Wnt signaling in cancer stem cell biology

Cancers

Volumn 8, Issue 7, 2016, Pages

  de Sousa e Melo, Felipe ^a   Vermeulen, Louis ^a  

^a ACADEMIC MEDICAL CENTER   (Netherlands)

Author keywords

Cancer; Cancer stem cell niche; Cancer stem cells; Stem cells; Targeted therapy; Wnt inhibition; Wnt signaling

Indexed keywords

APC PROTEIN; AXIN; BETA CATENIN; CARRIER PROTEINS AND BINDING PROTEINS; CASEIN KINASE I; G PROTEIN COUPLED RECEPTOR; GLYCOGEN SYNTHASE KINASE 3BETA; LEUCINE RICH REPEAT CONTAINING G PROTEIN COUPLED RECEPTOR 5; OSTEOPONTIN; PROTEIN BCL 2; R SPONDIN; SCATTER FACTOR; STROMAL CELL DERIVED FACTOR 1; UBIQUITIN PROTEIN LIGASE E3; UBIQUITIN PROTEIN LIGASE RNF43; UNCLASSIFIED DRUG; WNT PROTEIN;

BREAST CANCER; CANCER GROWTH; CANCER STEM CELL; CARCINOGENESIS; CELL FUNCTION; COLORECTAL CANCER; GENE MUTATION; GENETIC REGULATION; HUMAN; NONHUMAN; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; TUMOR MICROENVIRONMENT; WNT SIGNALING PATHWAY;

EID: 84976565130     PISSN: None     EISSN: 20726694     Source Type: Journal    
DOI: 10.3390/cancers8070060     Document Type: Review

References (118)

1. Simons, B.D.; Clevers, H. Strategies for homeostatic stem cell self-renewal in adult tissues. Cell 2011, 145, 851–862.
2. Visvader, J.E. Cells of origin in cancer. Nature 2011, 469, 314–322.
3. Vermeulen, L.; Sprick, M.R.; Kemper, K.; Stassi, G.; Medema, J.P. Cancer stem cells—Old concepts, new insights. Cell Death Differ. 2008, 15, 947–958.
4. Fearon, E.R. Molecular genetics of colorectal cancer. Annu. Rev. Pathol. 2011, 6, 479–507.
5. Seshagiri, S.; Stawiski, E.W.; Durinck, S.; Modrusan, Z.; Storm, E.E.; Conboy, C.B.; Chaudhuri, S.; Guan, Y.; Janakiraman, V.; Jaiswal, B.S., et al. Recurrent R-spondin fusions in colon cancer. Nature 2012, 488, 660–664.
6. Storm, E.E.; Durinck, S.; de Sousa eMelo, F.; Tremayne, J.; Kljavin, N.; Tan, C.; Ye, X.; Chiu, C.; Pham, T.; Hongo, J.A.; et al. Targeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem-cell function. Nature 2016, 529, 97–100.
7. Giannakis, M.; Hodis, E.; Jasmine Mu, X.; Yamauchi, M.; Rosenbluh, J.; Cibulskis, K.; Saksena, G.; Lawrence, M.S.; Qian, Z.R.; Nishihara, R.; et al. RNF43 is frequently mutated in colorectal and endometrial cancers. Nat. Genet. 2014, 46, 1264–1266.
8. van de Wetering, M.; Francies, H.E.; Francis, J.M.; Bounova, G.; Iorio, F.; Pronk, A.; van Houdt, W.; van Gorp, J.; Taylor-Weiner, A.; Kester, L.; et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 2015, 161, 933–945.
9. Fearon, E.R.; Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 1990, 61, 759–767.
10. Sjoblom, T.; Jones, S.; Wood, L.D.; Parsons, D.W.; Lin, J.; Barber, T.D.; Mandelker, D.; Leary, R.J.; Ptak, J.; Silliman, N.; et al. The consensus coding sequences of human breast and colorectal cancers. Science 2006, 314, 268–274.
11. Dow, L.E.; O’Rourke, K.P.; Simon, J.; Tschaharganeh, D.F.; van Es, J.H.; Clevers, H.; Lowe, S.W. Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer. Cell 2015, 161, 1539–1552.
12. Sekine, S.; Yamashita, S.; Tanabe, T.; Hashimoto, T.; Yoshida, H.; Taniguchi, H.; Kojima, M.; Shinmura, K.; Saito, Y.; Hiraoka, N.; et al. Frequent PTPRK-RSPO3 fusions and RNF43 mutations in colorectal traditional serrated adenoma. J. Pathol. 2016, 239, 133–138.
