Hedgehog signaling in the maintenance of cancer stem cells

Cancers

Volumn 7, Issue 3, 2015, Pages 1554-1585

  Cochrane, Catherine R ^a,b   Szczepny, Anette ^a,b   Watkins, D Neil ^c,d,e   Cain, Jason E ^a,b  

^a HUDSON INSTITUTE OF MEDICAL RESEARCH   (Australia)

^b MONASH UNIVERSITY   (Australia)

^c GARVAN INSTITUTE OF MEDICAL RESEARCH   (Australia)

^d UNIVERSITY OF NEW SOUTH WALES   (Australia)

^e ST VINCENT S HOSPITAL   (Australia)

Author keywords

Cancer stem cells; Hedgehog signaling; Tumourigenesis

Indexed keywords

4 [4 (4' CHLORO 2 BIPHENYLYLMETHYL) 1 PIPERAZINYL] N [4 [3 DIMETHYLAMINO 1 (PHENYLTHIOMETHYL)PROPYLAMINO] 3 NITROBENZENESULFONYL]BENZAMIDE; CARBOPLATIN; CISPLATIN; CYCLOPAMINE; CYTARABINE; DASATINIB; ERLOTINIB; ETOPOSIDE; FLUOROURACIL; GLASDEGIB; IMATINIB; MITOMYCIN; NILOTINIB; OXALIPLATIN; PACLITAXEL; PATIDEGIB; SONIC HEDGEHOG PROTEIN; SONIDEGIB; SORAFENIB; TEMOZOLOMIDE; VISMODEGIB;

ACUTE LYMPHOBLASTIC LEUKEMIA; ACUTE MYELOBLASTIC LEUKEMIA; AUTOCRINE EFFECT; BREAST CANCER; CANCER COMBINATION CHEMOTHERAPY; CANCER INHIBITION; CANCER RECURRENCE; CANCER RESISTANCE; CANCER STEM CELL; CARCINOGENESIS; CHRONIC MYELOID LEUKEMIA; DIGESTIVE SYSTEM CANCER; DRUG POTENTIATION; DRUG TARGETING; GLIOMA; HEMATOLOGIC MALIGNANCY; HUMAN; LUNG CANCER; MALIGNANT TRANSFORMATION; MELANOMA; METASTASIS; MULTIPLE MYELOMA; NONHUMAN; PANCREAS CANCER; PARACRINE SIGNALING; PROSTATE CANCER; REVIEW; SIGNAL TRANSDUCTION; SMALL CELL LUNG CANCER; SOLID TUMOR; STOMACH CANCER;

EID: 84940996114     PISSN: None     EISSN: 20726694     Source Type: Journal    
DOI: 10.3390/cancers7030851     Document Type: Review

References (185)

