. Tetrandrine inhibits Wnt/beta-catenin signaling and suppresses tumor growth of human colorectal cancer. Mol Pharmacol 2011;79:211-219.
334. Lu W, Lin C, King TD et al. Silibinin inhibits Wnt/beta-catenin signaling by suppressing Wnt co-receptor LRP6 expression in human prostate and breast cancer cells. Cell Signal 2012;24:2291-2296.
335. Lu W, Lin C, Li Y. Rottlerin induces Wnt co-receptor LRP6 degradation and suppresses both Wnt/beta-catenin and mTORC1 signaling in prostate and breast cancer cells. Cell Signal 2014;26:1303-1309.
336. Thorne CA, Hanson AJ, Schneider J et al. Small-molecule inhibition of Wnt signaling through activation of casein kinase 1alpha. Nat Chem Biol 2010;6:829-836.
337. Chen M, Wang J, Lu J et al. The anti-helminthic niclosamide inhibits Wnt/Frizzled1 signaling. Biochemistry 2009;48:10267-10274.
338. Lu W, Lin C, Roberts MJ et al. Niclosamide suppresses cancer cell growth by inducing Wnt co-receptor LRP6 degradation and inhibiting the Wnt/beta-catenin pathway. PLoS One 2011;6:e29290.
339. Osada T, Chen M, Yang XY et al. Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations. Cancer Res 2011;71: 4172-4182.
340. Arend RC, Londono-Joshi AI, Samant RS et al. Inhibition of Wnt/beta-catenin pathway by niclosamide: a therapeutic target for ovarian cancer. Gynecol Oncol 2014;134:112-120.
341. Liu C, Lou W, Armstrong C et al. Niclosamide suppresses cell migration and invasion in enzalutamide resistant prostate cancer cells via Stat3-AR axis inhibition. Prostate 2015;75:1341-1353.
342. Liu C, Lou W, Zhu Y et al. Niclosamide inhibits androgen receptor variants expression and overcomes enzalutamide resistance in castration-resistant prostate cancer. Clin Cancer Res 2014;20: 3198-3210.
343. Londono-Joshi AI, Arend RC, Aristizabal L et al. Effect of niclosamide on basal-like breast cancers. Mol Cancer Ther 2014;13:800-811.
344. Liao Z, Nan G, Yan Z et al. The anthelmintic drug niclosamide inhibits the proliferative activity of human osteosarcoma cells by targeting multiple signal pathways. Curr Cancer Drug Targets 2015;15:726-738.
345. Lu D, Choi MY, Yu J et al. Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells. Proc Natl Acad Sci USA 2011;108:13253-13257.
346. Tumova L, Pombinho AR, Vojtechova M et al. Monensin inhibits canonical Wnt signaling in human colorectal cancer cells and suppresses tumor growth in multiple intestinal neoplasia mice. Mol Cancer Ther 2014;13:812-822.