13. Satoh, S.; Daigo, Y.; Furukawa, Y.; Kato, T.; Miwa, N.; Nishiwaki, T.; Kawasoe, T.; Ishiguro, H.; Fujita, M.; Tokino, T.; 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.
14. Nusse, R.; Varmus, H.E. 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.
15. Bafico, A.; Liu, G.; Goldin, L.; Harris, V.; Aaronson, S.A. An autocrine mechanism for constitutive Wnt pathway activation in human cancer cells. Cancer Cell 2004, 6, 497–506.
16. Ai, L.; Tao, Q.; Zhong, S.; Fields, C.R.; Kim, W.J.; Lee, M.W.; Cui, Y.; Brown, K.D.; Robertson, K.D. Inactivation of Wnt inhibitory factor-1 (wif1) expression by epigenetic silencing is a common event in breast cancer. Carcinogenesis 2006, 27, 1341–1348.
17. Kool, M.; Koster, J.; Bunt, J.; Hasselt, N.E.; Lakeman, A.; van Sluis, P.; Troost, D.; Meeteren, N.S.; Caron, H.N.; Cloos, J.; et al. Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS ONE 2008, 3, e3088.
18. Md Zin, R.; Murch, A.; Charles, A. Pathology, genetics and cytogenetics of wilms’ tumour. Pathology 2011, 43, 302–312.
19. Leedham, S.J.; Rodenas-Cuadrado, P.; Howarth, K.; Lewis, A.; Mallappa, S.; Segditsas, S.; Davis, H.; Jeffery, R.; Rodriguez-Justo, M.; Keshav, S.; et al. A basal gradient of Wnt and stem-cell number influences regional tumour distribution in human and mouse intestinal tracts. Gut 2013, 62, 83–93.
20. Barker, N.; Ridgway, R.A.; van Es, J.H.; van de Wetering, M.; Begthel, H.; van den Born, M.; Danenberg, E.; Clarke, A.R.; Sansom, O.J.; Clevers, H. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 2009, 457, 608–611.
21. Lopez-Garcia, C.; Klein, A.M.; Simons, B.D.; Winton, D.J. Intestinal stem cell replacement follows a pattern of neutral drift. Science 2010, 330, 822–825.
22. Snippert, H.J.; van der Flier, L.G.; Sato, T.; van Es, J.H.; van den Born, M.; Kroon-Veenboer, C.; Barker, N.; Klein, A.M.; van Rheenen, J.; Simons, B.D.; et al. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing LGR5 stem cells. Cell 2010, 143, 134–144.
23. Vermeulen, L.; Morrissey, E.; van der Heijden, M.; Nicholson, A.M.; Sottoriva, A.; Buczacki, S.; Kemp, R.; Tavare, S.; Winton, D.J. Defining stem cell dynamics in models of intestinal tumor initiation. Science 2013, 342, 995–998.
24. Snippert, H.J.; Schepers, A.G.; van Es, J.H.; Simons, B.D.; Clevers, H. Biased competition between LGR5 intestinal stem cells driven by oncogenic mutation induces clonal expansion. EMBO Rep. 2014, 15, 62–69.
25. Schwitalla, S.; Fingerle, A.A.; Cammareri, P.; Nebelsiek, T.; Goktuna, S.I.; Ziegler, P.K.; Canli, O.; Heijmans, J.; Huels, D.J.; Moreaux, G.; et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 2013, 152, 25–38.
26. Davis, H.; Irshad, S.; Bansal, M.; Rafferty, H.; Boitsova, T.; Bardella, C.; Jaeger, E.; Lewis, A.; Freeman-Mills, L.; Giner, F.C., et al. Aberrant epithelial grem1 expression initiates colonic tumorigenesis from cells outside the stem cell niche. Nat. Med. 2015, 21, 62–70.
27. Westphalen, C.B.; Asfaha, S.; Hayakawa, Y.; Takemoto, Y.; Lukin, D.J.; Nuber, A.H.; Brandtner, A.; Setlik, W.; Remotti, H.; Muley, A.; et al. Long-lived intestinal tuft cells serve as colon cancer-initiating cells. J. Clin. Invest. 2014, 124, 1283–1295.
28. van der Heijden, M.; Zimberlin, C.D.; Nicholson, A.M.; Colak, S.; Kemp, R.; Meijer, S.L.; Medema, J.P.; Greten, F.R.; Jansen, M.; Winton, D.J.; et al. BCL-2 is a critical mediator of intestinal transformation. Nat. Commun. 2016.