1. Reya, T.; Morrison, S.J.; Clarke, M.F.; Weissman, I.L. Stem cells, cancer, and cancer stem cells. Nature 2001, 414, 105-111.
2. Karamboulas, C.; Ailles, L. Developmental signaling pathways in cancer stem cells of solid tumors. Biochim. Biophys. Acta-Gen. Subj. 2013, 1830, 2481-2495.
3. O'Brien, C.A.; Kreso, A.; Jamieson, C.H.M. Cancer stem cells and self-renewal. Clin. Cancer Res. 2010, 16, 3113-3120. [PubMed]
4. Chen, K.; Huang, Y.-H.; Chen, J.-L. Understanding and targeting cancer stem cells: Therapeutic implications and challenges. Acta Pharmacol. Sin. 2013, 34, 732-740. [PubMed]
5. Medema, J.P. Cancer stem cells: The challenges ahead. Nat. Cell Biol. 2013, 15, 338-344. [CrossRef] [PubMed]
6. Takebe, N.; Warren, R.Q.; Ivy, S.P. Breast cancer growth and metastasis: interplay between cancer stem cells, embryonic signaling pathways and epithelial-to-mesenchymal transition. Breast Cancer Res. 2011, 13, 211. [CrossRef] [PubMed]
7. McMahon, A.P.; Ingham, P.W.; Tabin, C.J. Developmental roles and clinical significance of Hedgehog signaling. Curr. Top. Dev. Biol. 2003, 53, 1-114. [PubMed]
8. Van Den Brink, G.R.; Peppelenbosch, M.P. Expression of hedgehog pathway components in the adult colon. Gastroenterology 2006, 130, 619. [CrossRef] [PubMed]
9. Wicking, C.; McGlinn, E. The role of hedgehog signalling in tumorigenesis. Cancer Lett. 2001, 173, 1-7. [CrossRef] [PubMed]
10. Peng, Y.-C.; Levine, C.M.; Zahid, S.; Wilson, E.L.; Joyner, A.L. Sonic hedgehog signals to multiple prostate stromal stem cells that replenish distinct stromal subtypes during regeneration. Proc. Natl. Acad. Sci. USA 2013, 110, 20611-20616. [CrossRef] [PubMed]
11. Ihrie, R.A.; Shah, J.K.; Harwell, C.C.; Levine, J.H.; Guinto, C.D.; Lezameta, M.; Kriegstein, A.R.; Alvarez-Buylla, A. Persistent sonic hedgehog signaling in adult brain determines neural stem cell positional identity. Neuron 2011, 71, 250-262. [CrossRef] [PubMed]
12. Perler, F.B. Protein splicing of inteins and hedgehog autoproteolysis: Structure, function, and evolution. Cell 1998, 92, 1-4. [CrossRef] [PubMed]
13. Chen, X.; Tukachinsky, H.; Huang, C.H.; Jao, C.; Chu, Y.R.; Tang, H.Y.; Mueller, B.; Schulman, S.; Rapoport, T.A.; Salic, A. Processing and turnover of the Hedgehog protein in the endoplasmic reticulum. J. Cell Biol. 2011, 192, 825-838. [CrossRef] [PubMed]
14. Chamoun, Z.; Mann, R.K.; Nellen, D.; von Kessler, D.P.; Bellotto, M.; Beachy, P.A.; Basler, K. Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal. Science 2001, 293, 2080-2084. [CrossRef] [PubMed]
15. Pepinsky, R.B.; Zeng, C.; Went, D.; Rayhorn, P.; Baker, D.P.; Williams, K.P.; Bixler, S.A.; Ambrose, C.M.; Garber, E.A.; Miatkowski, K.; et al. Identification of a palmitic acid-modified form of human Sonic hedgehog. J. Biol. Chem. 1998, 273, 14037-14045. [CrossRef] [PubMed]
16. Taylor, F.R.; Wen, D.; Garber, E.A.; Carmillo, A.N.; Baker, D.P.; Arduini, R.M.; Williams, K.P.; Weinreb, P.H.; Rayhorn, P.; Hronowski, X.; et al. Enhanced potency of human Sonic hedgehog by hydrophobic modification. Biochemistry 2001, 40, 4359-4371. [CrossRef] [PubMed]
17. Callejo, A.; Torroja, C.; Quijada, L.; Guerrero, I. Hedgehog lipid modifications are required for Hedgehog stabilization in the extracellular matrix. Development 2006, 133, 471-483. [CrossRef] [PubMed]
18. Tukachinsky, H.; Kuzmickas Ryan, P.; Jao, C.Y.; Liu, J.; Salic, A. Dispatched and scube mediate the efficient secretion of the cholesterol-modified hedgehog ligand. Cell Rep. 2012, 2, 308-320. [CrossRef] [PubMed]
19. Amanai, K.; Jiang, J. Distinct roles of central missing and dispatched in sending the Hedgehog signal. Development 2001, 128, 5119-5127. [PubMed]
20. Chen, M.-H.; Li, Y.-J.; Kawakami, T.; Xu, S.-M.; Chuang, P.-T. Palmitoylation is required for the production of a soluble multimeric Hedgehog protein complex and long-range signaling in vertebrates. Genes Dev. 2004, 18, 641-659. [CrossRef] [PubMed]
21. Goetz, J.A.; Singh, S.; Suber, L.M.; Kull, F.J.; Robbins, D.J. A highly conserved amino-terminal region of sonic hedgehog is required for the formation of its freely diffusible multimeric form. J. Biol. Chem. 2006, 281, 4087-4093. [CrossRef] [PubMed]
22. Gallet, A.; Rodriguez, R.; Ruel, L.; Therond, P.P. Cholesterol modification of hedgehog is required for trafficking and movement, revealing an asymmetric cellular response to hedgehog. Dev. Cell 2003, 4, 191-204. [CrossRef] [PubMed]
23. Bishop, B.; Aricescu, A.R.; Harlos, K.; O'Callaghan, C.A.; Jones, E.Y.; Siebold, C. Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP. Nat. Struct. Mol. Biol. 2009, 16, 698-703. [CrossRef] [PubMed]
24. Bosanac, I.; Maun, H.R.; Scales, S.J.; Wen, X.; Lingel, A.; Bazan, J.F.; de Sauvage, F.J.; Hymowitz, S.G.; Lazarus, R.A. The structure of SHH in complex with HHIP reveals a recognition role for the Shh pseudo active site in signaling. Nat. Struct. Mol. Biol. 2009, 16, 691-697. [CrossRef] [PubMed]
25. Capurro, M.I.; Shi, W.; Filmus, J. LRP1 mediates Hedgehog-induced endocytosis of the GPC3-Hedgehog complex. J. Cell Sci. 2012, 125, 3380-3389. [CrossRef] [PubMed]
26. Capurro, M.I.; Xu, P.; Shi, W.; Li, F.; Jia, A.; Filmus, J. Glypican-3 inhibits hedgehog signaling during development by competing with patched for hedgehog binding. Dev. Cell 2008, 14, 700-711. [CrossRef] [PubMed]
27. Chang, S.-C.; Mulloy, B.; Magee, A.I.; Couchman, J.R. Two distinct sites in sonic hedgehog combine for heparan sulfate interactions and cell signaling functions. J. Biol. Chem. 2011, 286, 44391-44402. [CrossRef] [PubMed]
28. Chen, Y.; Struhl, G. Dual roles for patched in sequestering and transducing Hedgehog. Cell 1996, 87, 553-563. [CrossRef]
29. Briscoe, J.; Chen, Y.; Jessell, T.M.; Struhl, G. A hedgehog-insensitive form of Patched provides evidence for direct long-range morphogen activity of Sonic hedgehog in the neural tube. Mol. Cell 2001, 7, 1279-1291. [CrossRef]