29. Hoffmeyer, K.; Raggioli, A.; Rudloff, S.; Anton, R.; Hierholzer, A.; Del Valle, I.; Hein, K.; Vogt, R.; Kemler, R. Wnt/beta-catenin signaling regulates telomerase in stem cells and cancer cells. Science 2012, 336, 1549–1554.
30. Gibson, P.; Tong, Y.; Robinson, G.; Thompson, M.C.; Currle, D.S.; Eden, C.; Kranenburg, T.A.; Hogg, T.; Poppleton, H.; Martin, J.; et al. Subtypes of medulloblastoma have distinct developmental origins. Nature 2010, 468, 1095–1099.
31. Vermeulen, L.; De Sousa, E.M.F.; van der Heijden, M.; Cameron, K.; de Jong, J.H.; Borovski, T.; Tuynman, J.B.; Todaro, M.; Merz, C.; Rodermond, H.; et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat. Cell Biol. 2010, 12, 468–476.
32. Prasetyanti, P.R.; Zimberlin, C.D.; Bots, M.; Vermeulen, L.; Melo Fde, S.; Medema, J.P. Regulation of stem cell self-renewal and differentiation by Wnt and Notch are conserved throughout the adenoma-carcinoma sequence in the colon. Mol. Cancer. 2013.
33. Su, Y.J.; Chang, Y.W.; Lin, W.H.; Liang, C.L.; Lee, J.L. An aberrant nuclear localization of E-cadherin is a potent inhibitor of wnt/beta-catenin-elicited promotion of the cancer stem cell phenotype. Oncogenesis 2015.
34. Junttila, M.R.; Mao, W.; Wang, X.; Wang, B.E.; Pham, T.; Flygare, J.; Yu, S.F.; Yee, S.; Goldenberg, D.; Fields, C.; et al. Targeting LGR5+ cells with an antibody-drug conjugate for the treatment of colon cancer. Sci. Transl. Med. 2015.
35. Kemper, K.; Prasetyanti, P.R.; De Lau, W.; Rodermond, H.; Clevers, H.; Medema, J.P. Monoclonal antibodies against LGR5 identify human colorectal cancer stem cells. Stem Cells 2012, 30, 2378–2386.
36. Al-Hajj, M.; Wicha, M.S.; Benito-Hernandez, A.; Morrison, S.J.; Clarke, M.F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. USA 2003, 100, 3983–3988.
37. Dalerba, P.; Dylla, S.J.; Park, I.K.; Liu, R.; Wang, X.; Cho, R.W.; Hoey, T.; Gurney, A.; Huang, E.H.; Simeone, D.M.; et al. Phenotypic characterization of human colorectal cancer stem cells. Proc. Natl. Acad. Sci. USA 2007, 104, 10158–10163.
38. Yan, Y.; Zuo, X.; Wei, D. Concise review: Emerging role of CD44 in cancer stem cells: A promising biomarker and therapeutic target. Stem Cells Transl. Med. 2015, 4, 1033–1043.
39. Horst, D.; Chen, J.; Morikawa, T.; Ogino, S.; Kirchner, T.; Shivdasani, R.A. Differential Wnt activity in colorectal cancer confers limited tumorigenic potential and is regulated by mapk signaling. Cancer Res. 2012, 72, 1547–1556.
40. Shenoy, A.K.; Fisher, R.C.; Butterworth, E.A.; Pi, L.; Chang, L.J.; Appelman, H.D.; Chang, M.; Scott, E.W.; Huang, E.H. Transition from colitis to cancer: High Wnt activity sustains the tumor-initiating potential of colon cancer stem cell precursors. Cancer Res. 2012, 72, 5091–5100.
41. Malanchi, I.; Peinado, H.; Kassen, D.; Hussenet, T.; Metzger, D.; Chambon, P.; Huber, M.; Hohl, D.; Cano, A.; Birchmeier, W.; et al. Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling. Nature 2008, 452, 650–653.
42. Chartier, C.; Raval, J.; Axelrod, F.; Bond, C.; Cain, J.; Dee-Hoskins, C.; Ma, S.; Fischer, M.M.; Shah, J.; Wei, J.; et al. Therapeutic targeting of tumor-derived R-spondin attenuates beta-catenin signaling and tumorigenesis in multiple cancer types. Cancer Res. 2016, 76, 713–723.
43. Moor, A.E.; Anderle, P.; Cantu, C.; Rodriguez, P.; Wiedemann, N.; Baruthio, F.; Deka, J.; Andre, S.; Valenta, T.; Moor, M.B.; et al. BCL9/9l-beta-catenin signaling is associated with poor outcome in colorectal cancer. EBioMedicine 2015, 2, 1932–1943.
44. Yong, X.; Tang, B.; Xiao, Y.F.; Xie, R.; Qin, Y.; Luo, G.; Hu, C.J.; Dong, H.; Yang, S.M. Helicobacter pylori upregulates nanog and OCT4 via Wnt/beta-catenin signaling pathway to promote cancer stem cell-like properties in human gastric cancer. Cancer Lett. 2016, 374, 292–303.
45. Yeung, T.M.; Gandhi, S.C.; Wilding, J.L.; Muschel, R.; Bodmer, W.F. Cancer stem cells from colorectal cancer-derived cell lines. Proc. Natl. Acad. Sci. USA 2010, 107, 3722–3727.
46. Hermann, P.C.; Huber, S.L.; Herrler, T.; Aicher, A.; Ellwart, J.W.; Guba, M.; Bruns, C.J.; Heeschen, C. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 2007, 1, 313–323.
47. O’Brien, C.A.; Pollett, A.; Gallinger, S.; Dick, J.E. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007, 445, 106–110.
48. Ricci-Vitiani, L.; Lombardi, D.G.; Pilozzi, E.; Biffoni, M.; Todaro, M.; Peschle, C.; De Maria, R. Identification and expansion of human colon-cancer-initiating cells. Nature 2007, 445, 111–115.
49. Singh, S.K.; Hawkins, C.; Clarke, I.D.; Squire, J.A.; Bayani, J.; Hide, T.; Henkelman, R.M.; Cusimano, M.D.; Dirks, P.B. Identification of human brain tumour initiating cells. Nature 2004, 432, 396–401.
50. Li, C.; Heidt, D.G.; Dalerba, P.; Burant, C.F.; Zhang, L.; Adsay, V.; Wicha, M.; Clarke, M.F.; Simeone, D.M. Identification of pancreatic cancer stem cells. Cancer Res. 2007, 67, 1030–1037.
51. Zeilstra, J.; Joosten, S.P.; Dokter, M.; Verwiel, E.; Spaargaren, M.; Pals, S.T. Deletion of the Wnt target and cancer stem cell marker CD44 in Apc(Min/+) mice attenuates intestinal tumorigenesis. Cancer Res. 2008, 68, 3655–3661.
52. Todaro, M.; Gaggianesi, M.; Catalano, V.; Benfante, A.; Iovino, F.; Biffoni, M.; Apuzzo, T.; Sperduti, I.; Volpe, S.; Cocorullo, G.; et al. CD44V6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell 2014, 14, 342–356.
53. Ginestier, C.; Hur, M.H.; Charafe-Jauffret, E.; Monville, F.; Dutcher, J.; Brown, M.; Jacquemier, J.; Viens, P.; Kleer, C.G.; Liu, S., et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 2007, 1, 555–567.
54. Huang, E.H.; Hynes, M.J.; Zhang, T.; Ginestier, C.; Dontu, G.; Appelman, H.; Fields, J.Z.; Wicha, M.S.; Boman, B.M. Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res. 2009, 69, 3382–3389.
55. Fodde, R.; Brabletz, T. Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr. Opin. Cell Biol. 2007, 19, 150–158.
56. Malhotra, S.; Kincade, P.W. Wnt-related molecules and signaling pathway equilibrium in hematopoiesis. Cell Stem Cell 2009, 4, 27–36.
57. Lamb, R.; Ablett, M.P.; Spence, K.; Landberg, G.; Sims, A.H.; Clarke, R.B. Wnt pathway activity in breast cancer sub-types and stem-like cells. PLoS ONE 2013, 8, e67811.
58. Kaur, N.; Chettiar, S.; Rathod, S.; Rath, P.; Muzumdar, D.; Shaikh, M.L.; Shiras, A. Wnt3a mediated activation of wnt/beta-catenin signaling promotes tumor progression in glioblastoma. Mol. Cell Neurosci. 2013, 54, 44–57.
59. Scheel, C.; Eaton, E.N.; Li, S.H.; Chaffer, C.L.; Reinhardt, F.; Kah, K.J.; Bell, G.; Guo, W.; Rubin, J.; Richardson, A.L.; et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 2011, 145, 926–940.
60. Yang, L.; Tang, H.; Kong, Y.; Xie, X.; Chen, J.; Song, C.; Liu, X.; Ye, F.; Li, N.; Wang, N.; 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.