30. Allen, B.; Song, J.; Izzi, L.; Althaus, I.; Kang, J.S.; Charron, F.; Krauss, R.; McMahon, A. Overlapping roles and collective requirement for the coreceptors GAS1, CDO, and BOC in SHH pathway function. Dev. Cell 2011, 20, 775-787. [CrossRef] [PubMed]
31. Izzi, L.; Lévesque, M.; Morin, S.; Laniel, D.; Wilkes, B.C.; Mille, F.; Krauss, R.S.; McMahon, A.P.; Allen, B.L.; Charron, F. Boc and Gas1 each form distinct Shh receptor complexes with Ptch1 and are required for Shh-mediated cell proliferation. Dev. Cell 2011, 20, 788-801. [CrossRef] [PubMed]
32. Huangfu, D.; Liu, A.; Rakeman, A.S.; Murcia, N.S.; Niswander, L.; Anderson, K.V. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 2003, 426, 83-87. [CrossRef] [PubMed]
33. Rohatgi, R.; Milenkovic, L.; Corcoran, R.B.; Scott, M.P. Hedgehog signal transduction by Smoothened: Pharmacologic evidence for a 2-step activation process. Proc. Natl. Acad. Sci. USA 2009, 106, 3196-3201. [CrossRef] [PubMed]
34. Zhao, Y.; Tong, C.; Jiang, J. Hedgehog regulates smoothened activity by inducing a conformational switch. Nature 2007, 450, 252-258. [CrossRef] [PubMed]
35. Kim, J.; Kato, M.; Beachy, P.A. Gli2 trafficking links Hedgehog-dependent activation of Smoothened in the primary cilium to transcriptional activation in the nucleus. Proc. Natl. Acad. Sci. USA 2009, 106, 21666-21671. [CrossRef] [PubMed]
36. Barnfield, P.C.; Zhang, X.; Thanabalasingham, V.; Yoshida, M.; Hui, C.-C. Negative regulation of Gli1 and Gli2 activator function by Suppressor of fused through multiple mechanisms. Differentiation 2005, 73, 397-405. [CrossRef] [PubMed]
37. Goetz, S.C.; Anderson, K.V. The primary cilium: A signalling centre during vertebrate development. Nat. Rev. Genet. 2010, 11, 331-344. [CrossRef] [PubMed]
38. Niewiadomski, P.; Kong, J.H.; Ahrends, R.; Ma, Y.; Humke, E.W.; Khan, S.; Teruel, M.N.; Novitch, B.G.; Rohatgi, R. Gli protein activity is controlled by multisite phosphorylation in vertebrate Hedgehog signaling. Cell Rep. 2014, 6, 168-181. [CrossRef] [PubMed]
39. Jia, J.; Zhang, L.; Zhang, Q.; Tong, C.; Wang, B.; Hou, F.; Amanai, K.; Jiang, J. Phosphorylation by double-time/CKIε and CKIα targets cubitus interruptus for Slimb/β-TRCP-mediated proteolytic processing. Dev. Cell 2005, 9, 819-830. [CrossRef] [PubMed]
40. Zhang, Q.; Shi, Q.; Chen, Y.; Yue, T.; Li, S.; Wang, B.; Jiang, J. Multiple Ser/Thr-rich degrons mediate the degradation of Ci/Gli by the Cul3-HIB/SPOP E3 ubiquitin ligase. Proc. Natl. Acad. Sci. USA 2009, 106, 21191-21196. [CrossRef] [PubMed]
41. Ruiz I Altaba, A.; Palma, V.; Dahmane, N. Hedgehog-Gli signalling and the growth of the brain. Nat. Rev. Neurosci. 2002, 3, 24-33. [CrossRef] [PubMed]
42. Briscoe, J.; Thérond, P.P. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat. Rev. Mol. Cell Biol. 2013, 14, 418-431. [CrossRef] [PubMed]
43. Chen, Y.; Sasai, N.; Ma, G.; Yue, T.; Jia, J.; Briscoe, J.; Jiang, J. Sonic hedgehog dependent phosphorylation by CK1α and GRK2 is required for ciliary accumulation and activation of smoothened. PLoS Biol. 2011, 9, e1001083. [CrossRef] [PubMed]
44. Chen, W.; Ren, X.R.; Nelson, C.D.; Barak, L.S.; Chen, J.K.; Beachy, P.A.; de Sauvage, F.; Lefkowitz, R.J. Activity-dependent internalization of smoothened mediated by β-Arrestin 2 and GRK2. Science 2004, 306, 2257-2260. [CrossRef] [PubMed]
45. Liu, A.; Wang, B.; Niswander, L.A. Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development 2005, 132, 3103-3111. [CrossRef] [PubMed]
46. Vokes, S.A.; Ji, H.; Wong, W.H.; McMahon, A.P. A genome-scale analysis of the cis-regulatory circuitry underlying sonic hedgehog-mediated patterning of the mammalian limb. Genes Dev. 2008, 22, 2651-2663. [CrossRef] [PubMed]
47. Okolowsky, N.; Furth, P.A.; Hamel, P.A. Oestrogen receptor-alpha regulates non-canonical Hedgehog-signalling in the mammary gland. Dev. Biol. 2014, 391, 219-229. [CrossRef] [PubMed]
48. Razumilava, N.; Gradilone, S.A.; Smoot, R.L.; Mertens, J.C.; Bronk, S.F.; Sirica, A.E.; Gores, G.J. Non-canonical Hedgehog signaling contributes to chemotaxis in cholangiocarcinoma. J. Hepatol. 2014, 60, 599-605. [CrossRef] [PubMed]
49. Jenkins, D. Hedgehog signalling: Emerging evidence for non-canonical pathways. Cell. Signal. 2009, 21, 1023-1034. [CrossRef] [PubMed]
50. Chang, H.; Li, Q.; Moraes, R.C.; Lewis, M.T.; Hamel, P.A. Activation of Erk by sonic hedgehog independent of canonical hedgehog signalling. Int. J. Biochem. Cell Biol. 2010, 42, 1462-1471. [CrossRef] [PubMed]
51. Mille, F.; Thibert, C.; Fombonne, J.; Rama, N.; Guix, C.; Hayashi, H.; Corset, V.; Reed, J.C.; Mehlen, P. The Patched dependence receptor triggers apoptosis through a DRAL-caspase-9 complex. Nat. Cell Biol. 2009, 11, 739-746. [CrossRef] [PubMed]
52. Thibert, C.; Teillet, M.A.; Lapointe, F.; Mazelin, L.; Le Douarin, N.M.; Mehlen, P. Inhibition of neuroepithelial patched-induced apoptosis by Sonic hedgehog. Science 2003, 301, 843-846. [CrossRef] [PubMed]
53. Barnes, E.A.; Kong, M.; Ollendorff, V.; Donoghue, D.J. Patched1 interacts with cyclin B1 to regulate cell cycle progression. EMBO J. 2001, 20, 2214-2223. [CrossRef] [PubMed]
54. Adolphe, C.; Hetherington, R.; Ellis, T.; Wainwright, B. Patched1 functions as a gatekeeper by promoting cell cycle progression. Cancer Res. 2006, 66, 2081-2088. [CrossRef] [PubMed]
55. Jenkins, D.; Winyard, P.J.D.; Woolf, A.S. Immunohistochemical analysis of Sonic hedgehog signalling in normal human urinary tract development. J. Anat. 2007, 211, 620-629. [CrossRef] [PubMed]
56. Polizio, A.H.; Chinchilla, P.; Chen, X.; Kim, S.; Manning, D.R.; Riobo, N.A. Heterotrimeric Gi proteins link hedgehog signaling to activation of Rho small GTPases to promote fibroblast migration. J. Biol. Chem. 2011, 286, 19589-19596. [CrossRef] [PubMed]