61. Vieira, G.C.; Chockalingam, S.; Melegh, Z.; Greenhough, A.; Malik, S.; Szemes, M.; Park, J.H.; Kaidi, A.; Zhou, L.; Catchpoole, D.; et al. LGR5 regulates pro-survival MEK/ERK and proliferative Wnt/beta-catenin signalling in neuroblastoma. Oncotarget 2015, 6, 40053–40067.
62. Scannell, C.A.; Pedersen, E.A.; Mosher, J.T.; Krook, M.A.; Nicholls, L.A.; Wilky, B.A.; Loeb, D.M.; Lawlor, E.R. LGR5 is expressed by ewing sarcoma and potentiates wnt/beta-catenin signaling. Front. Oncol. 2013.
63. Wu, C.; Qiu, S.; Lu, L.; Zou, J.; Li, W.F.; Wang, O.; Zhao, H.; Wang, H.; Tang, J.; Chen, L., et al. Rspo2-lgr5 signaling has tumour-suppressive activity in colorectal cancer. Nat Commun 2014.
64. Wu, X.S.; Xi, H.Q.; Chen, L. LGR5 is a potential marker of colorectal carcinoma stem cells that correlates with patient survival. World J. Surg. Oncol. 2012.
65. Su, S.; Hong, F.; Liang, Y.; Zhou, J.; Liang, Y.; Chen, K.; Wang, X.; Wang, Z.; Wang, Z.; Chang, C., et al. LGR5 methylation in cancer stem cell differentiation and prognosis-prediction in colorectal cancer. PLoS ONE 2015, 10, e0143513.
66. Merlos-Suarez, A.; Barriga, F.M.; Jung, P.; Iglesias, M.; Cespedes, M.V.; Rossell, D.; Sevillano, M.; Hernando-Momblona, X.; da Silva-Diz, V.; Munoz, P., et al. The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell 2011, 8, 511–524.
67. Han, Y.; Xue, X.; Jiang, M.; Guo, X.; Li, P.; Liu, F.; Yuan, B.; Shen, Y.; Guo, X.; Zhi, Q.; et al. LGR5, a relevant marker of cancer stem cells, indicates a poor prognosis in colorectal cancer patients: A meta-analysis. Clin. Res. Hepatol. Gastroenterol. 2015, 39, 267–273.
68. de Sousa, E.M.F.; Colak, S.; Buikhuisen, J.; Koster, J.; Cameron, K.; de Jong, J.H.; Tuynman, J.B.; Prasetyanti, P.R.; Fessler, E.; van den Bergh, S.P.; et al. Methylation of cancer-stem-cell-associated Wnt target genes predicts poor prognosis in colorectal cancer patients. Cell Stem Cell 2011, 9, 476–485.
69. Chen, Q.; Zhang, X.; Li, W.M.; Ji, Y.Q.; Cao, H.Z.; Zheng, P. Prognostic value of LGR5 in colorectal cancer: A meta-analysis. PLoS ONE 2014, 9, e107013.
70. Lotti, F.; Jarrar, A.M.; Pai, R.K.; Hitomi, M.; Lathia, J.; Mace, A.; Gantt, G.A., Jr.; Sukhdeo, K.; DeVecchio, J.; Vasanji, A.; et al. Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J. Exp. Med. 2013, 210, 2851–2872.
71. Gupta, P.B.; Fillmore, C.M.; Jiang, G.; Shapira, S.D.; Tao, K.; Kuperwasser, C.; Lander, E.S. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 2011, 146, 633–644.
72. Curtis, S.J.; Sinkevicius, K.W.; Li, D.; Lau, A.N.; Roach, R.R.; Zamponi, R.; Woolfenden, A.E.; Kirsch, D.G.; Wong, K.K.; Kim, C.F. Primary tumor genotype is an important determinant in identification of lung cancer propagating cells. Cell Stem Cell 2010, 7, 127–133.
73. Wang, X.; Jung, Y.S.; Jun, S.; Lee, S.; Wang, W.; Schneider, A.; Sun Oh, Y.; Lin, S.H.; Park, B.J.; Chen, J., et al. PAF-Wnt signaling-induced cell plasticity is required for maintenance of breast cancer cell stemness. Nat. Commun. 2016.
74. Jung, H.Y.; Jun, S.; Lee, M.; Kim, H.C.; Wang, X.; Ji, H.; McCrea, P.D.; Park, J.I. PAF and EZH2 induce Wnt/beta-catenin signaling hyperactivation. Mol. Cell 2013, 52, 193–205.
75. Koinuma, K.; Yamashita, Y.; Liu, W.; Hatanaka, H.; Kurashina, K.; Wada, T.; Takada, S.; Kaneda, R.; Choi, Y.L.; Fujiwara, S.I., et al. Epigenetic silencing of axin2 in colorectal carcinoma with microsatellite instability. Oncogene 2006, 25, 139–146.
76. Sato, H.; Suzuki, H.; Toyota, M.; Nojima, M.; Maruyama, R.; Sasaki, S.; Takagi, H.; Sogabe, Y.; Sasaki, Y.; Idogawa, M., et al. Frequent epigenetic inactivation of dickkopf family genes in human gastrointestinal tumors. Carcinogenesis 2007, 28, 2459–2466.
77. Griffiths, E.A.; Gore, S.D.; Hooker, C.; McDevitt, M.A.; Karp, J.E.; Smith, B.D.; Mohammad, H.P.; Ye, Y.; Herman, J.G.; Carraway, H.E. Acute myeloid leukemia is characterized by Wnt pathway inhibitor promoter hypermethylation. Leuk. Lymphoma 2010, 51, 1711–1719.
78. Klarmann, G.J.; Decker, A.; Farrar, W.L. Epigenetic gene silencing in the Wnt pathway in breast cancer. Epigenetics 2008, 3, 59–63.
79. Kocemba, K.A.; Groen, R.W.; van Andel, H.; Kersten, M.J.; Mahtouk, K.; Spaargaren, M.; Pals, S.T. Transcriptional silencing of the Wnt-antagonist DKK1 by promoter methylation is associated with enhanced Wnt signaling in advanced multiple myeloma. PLoS ONE 2012, 7, e30359.
80. Paluszczak, J.; Sarbak, J.; Kostrzewska-Poczekaj, M.; Kiwerska, K.; Jarmuz-Szymczak, M.; Grenman, R.; Mielcarek-Kuchta, D.; Baer-Dubowska, W. The negative regulators of Wnt pathway-DACH1, DKK1, and WIF1 are methylated in oral and oropharyngeal cancer and WIF1 methylation predicts shorter survival. Tumour Biol. 2015, 36, 2855–2861.
81. Yu, Y.; Kanwar, S.S.; Patel, B.B.; Oh, P.S.; Nautiyal, J.; Sarkar, F.H.; Majumdar, A.P. MicroRNA-21 induces stemness by downregulating transforming growth factor beta receptor 2 (TGFβR2) in colon cancer cells. Carcinogenesis 2012, 33, 68–76.
82. Yu, Y.; Sarkar, F.H.; Majumdar, A.P. Down-regulation of MIR-21 induces differentiation of chemoresistant colon cancer cells and enhances susceptibility to therapeutic regimens. Transl. Oncol. 2013, 6, 180–186.
83. Bandres, E.; Bitarte, N.; Arias, F.; Agorreta, J.; Fortes, P.; Agirre, X.; Zarate, R.; Diaz-Gonzalez, J.A.; Ramirez, N.; Sola, J.J.; et al. MicroRNA-451 regulates macrophage migration inhibitory factor production and proliferation of gastrointestinal cancer cells. Clin. Cancer Res. 2009, 15, 2281–2290.
84. Bitarte, N.; Bandres, E.; Boni, V.; Zarate, R.; Rodriguez, J.; Gonzalez-Huarriz, M.; Lopez, I.; Javier Sola, J.; Alonso, M.M.; Fortes, P., et al. MicroRNA-451 is involved in the self-renewal, tumorigenicity, and chemoresistance of colorectal cancer stem cells. Stem Cells 2011, 29, 1661–1671.
85. Hsieh, I.S.; Chang, K.C.; Tsai, Y.T.; Ke, J.Y.; Lu, P.J.; Lee, K.H.; Yeh, S.D.; Hong, T.M.; Chen, Y.L. MicroRNA-320 suppresses the stem cell-like characteristics of prostate cancer cells by downregulating the Wnt/beta-catenin signaling pathway. Carcinogenesis 2013, 34, 530–538.
86. Isobe, T.; Hisamori, S.; Hogan, D.J.; Zabala, M.; Hendrickson, D.G.; Dalerba, P.; Cai, S.; Scheeren, F.; Kuo, A.H.; Sikandar, S.S.; et al. MIR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical Wnt signaling pathway. Elife 2014.
87. Shimono, Y.; Zabala, M.; Cho, R.W.; Lobo, N.; Dalerba, P.; Qian, D.; Diehn, M.; Liu, H.; Panula, S.P.; Chiao, E.; et al. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 2009, 138, 592–603.
88. Wang, Y.; He, L.; Du, Y.; Zhu, P.; Huang, G.; Luo, J.; Yan, X.; Ye, B.; Li, C.; Xia, P.; et al. The long noncoding rna lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling. Cell Stem Cell 2015, 16, 413–425.