57. Chinchilla, P.; Xiao, L.; Kazanietz, M.G.; Riobo, N.A. Hedgehog proteins activate pro-angiogenic responses in endothelial cells through non-canonical signaling pathways. Cell Cycle 2010, 9, 570-579. [CrossRef] [PubMed]
58. Bijlsma, M.F.; Borensztajn, K.S.; Roelink, H.; Peppelenbosch, M.P.; Spek, C.A. Sonic hedgehog induces transcription-independent cytoskeletal rearrangement and migration regulated by arachidonate metabolites. Cell. Signal. 2007, 19, 2596-2604. [CrossRef] [PubMed]
59. Yam, P.T.; Langlois, S.D.; Morin, S.; Charron, F. Sonic hedgehog guides axons through a noncanonical, Src-family-kinase-dependent signaling pathway. Neuron 2009, 62, 349-362. [CrossRef] [PubMed]
60. Belgacem, Y.H.; Borodinsky, L.N. Sonic hedgehog signaling is decoded by calcium spike activity in the developing spinal cord. Proc. Natl. Acad. Sci. 2011, 108, 4482-4487. [CrossRef] [PubMed]
61. Marini, K.D.; Payne, B.J.; Watkins, D.N.; Martelotto, L.G. Mechanisms of Hedgehog signalling in cancer. Growth Factors 2011, 29, 221-234. [CrossRef] [PubMed]
62. Brennan, D.; Chen, X.; Cheng, L.; Mahoney, M.; Riobo, N.A. Noncanonical hedgehog signaling. Vitam. Horm. 2012, 88, 55-72. [PubMed]
63. Teglund, S.; Toftgård, R. Hedgehog beyond medulloblastoma and basal cell carcinoma. Biochim. Biophys. Acta (BBA)-Rev. Cancer 2010, 1805, 181-208. [CrossRef] [PubMed]
64. Hahn, H.; Wicking, C.; Zaphiropoulos, P.G.; Gailani, M.R.; Shanley, S.; Chidambaram, A.; Vorechovsky, I.; Holmberg, E.; Unden, A.B.; Gillies, S.; et al. Mutations of the human homolog of drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996, 85, 841-851. [CrossRef]
65. Johnson, R.L.; Rothman, A.L.; Xie, J.; Goodrich, L.V.; Bare, J.W.; Bonifas, J.M.; Quinn, A.G.; Myers, R.M.; Cox, D.R.; Epstein, E.H., Jr.; et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 1996, 272, 1668-1671. [CrossRef] [PubMed]
66. Pietsch, T.; Waha, A.; Koch, A.; Kraus, J.; Albrecht, S.; Tonn, J.; Sörensen, N.; Berthold, F.; Henk, B.; Schmandt, N.; et al. Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res. 1997, 57, 2085-2088. [PubMed]
67. Taylor, M.D.; Liu, L.; Raffel, C.; Hui, C.C.; Mainprize, T.G.; Zhang, X.; Agatep, R.; Chiappa, S.; Gao, L.; Lowrance, A.; et al. Mutations in SUFU predispose to medulloblastoma. Nat. Genet. 2002, 31, 306-310. [CrossRef] [PubMed]
68. Pastorino, L.; Ghiorzo, P.; Nasti, S.; Battistuzzi, L.; Cusano, R.; Marzocchi, C.; Garré, M.L.; Clementi, M.; Bianchi Scarrá, G. Identification of a SUFU germline mutation in a family with Gorlin syndrome. Am. J. Med. Genet. Part A 2009, 149, 1539-1543. [CrossRef] [PubMed]
69. Tostar, U.; Malm, C.J.; Meis-Kindblom, J.M.; Kindblom, L.G.; Toftgård, R.; Undén, A.B. Deregulation of the hedgehog signalling pathway: A possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development. J. Pathol. 2006, 208, 17-25. [CrossRef] [PubMed]
70. Xie, J.; Murone, M.; Luoh, S.M.; Ryan, A.; Gu, Q.; Zhang, C.; Bonifas, J.M.; Lam, C.W.; Hynes, M.; Goddard, A.; et al. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 1998, 391, 90-92. [PubMed]
71. Reifenberger, J.;Wolter, M.;Weber, R.G.; Megahed, M.; Ruzicka, T.; Lichter, P.; Reifenberger, G. Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res. 1998, 58, 1798-1803. [PubMed]
72. Kinzler, K.W.; Bigner, S.H.; Bigner, D.D.; Trent, J.M.; Law, M.L.; O'Brien, S.J.; Wong, A.J.; Vogelstein, B. Identification of an amplified, highly expressed gene in a human glioma. Science 1987, 236, 70-73. [CrossRef] [PubMed]
73. Wetmore, C.; Eberhart, D.E.; Curran, T. Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. Cancer Res. 2001, 61, 513-516. [PubMed]
74. Barakat, M.T.; Humke, E.W.; Scott, M.P. Learning from Jekyll to control Hyde: Hedgehog signaling in development and cancer. Trends Mol. Med. 2010, 16, 337-348. [CrossRef] [PubMed]
75. Xie, J.; Johnson, R.L.; Zhang, X.; Bare, J.W.; Waldman, F.M.; Cogen, P.H.; Menon, A.G.; Warren, R.S.; Chen, L.C.; Scott, M.P.; et al. Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors. Cancer Res. 1997, 57, 2369-2372. [PubMed]
76. Goodrich, L.V.; Milenković, L.; Higgins, K.M.; Scott, M.P. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 1997, 277, 1109-1113. [CrossRef] [PubMed]
77. Hahn, H.; Wojnowski, L.; Zimmer, A.M.; Hall, J.; Miller, G.; Zimmer, A. Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome. Nat. Med. 1998, 4, 619-622. [CrossRef] [PubMed]
78. Williams, J.A.; Guicherit, O.M.; Zaharian, B.I.; Xu, Y.; Chai, L.; Wichterle, H.; Kon, C.; Gatchalian, C.; Porter, J.A.; Rubin, L.L.; et al. Identification of a small molecule inhibitor of the hedgehog signaling pathway: Effects on basal cell carcinoma-like lesions. Proc. Natl. Acad. Sci. USA 2003, 100, 4616-4621. [CrossRef] [PubMed]
79. Kawahira, H.; Scheel, D.W.; Smith, S.B.; German, M.S.; Hebrok, M. Hedgehog signaling regulates expansion of pancreatic epithelial cells. Dev. Biol. 2005, 280, 111-121. [CrossRef] [PubMed]
80. Talpale, J.; Chen, J.K.; Cooper, M.K.; Wang, B.; Mann, R.K.; Milenkovic, L.; Scott, M.P.; Beachy, P.A. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 2000, 406, 1005-1009.
81. Chen, J.K.; Taipale, J.; Cooper, M.K.; Beachy, P.A. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev. 2002, 16, 2743-2748. [CrossRef] [PubMed]
82. Watkins, D.N.; Berman, D.M.; Burkholder, S.G.; Wang, B.; Beachy, P.A.; Baylin, S.B. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 2003, 422, 313-317. [CrossRef] [PubMed]
83. Varnat, F.; Duquet, A.; Malerba, M.; Zbinden, M.; Mas, C.; Gervaz, P.; Ruiz I Altaba, A. Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion. EMBO Mol. Med. 2009, 1, 338-351. [CrossRef] [PubMed]
84. Maun, H.R.; Wen, X.; Lingel, A.; de Sauvage, F.J.; Lazarus, R.A.; Scales, S.J.; Hymowitz, S.G. Hedgehog pathway antagonist 5E1 binds hedgehog at the pseudo-active site. J. Biol. Chem. 2010, 285, 26570-26580. [CrossRef] [PubMed]