89. Del Vecchio, C.A.; Jensen, K.C.; Nitta, R.T.; Shain, A.H.; Giacomini, C.P.; Wong, A.J. Epidermal growth factor receptor variant III contributes to cancer stem cell phenotypes in invasive breast carcinoma. Cancer Res. 2012, 72, 2657–2671.
90. Lau, T.; Chan, E.; Callow, M.; Waaler, J.; Boggs, J.; Blake, R.A.; Magnuson, S.; Sambrone, A.; Schutten, M.; Firestein, R.; et al. A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth. Cancer Res. 2013, 73, 3132–3144.
91. Waaler, J.; Machon, O.; Tumova, L.; Dinh, H.; Korinek, V.; Wilson, S.R.; Paulsen, J.E.; Pedersen, N.M.; Eide, T.J.; Machonova, O.; 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.
92. Wu, X.; Luo, F.; Li, J.; Zhong, X.; Liu, K. Tankyrase 1 inhibitior XAV939 increases chemosensitivity in colon cancer cell lines via inhibition of the Wnt signaling pathway. Int. J. Oncol. 2016, 48, 1333–1340.
93. Arques, O.; Chicote, I.; Puig, I.; Tenbaum, S.P.; Argiles, G.; Dienstmann, R.; Fernandez, N.; Caratu, G.; Matito, J.; Silberschmidt, D., et al. Tankyrase inhibition blocks Wnt/beta-catenin pathway and reverts resistance to PI3K and akt inhibitors in the treatment of colorectal cancer. Clin. Cancer Res. 2016, 22, 644–656.
94. Bao, R.; Christova, T.; Song, S.; Angers, S.; Yan, X.; Attisano, L. Inhibition of tankyrases induces axin stabilization and blocks Wnt signalling in breast cancer cells. PLoS ONE 2012, 7, e48670.
95. Stratford, E.W.; Daffinrud, J.; Munthe, E.; Castro, R.; Waaler, J.; Krauss, S.; Myklebost, O. The tankyrase-specific inhibitor JW74 affects cell cycle progression and induces apoptosis and differentiation in osteosarcoma cell lines. Cancer Med. 2014, 3, 36–46.
96. Tian, X.; Hou, W.; Bai, S.; Fan, J.; Tong, H.; Xu, H. XAV939 inhibits the stemness and migration of neuroblastoma cancer stem cells via repression of tankyrase 1. Int. J. Oncol. 2014, 45, 121–128.
97. Shan, J.; Shi, D.L.; Wang, J.; Zheng, J. Identification of a specific inhibitor of the dishevelled PDZ domain. Biochemistry 2005, 44, 15495–15503.
98. Grandy, D.; Shan, J.; Zhang, X.; Rao, S.; Akunuru, S.; Li, H.; Zhang, Y.; Alpatov, I.; Zhang, X.A.; Lang, R.A.; et al. Discovery and characterization of a small molecule inhibitor of the PDZ domain of dishevelled. J. Biol. Chem. 2009, 284, 16256–16263.
99. Proffitt, K.D.; Madan, B.; Ke, Z.; Pendharkar, V.; Ding, L.; Lee, M.A.; Hannoush, R.N.; Virshup, D.M. Pharmacological inhibition of the Wnt acyltransferase porcn prevents growth of Wnt-driven mammary cancer. Cancer Res. 2013, 73, 502–507.
100. Liu, J.; Pan, S.; Hsieh, M.H.; Ng, N.; Sun, F.; Wang, T.; Kasibhatla, S.; Schuller, A.G.; Li, A.G.; Cheng, D.; et al. Targeting Wnt-driven cancer through the inhibition of porcupine by LGK974. Proc. Natl. Acad. Sci. USA 2013, 110, 20224–20229.
101. Shinmura, K.; Kahyo, T.; Kato, H.; Igarashi, H.; Matsuura, S.; Nakamura, S.; Kurachi, K.; Nakamura, T.; Ogawa, H.; Funai, K., et al. RSPO fusion transcripts in colorectal cancer in japanese population. Mol. Biol. Rep. 2014, 41, 5375–5384.
102. Jiang, X.; Hao, H.X.; Growney, J.D.; Woolfenden, S.; Bottiglio, C.; Ng, N.; Lu, B.; Hsieh, M.H.; Bagdasarian, L.; Meyer, R.; et al. Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proc. Natl. Acad. Sci. USA 2013, 110, 12649–12654.