85. El Khatib, M.; Kalnytska, A.; Palagani, V.; Kossatz, U.; Manns, M.P.; Malek, N.P.; Wilkens, L.; Plentz, R.R. Inhibition of hedgehog signaling attenuates carcinogenesis in vitro and increases necrosis of cholangiocellular carcinoma. Hepatology 2013, 57, 1035-1045. [CrossRef] [PubMed]
86. Fu, J.; Rodova, M.; Roy, S.K.; Sharma, J.; Singh, K.P.; Srivastava, R.K.; Shankar, S. GANT-61 inhibits pancreatic cancer stem cell growth in vitro and in NOD/SCID/IL2R gamma null mice xenograft. Cancer Lett. 2013, 330, 22-32. [CrossRef] [PubMed]
87. Wicking, C.; Smyth, I.; Bale, A. The hedgehog signalling pathway in tumorigenesis and development. Oncogene 1999, 18, 7844-7851. [CrossRef] [PubMed]
88. Ingham, P.W.; McMahon, A.P. Hedgehog signaling in animal development: Paradigms and principles. Genes Dev. 2001, 15, 3059-3087. [CrossRef] [PubMed]
89. Theunissen, J.-W.; de Sauvage, F.J. Paracrine Hedgehog Signaling in Cancer. Cancer Res. 2009, 69, 6007-6010. [CrossRef] [PubMed]
90. Yauch, R.L.; Gould, S.E.; Scales, S.J.; Tang, T.; Tian, H.; Ahn, C.P.; Marshall, D.; Fu, L.; Januario, T.; Kallop, D.; et al. A paracrine requirement for hedgehog signalling in cancer. Nature 2008, 455, 406-410. [CrossRef] [PubMed]
91. Scales, S.J.; de Sauvage, F.J. Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol. Sci. 2009, 30, 303-312. [CrossRef] [PubMed]
92. Nolan-Stevaux, O.; Lau, J.; Truitt, M.L.; Chu, G.C.; Hebrok, M.; Fernández-Zapico, M.E.; Hanahan, D. GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev. 2009, 23, 24-36. [CrossRef] [PubMed]
93. Tian, H.; Callahan, C.A.; Dupree, K.J.; Darbonne, W.C.; Ahn, C.P.; Scales, S.J.; de Sauvage, F.J. Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc. Natl. Acad. Sci. USA 2009, 106, 4254-4259. [CrossRef] [PubMed]
94. Chen, W.; Tang, T.; Eastham-Anderson, J.; Dunlap, D.; Alicke, B.; Nannini, M.; Gould, S.; Yauch, R.; Modrusan, Z.; DuPree, K.J.; et al. Canonical hedgehog signaling augments tumor angiogenesis by induction of VEGF-A in stromal perivascular cells. Proc. Natl. Acad. Sci. USA 2011, 108, 9589-9594. [CrossRef] [PubMed]
95. Moran, C.M.; Myers, C.T.; Lewis, C.M.; Krieg, P.A. Hedgehog regulates angiogenesis of intersegmental vessels through the VEGF signaling pathway. Dev. Dyn. 2012, 241, 1034-1042. [CrossRef] [PubMed]
96. Lindemann, R.K. Stroma-initiated Hedgehog signaling takes center stage in B-cell lymphoma. Cancer Res. 2008, 68, 961-964. [CrossRef] [PubMed]
97. Dierks, C.; Grbic, J.; Zirlik, K.; Beigi, R.; Englund, N.P.; Guo, G.R.; Veelken, H.; Engelhardt, M.; Mertelsmann, R.; Kelleher, J.F.; et al. Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nat. Med. 2007, 13, 944-951. [CrossRef] [PubMed]
98. Peacock, C.D.; Wang, Q.; Gesell, G.S.; Corcoran-Schwartz, I.M.; Jones, E.; Kim, J.; Devereux, W.L.; Rhodes, J.T.; Huff, C.A.; Beachy, P.A.; et al. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc. Natl. Acad. Sci. USA 2007, 104, 4048-4053. [CrossRef] [PubMed]
99. Becher, O.J.; Hambardzumyan, D.; Fomchenko, E.I.; Momota, H.; Mainwaring, L.; Bleau, A.M.; Katz, A.M.; Edgar, M.; Kenney, A.M.; Cordon-Cardo, C.; et al. Gli activity correlates with tumor grade in platelet-derived growth factor-induced gliomas. Cancer Res. 2008, 68, 2241-2249. [CrossRef] [PubMed]
100. Po, A.; Ferretti, E.; Miele, E.; De Smaele, E.; Paganelli, A.; Canettieri, G.; Coni, S.; di Marcotullio, L.; Biffoni, M.; Massimi, L.; et al. Hedgehog controls neural stem cells through p53-independent regulation of Nanog. EMBO J. 2010, 29, 2646-2658. [CrossRef] [PubMed]
101. Clement, V.; Sanchez, P.; de Tribolet, N.; Radovanovic, I.; Ruizi Altaba, A. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr. Biol. 2007, 17, 165-172. [CrossRef] [PubMed]
102. Batsaikhan, B.E.; Yoshikawa, K.; Kurita, N.; Iwata, T.; Takasu, C.; Kashihara, H.; Shimada, M. Cyclopamine decreased the expression of sonic hedgehog and its downstream genes in colon cancer stem cells. Anticancer Res. 2014, 34, 6339-6344. [PubMed]
103. Justilien, V.; Walsh, M.P.; Ali, S.; Thompson, E.; Murray, N.; Fields, A. The PRKCI and SOX2 oncogenes are coamplified and cooperate to activate hedgehog signaling in lung squamous cell carcinoma. Cancer Cell 2014, 25, 139-151. [CrossRef] [PubMed]
104. Zhao, C.; Chen, A.; Jamieson, C.H.; Fereshteh, M.; Abrahamsson, A.; Blum, J.; Kwon, H.Y.; Kim, J.; Chute, J.P.; Rizzieri, D.; et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 2009, 458, 776-779. [PubMed]
105. Dierks, C.; Beigi, R.; Guo, G.-R.; Zirlik, K.; Stegert, M.R.; Manley, P.; Trussell, C.; Schmitt-Graeff, A.; Landwerlin, K.; Veelken, H.; et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on hedgehog pathway activation. Cancer Cell 2008, 14, 238-249. [CrossRef] [PubMed]
106. Babashah, S.; Sadeghizadeh, M.; Hajifathali, A.; Tavirani, M.R.; Zomorod, M.S.; Ghadiani, M.; Soleimani, M. Targeting of the signal transducer Smo links microRNA-326 to the oncogenic Hedgehog pathway in CD34+ CML stem/progenitor cells. Int. J. Cancer 2013, 133, 579-589. [CrossRef] [PubMed]
107. Queiroz, K.C.S.; Ruela-de-Sousa, R.R.; Fuhler, G.M.; Aberson, H.L.; Ferreira, C.V.; Peppelenbosch, M.P.; Spek, C.A. Hedgehog signaling maintains chemoresistance in myeloid leukemic cells. Oncogene 2010, 29, 6314-6322. [PubMed]
108. Sadarangani, A.; Pineda, G.; Lennon, K.M.; Chun, H.-J.; Shih, A.; Schairer, A.E.; Court, A.C.; Goff, D.J.; Prashad, S.L.; Geron, I.; et al. GLI2 inhibition abrogates human leukemia stem cell dormancy. J. Transl. Med. 2015, 13, 98. [CrossRef] [PubMed]
109. Lim, Y.; Gondek, L.; Li, L.; Wang, Q.; Ma, H.; Chang, E.; Huso, D.L.; Foerster, S.; Marchionni, L.; McGovern, K.; et al. Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia. Sci. Transl. Med. 2015, 7, 291ra296.
110. Minami, Y.; Fukushima, N.; Kakiuchi, S.; Minami, H.; Naoe, T. Treatment with hedgehog inhibitor PF-913 attenuates leukemia-initiation potential in acute myeloid leukemic cells. Cancer Res. 2014, 74, 1884. [CrossRef]
111. Takahashi, T.; Kawakami, K.; Mishima, S.; Akimoto, M.; Takenaga, K.; Suzumiya, J.; Honma, Y. Cyclopamine induces eosinophilic differentiation and upregulates CD44 expression in myeloid leukemia cells. Leuk. Res. 2011, 35, 638-645. [CrossRef] [PubMed]
112. Kobune, M.; Takimoto, R.; Murase, K.; Iyama, S.; Sato, T.; Kikuchi, S.; Kawano, Y.; Miyanishi, K.; Sato, Y.; Niitsu, Y.; et al. Drug resistance is dramatically restored by hedgehog inhibitors in CD34+ leukemic cells. Cancer Sci. 2009, 100, 948-955. [CrossRef] [PubMed]
113. Lin, T.L.; Wang, Q.H.; Brown, P.; Peacock, C.; Merchant, A.A.; Brennan, S.; Jones, E.; McGovern, K.; Watkins, D.N.; Sakamoto, K.M.; et al. Self-renewal of acute lymphocytic leukemia cells is limited by the Hedgehog pathway inhibitors cyclopamine and IPI-926. PLoS ONE 2010, 5, e15262. [CrossRef] [PubMed]
114. Lang, F.; Badura, S.; Ruthardt, M.; Rieger, M.A.; Ottmann, O.G. Modulation of leukemic stem cell self-renewal and cell fate decisions by inhibition of hedgehog signalling in human acute lymphoblastic leukemia. Blood 2012, 120, s2578.
115. Bar, E.E.; Chaudhry, A.; Lin, A.; Fan, X.; Schreck, K.; Matsui, W.; Piccirillo, S.; Vescovi, A.L.; DiMeco, F.; Olivi, A.; et al. Cyclopamine-mediated Hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells 2007, 25, 2524-2533. [CrossRef] [PubMed]
116. Ehtesham, M.; Sarangi, A.; Valadez, J.G.; Chanthaphaychith, S.; Becher, M.W.; Abel, T.W.; Thompson, R.C.; Cooper, M.K. Ligand-dependent activation of the hedgehog pathway in glioma progenitor cells. Oncogene 2007, 26, 5752-5761. [CrossRef] [PubMed]
117. Morgenroth, A.; Vogg, A.T.J.; Ermert, K.; Zlatopolskiy, B.; Mottaghy, F.M. Hedgehog signaling sensitizes Glioma stem cells to endogenous nano-irradiation. Oncotarget 2014, 5, 5483-5493. [PubMed]
118. Liu, S.; Dontu, G.; Mantle, I.D.; Patel, S.; Ahn, N.S.; Jackson, K.W.; Suri, P.; Wicha, M.S. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 2006, 66, 6063-6071. [CrossRef] [PubMed]
119. Memmi, E.M.; Sanarico, A.G.; Giacobbe, A.; Peschiaroli, A.; Frezza, V.; Cicalese, A.; Pisati, F.; Tosoni, D.; Zhou, H.; Tonon, G.; et al. p63 sustains self-renewal of mammary cancer stem cells through regulation of Sonic Hedgehog signaling. Proc. Natl. Acad. Sci. USA 2015, 112, 3499-3504. [CrossRef] [PubMed]
120. Wang, X.; Zhang, N.; Huo, Q.; Sun, M.; Dong, L.; Zhang, Y.; Xu, G.; Yang, Q. Huaier aqueous extract inhibits stem-like characteristics of MCF7 breast cancer cells via inactivation of hedgehog pathway. Tumour Biol. 2014, 35, 10805-10813. [CrossRef] [PubMed]
121. Park, K.S.; Martelotto, L.G.; Peifer, M.; Sos, M.L.; Karnezis, A.N.; Mahjoub, M.R.; Bernard, K.; Conklin, J.F.; Szczepny, A.; Yuan, J.; et al. A crucial requirement for Hedgehog signaling in small cell lung cancer. Nat. Med. 2011, 17, 1504-1508. [CrossRef] [PubMed]
122. Tian, F.; Mysliwietz, J.; Ellwart, J.; Gamarra, F.; Huber, R.M.; Bergner, A. Effects of the Hedgehog pathway inhibitor GDC-0449 on lung cancer cell lines are mediated by side populations. Clin. Exp. Med. 2012, 12, 25-30. [CrossRef] [PubMed]
123. Ahmad, A.; Maitah, M.Y.; Ginnebaugh, K.R.; Li, Y.; Bao, B.; Gadgeel, S.M.; Sarkar, F.H. Inhibition of Hedgehog signaling sensitizes NSCLC cells to standard therapies through modulation of EMT-regulating miRNAs. J. Hematol. Oncol. 2013, 6, 77. [CrossRef] [PubMed]
124. Yoon, C.; Park, D.J.; Schmidt, B.; Thomas, N.J.; Lee, H.J.; Kim, T.S.; Janjigian, Y.Y.; Cohen, D.J.; Yoon, S.S. CD44 expression denotes a subpopulation of gastric cancer cells in which Hedgehog signaling promotes chemotherapy resistance. Clin. Cancer Res. 2014, 20, 3974-3988. [CrossRef] [PubMed]
125. Song, Z.; Yue, W.; Wei, B.; Wang, N.; Li, T.; Guan, L.; Shi, S.; Zeng, Q.; Pei, X.; Chen, L. Sonic hedgehog pathway is essential for maintenance of cancer stem-like cells in human gastric cancer. PLoS ONE 2011, 6, e17687. [CrossRef] [PubMed]
126. Rodova, M.; Fu, J.; Watkins, D.N.; Srivastava, R.K.; Shankar, S. Sonic hedgehog signaling inhibition provides opportunities for targeted therapy by sulforaphane in regulating pancreatic cancer stem cell self-renewal. PLoS ONE 2012, 7, e46083. [CrossRef] [PubMed]
127. Huang, F.T.; Zhuan-Sun, Y.X.; Zhuang, Y.Y.; Wei, S.L.; Tang, J.; Chen, W.B.; Zhang, S.N. Inhibition of hedgehog signaling depresses self-renewal of pancreatic cancer stem cells and reverses chemoresistance. Int. J. Oncol. 2012, 41, 1707-1714. [PubMed]
128. Gu, D.; Liu, H.; Su, G.H.; Zhang, X.; Chin-Sinex, H.; Hanenberg, H.; Mendonca, M.S.; Shannon, H.E.; Chiorean, E.G.; Xie, J. Combining hedgehog signaling inhibition with focal irradiation on reduction of pancreatic cancer metastasis. Mol. Cancer Ther. 2013, 12, 1038-1048. [CrossRef] [PubMed]
129. Singh, B.N.; Fu, J.; Srivastava, R.K.; Shankar, S. Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem cell characteristics: Molecular mechanisms. PLoS ONE 2011, 6, e27306. [CrossRef] [PubMed]
130. Yao, J.; An, Y.; Wei, J.S.; Ji, Z.L.; Lu, Z.P.; Wu, J.L.; Jiang, K.R.; Chen, P.; Xu, Z.K.; Miao, Y. Cyclopamine reverts acquired chemoresistance and down-regulates cancer stem cell markers in pancreatic cancer cell lines. Swiss Medical Weekly 2011, 141, w13208. [CrossRef] [PubMed]
131. Tang, S.N.; Fu, J.; Nall, D.; Rodova, M.; Shankar, S.; Srivastava, R.K. Inhibition of sonic hedgehog pathway and pluripotency maintaining factors regulate human pancreatic cancer stem cell characteristics. Int. J. Cancer 2012, 131, 30-40. [CrossRef] [PubMed]
132. Han, J.B.; Sang, F.; Chang, J.J.; Hua, Y.Q.; Shi, W.D.; Tang, L.H.; Liu, L.M. Arsenic trioxide inhibits viability of pancreatic cancer stem cells in culture and in a xenograft model via binding to SHH-Gli. OncoTargets Ther. 2013, 6, 1129-1138. [CrossRef] [PubMed]