103. Madan, B.; Ke, Z.; Harmston, N.; Ho, S.Y.; Frois, A.O.; Alam, J.; Jeyaraj, D.A.; Pendharkar, V.; Ghosh, K.; Virshup, I.H., et al. Wnt addiction of genetically defined cancers reversed by porcn inhibition. Oncogene 2015, 35, 2197–2207.
104. Gurney, A.; Axelrod, F.; Bond, C.J.; Cain, J.; Chartier, C.; Donigan, L.; Fischer, M.; Chaudhari, A.; Ji, M.; Kapoun, A.M., 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 2012, 109, 11717–11722.
105. Le, P.N.; McDermott, J.D.; Jimeno, A. Targeting the Wnt pathway in human cancers: Therapeutic targeting with a focus on OMP-54F28. Pharmacol. Ther. 2015, 146, 1–11.
106. Ma, H.; Nguyen, C.; Lee, K.S.; Kahn, M. Differential roles for the coactivators CBP and p300 on TCF/beta-catenin-mediated survivin gene expression. Oncogene 2005, 24, 3619–3631.
107. Lenz, H.J.; Kahn, M. Safely targeting cancer stem cells via selective catenin coactivator antagonism. Cancer Sci. 2014, 105, 1087–1092.
108. Duchartre, Y.; Kim, Y.M.; Kahn, M. The Wnt signaling pathway in cancer. Crit. Rev. Oncol. Hematol. 2016, 99, 141–149.
109. Fang, L.; Zhu, Q.; Neuenschwander, M.; Specker, E.; Wulf-Goldenberg, A.; Weis, W.I.; von Kries, J.P.; Birchmeier, W. A small-molecule antagonist of the beta-catenin/TCF4 interaction blocks the self-renewal of cancer stem cells and suppresses tumorigenesis. Cancer Res. 2016, 76, 891–901.
110. van der Horst, E.H.; Chinn, L.; Wang, M.; Velilla, T.; Tran, H.; Madrona, Y.; Lam, A.; Ji, M.; Hoey, T.C.; Sato, A.K. Discovery of fully human anti-met monoclonal antibodies with antitumor activity against colon cancer tumor models in vivo. Neoplasia 2009, 11, 355–364.
111. Rasola, A.; Fassetta, M.; De Bacco, F.; D’Alessandro, L.; Gramaglia, D.; Di Renzo, M.F.; Comoglio, P.M. A positive feedback loop between hepatocyte growth factor receptor and beta-catenin sustains colorectal cancer cell invasive growth. Oncogene 2007, 26, 1078–1087.
112. Sun, S.; Liu, S.; Duan, S.Z.; Zhang, L.; Zhou, H.; Hu, Y.; Zhou, X.; Shi, C.; Zhou, R.; Zhang, Z. Targeting the c-Met/Fzd8 signaling axis eliminates patient-derived cancer stem-like cells in head and neck squamous carcinomas. Cancer Res. 2014, 74, 7546–7559.
113. Warrier, S.; Bhuvanalakshmi, G.; Arfuso, F.; Rajan, G.; Millward, M.; Dharmarajan, A. Cancer stem-like cells from head and neck cancers are chemosensitized by the Wnt antagonist, SFRP4, by inducing apoptosis, decreasing stemness, drug resistance and epithelial to mesenchymal transition. Cancer Gene Ther. 2014, 21, 381–388.
114. Malladi, S.; Macalinao, D.G.; Jin, X.; He, L.; Basnet, H.; Zou, Y.; de Stanchina, E.; Massague, J. Metastatic latency and immune evasion through autocrine inhibition of Wnt. Cell 2016, 165, 45–60.
115. Van der Flier, L.G.; Sabates-Bellver, J.; Oving, I.; Haegebarth, A.; De Palo, M.; Anti, M.; Van Gijn, M.E.; Suijkerbuijk, S.; Van de Wetering, M.; Marra, G.; et al. The intestinal Wnt/TCF signature. Gastroenterology 2007, 132, 628–632.
116. Katoh, Y.; Katoh, M. Comparative genomics on prom1 gene encoding stem cell marker CD133. Int. J. Mol. Med. 2007, 19, 967–970.
117. Koo, B.K.; van Es, J.H.; van den Born, M.; Clevers, H. Porcupine inhibitor suppresses paracrine Wnt-driven growth of RNF43;ZNRF3-mutant neoplasia. Proc. Natl. Acad. Sci. USA 2015, 112, 7548–7550.
118. Kahn, M. Can we safely target the Wnt pathway? Nat. Rev. Drug Discov. 2014, 13, 513–532.