133. Zhang, L.; Li, L.; Jiao, M.; Wu, D.; Wu, K.; Li, X.; Zhu, G.; Yang, L.; Wang, X.; Hsieh, J.T.; et al. Genistein inhibits the stemness properties of prostate cancer cells through targeting Hedgehog-Gli1 pathway. Cancer Lett. 2012, 323, 48-57. [CrossRef] [PubMed]
134. Singh, S.; Chitkara, D.; Mehrazin, R.; Behrman, S.W.;Wake, R.W.; Mahato, R.I. Chemoresistance in prostate cancer cells is regulated by miRNAs and Hedgehog pathway. PLoS ONE 2012, 7, e40021. [CrossRef] [PubMed]
135. Domingo-Domenech, J.; Vidal, S.J.; Rodriguez-Bravo, V.; Castillo-Martin, M.; Quinn, S.; Rodriguez-Barrueco, R.; Bonal, D.; Charytonowicz, E.; Gladoun, N.; de la Iglesia-Vicente, J.; et al. Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch-and hedgehog-dependent tumor-initiating cells. Cancer Cell 2012, 22, 373-388. [CrossRef] [PubMed]
136. Chang, H.H.; Chen, B.Y.; Wu, C.Y.; Tsao, Z.J.; Chen, Y.Y.; Chang, C.P.; Yang, C.R.; Lin, D.P.C. Hedgehog overexpression leads to the formation of prostate cancer stem cells with metastatic property irrespective of androgen receptor expression in the mouse model. J. Biomed. Sci. 2011, 18, 6. [CrossRef] [PubMed]
137. Santini, R.; Vinci, M.C.; Pandolfi, S.; Penachioni, J.Y.; Montagnani, V.; Olivito, B.; Gattai, R.; Pimpinelli, N.; Gerlini, G.; Borgognoni, L.; et al. HEDGEHOG-GLI signaling drives self-renewal and tumorigenicity of human melanoma-initiating cells. Stem Cells 2012, 30, 1808-1818. [CrossRef] [PubMed]
138. Santini, R.; Pietrobono, S.; Pandolfi, S.; Montagnani, V.; D'Amico, M.; Penachioni, J.Y.; Vinci, M.C.; Borgognoni, L.; Stecca, B. SOX2 regulates self-renewal and tumorigenicity of human melanoma-initiating cells. Oncogene 2014, 33, 4697-4708. [CrossRef] [PubMed]
139. Pandolfi, S.; Montagnani, V.; Penachioni, J.Y.; Vinci, M.C.; Olivito, B.; Borgognoni, L.; Stecca, B. WIP1 phosphatase modulates the Hedgehog signaling by enhancing GLI1 function. Oncogene 2013, 32, 4737-4747. [CrossRef] [PubMed]
140. Riether, C.; Schurch, C.M.; Ochsenbein, A.F. Regulation of hematopoietic and leukemic stem cells by the immune system. Cell Death Differ 2015, 22, 187-198. [CrossRef] [PubMed]
141. Testa, U. Leukemia stem cells. Ann. Hematol. 2011, 90, 245-271. [CrossRef] [PubMed]
142. Huntly, B.J.P.; Gilliland, D.G. Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat. Rev. Cancer 2005, 5, 311-321. [CrossRef] [PubMed]
143. Goardon, N.; Marchi, E.; Atzberger, A.; Quek, L.; Schuh, A.; Soneji, S.; Woll, P.; Mead, A.; Alford, K.A.; Rout, R.; et al. Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell 2011, 19, 138-152. [CrossRef] [PubMed]
144. Deininger, M.W.N.; Goldman, J.M.; Melo, J.V. The molecular biology of chronic myeloid leukemia. Blood 2000, 96, 3343-3356. [PubMed]
145. Mehrotra, B.; George, T.I.; Kavanau, K.; Avet-Loiseau, H.; Moore Ii, D.; Willman, C.L.; Slovak, M.L.; Atwater, S.; Head, D.R.; Pallavicini, M.G. Cytogenetically aberrant cells in the stem cell compartment (CD34+lin-) in acute myeloid leukemia. Blood 1995, 86, 1139-1147. [PubMed]
146. Haase, D.; Feuring-Buske, M.; Konemann, S.; Fonatsch, C.; Troff, C.; Verbeek, W.; Pekrun, A.; Hiddemann, W.; Wormann, B. Evidence for malignant transformation in acute myeloid leukemia at the level of early hematopoietic stem cells by cytogenetic analysis of CD34+ subpopulations. Blood 1995, 86, 2906-2912. [PubMed]
147. Quijano, C.A.; Moore Ii, D.; Arthur, D.; Feusner, J.; Winter, S.S.; Pallavicini, M.G. Cytogenetically aberrant cells are present in the CD34+CD33-38-19-marrow compartment in children with acute lymphoblastic leukemia. Leukemia 1997, 11, 1508-1515. [CrossRef] [PubMed]
148. Martin, P.J.; Najfeld, V.; Hansen, J.A.; Penfold, G.K.; Jacobson, R.J.; Fialkow, P.J. Involvement of the B-lymphoid system in chronic myelogenous leukaemia. Nature 1980, 287, 49-50. [CrossRef] [PubMed]
149. Passegué, E.;Wagner, E.F.;Weissman, I.L. JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells. Cell 2004, 119, 431-443. [CrossRef] [PubMed]
150. Taussig, D.C.; Vargaftig, J.; Miraki-Moud, F.; Griessinger, E.; Sharrock, K.; Luke, T.; Lillington, D.; Oakervee, H.; Cavenagh, J.; Agrawal, S.G.; et al. Leukemia-initiating cells from some acute myeloid leukemia patients with mutated nucleophosmin reside in the CD34-fraction. Blood 2010, 115, 1976-1984. [CrossRef] [PubMed]
151. Deguchi, K.; Ayton, P.M.; Carapeti, M.; Kutok, J.L.; Snyder, C.S.; Williams, I.R.; Cross, N.C.P.; Glass, C.K.; Cleary, M.L.; Gilliland, D.G. MOZ-TIF2-induced acute myeloid leukemia requires the MOZ nucleosome binding motif and TIF2-mediated recruitment of CBP. Cancer Cell 2003, 3, 259-271. [CrossRef]
152. Schreiner, S.; Birke, M.; García-Cuéllar, M.P.; Zilles, O.; Greil, J.; Slany, R.K. MLL-ENL causes a reversible and myc-dependent block of myelomonocytic cell differentiation. Cancer Res. 2001, 61, 6480-6486. [PubMed]
153. Jørgensen, H.G.; Allan, E.K.; Jordanides, N.E.; Mountford, J.C.; Holyoake, T.L. Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. Blood 2007, 109, 4016-4019. [CrossRef] [PubMed]
154. Long, B.; Zhu, H.; Zhu, C.; Liu, T.; Meng, W. Activation of the hedgehog pathway in chronic myelogeneous leukemia patients. J. Exp. Clin. Cancer Res.: CR 2011, 30, 8. [CrossRef] [PubMed]
155. van Rhenen, A.; Moshaver, B.; Kelder, A.; Feller, N.; Nieuwint, A.W.M.; Zweegman, S.; Ossenkoppele, G.J.; Schuurhuis, G.J. Aberrant marker expression patterns on the CD34+CD38-stem cell compartment in acute myeloid leukemia allows to distinguish the malignant from the normal stem cell compartment both at diagnosis and in remission. Leukemia 2007, 21, 1700-1707. [CrossRef] [PubMed]
156. Bai, L.Y.; Chiu, C.F.; Lin, C.W.; Hsu, N.Y.; Lin, C.L.; Lo, W.J.; Kao, M.C. Differential expression of Sonic hedgehog and Gli1 in hematological malignancies. Leukemia 2007, 22, 226-228. [CrossRef] [PubMed]
157. Gao, J.; Graves, S.; Koch, U.; Liu, S.; Jankovic, V.; Buonamici, S.; El Andaloussi, A.; Nimer, S.D.; Kee, B.L.; Taichman, R.; et al. Hedgehog Signaling Is Dispensable for Adult Hematopoietic Stem Cell Function. Cell Stem Cell 2009, 4, 548-558. [CrossRef] [PubMed]
158. Hofmann, I.; Stover, E.H.; Cullen, D.E.; Mao, J.; Morgan, K.J.; Lee, B.H.; Kharas, M.G.; Miller, P.G.; Cornejo, M.G.; Okabe, R.; et al. Hedgehog signaling is dispensable for adult murine hematopoietic stem cell function and hematopoiesis. Cell Stem Cell 2009, 4, 559-567. [CrossRef] [PubMed]
159. Campbell, V.; Copland, M. Hedgehog signaling in cancer stem cells: A focus on hematological cancers. Stem Cells Cloning 2015, 8, 27-38. [PubMed]
160. Ji, Z.; Mei, F.C.; Johnson, B.H.; Thompson, E.B.; Cheng, X. Protein kinase A, not Epac, suppresses hedgehog activity and regulates glucocorticoid sensitivity in acute lymphoblastic leukemia cells. J. Biol. Chem. 2007, 282, 37370-37377. [CrossRef] [PubMed]
161. Matsui, W.; Huff, C.A.; Wang, Q.; Malehorn, M.T.; Barber, J.; Tanhehco, Y.; Smith, B.D.; Civin, C.I.; Jones, R.J. Characterization of clonogenic multiple myeloma cells. Blood 2003, 103, 2332-2336. [CrossRef] [PubMed]
162. Liu, Z.; Xu, J.; He, J.; Zheng, Y.; Li, H.; Lu, Y.; Qian, J.; Lin, P.; Weber, D.M.; Yang, J.; et al. A critical role of autocrine sonic hedgehog signaling in human CD138+ myeloma cell survival and drug resistance. Blood 2014, 124, 2061-2071. [CrossRef] [PubMed]
163. Merchant, A.A.; Matsui, W. Targeting hedgehog-a cancer stem cell pathway. Clin. Cancer Res. 2010, 16, 3130-3140. [CrossRef] [PubMed]
164. Liu, Y.; Liu, X.; Chen, L.; Du, W.; Cui, Y.; Piao, X.; Li, Y.; Jiang, C. Targeting glioma stem cells via the Hedgehog signaling pathway. Neuroimmunol. Neuroinflamm. 2014, 1, 51-59.
165. Hermann, P.C.; Bhaskar, S.; Cioffi, M.; Heeschen, C. Cancer stem cells in solid tumors. Semin. Cancer Biol. 2010, 20, 77-84. [CrossRef] [PubMed]
166. Lewis, M.T.; Ross, S.; Strickland, P.A.; Sugnet, C.W.; Jimenez, E.; Scott, M.P.; Daniel, C.W. Defects in mouse mammary gland development caused by conditional haploinsufficiency of Patched-1. Development 1999, 126, 5181-5193. [PubMed]
167. Moraes, R.C.; Zhang, X.; Harrington, N.; Fung, J.Y.; Wu, M.F.; Hilsenbeck, S.G.; Allred, D.C.; Lewis, M.T. Constitutive activation of smoothened (SMO) in mammary glands of transgenic mice leads to increased proliferation, altered differentiation and ductal dysplasia. Development 2007, 134, 1231-1242. [CrossRef] [PubMed]
168. Kasper, M.; Jaks, V.; Fiaschi, M.; Toftgård, R. Hedgehog signalling in breast cancer. Carcinogenesis 2009, 30, 903-911. [CrossRef] [PubMed]
169. Zhang, C.; Li, C.; He, F.; Cai, Y.; Yang, H. Identification of CD44+CD24+ gastric cancer stem cells. J. Cancer Res. Clin. Oncol. 2011, 137, 1679-1686. [CrossRef] [PubMed]
170. Humphries, A.; Wright, N.A. Colonic crypt organization and tumorigenesis. Nat. Rev. Cancer 2008, 8, 415-424. [CrossRef] [PubMed]
171. Li, C.; Lee, C.J.; Simeone, D.M. Identification of human pancreatic cancer stem cells. Methods Mol. Biol. 2009, 568, 161-173. [PubMed]
172. Kelleher, F.C. Hedgehog signaling and therapeutics in pancreatic cancer. Carcinogenesis 2011, 32, 445-451. [CrossRef] [PubMed]
173. Onishi, H.; Katano, M. Hedgehog signaling pathway as a new therapeutic target in pancreatic cancer. World J. Gastroenterol. 2014, 20, 2335-2342. [CrossRef] [PubMed]
174. Kumar, S.K.; Roy, I.; Anchoori, R.K.; Fazli, S.; Maitra, A.; Beachy, P.A.; Khan, S.R. Targeted inhibition of hedgehog signaling by cyclopamine prodrugs for advanced prostate cancer. Bioorg. Med. Chem. 2008, 16, 2764-2768. [CrossRef] [PubMed]
175. Ni, J.; Cozzi, P.; Hao, J.; Duan, W.; Graham, P.; Kearsley, J.; Li, Y. Cancer stem cells in prostate cancer chemoresistance. Curr. Cancer Drug Targets 2014, 14, 225-240. [CrossRef] [PubMed]
176. Watkins, D.N.; Berman, D.M.; Baylin, S.B. Hedgehog signaling: progenitor phenotype in small-cell lung cancer. Cell cycle 2003, 2, 196-198. [CrossRef] [PubMed]
177. Daniel, V.C.; Peacock, C.D.; Watkins, D.N. Developmental signalling pathways in lung cancer. Respirology 2006, 11, 234-240. [CrossRef] [PubMed]
178. Justilien, V.; Fields, A.P. Molecular pathways: Novel approaches for improved therapeutic targeting of hedgehog signaling in cancer stem cells. Clin. Cancer Res. 2015, 21, 505-513. [PubMed]
179. Schatton, T.; Frank, M.H. Cancer stem cells and human malignant melanoma. Pigment Cell Melanoma Res. 2008, 21, 39-55. [PubMed]
180. O'Reilly, K.E.; de Miera, E.V.S.; Segura, M.F.; Friedman, E.; Poliseno, L.; Han, S.W.; Zhong, J.; Zavadil, J.; Pavlick, A.; Hernando, E.; et al. Hedgehog pathway blockade inhibits melanoma cell growth in vitro and in vivo. Pharmaceuticals 2013, 6, 1429-1450. [PubMed]
181. Sun, G.G.; Wang, Y.D.; Liu, Q.; Hu, W.N. Expression of Wip1 in kidney carcinoma and its correlation with tumor metastasis and clinical significance. Pathol. Oncol. Res. 2015, 21, 219-224. [PubMed]
182. Yang, D.H.; He, J.A.; Li, J.; Ma, W.F.; Hu, X.H.; Xin, S.J.; Duan, Z.Q. Expression of proto-oncogene Wip1 in breast cancer and its clinical significance. Natl. Med. J. China 2010, 90, 519-522.
183. Harrison, M.; Li, J.; Degenhardt, Y.; Hoey, T.; Powers, S. Wip1-deficient mice are resistant to common cancer genes. Trends Mol. Med. 2004, 10, 359-361. [CrossRef] [PubMed]
184. Li, Z.T.; Zhang, L.; Gao, X.Z.; Jiang, X.H.; Sun, L.Q. Expression and significance of the Wip1 proto-oncogene in colorectal cancer. Asian Pac. J. Cancer Prev. 2013, 14, 1975-1979. [CrossRef] [PubMed]
185. Liu, S.; Qi, L.; Han, W.; Wan, X.; Jiang, S.; Li, Y.; Xie, Y.; Liu, L.; Zeng, F.; Liu, Z.; et al. Overexpression of Wip1 is associated with biologic behavior in human clear cell renal cell carcinoma. PLoS ONE 2014, 9, e110218. [CrossRef] [PubMed]