Targeting hedgehog signaling in cancer: Research and clinical developments

OncoTargets and Therapy

Volumn 6, Issue , 2013, Pages 1425-1435

  Xie, Jingwu ^a   Bartels, Christopher M ^a   Barton, Scott W ^a   Gu, Dongsheng ^a  

^a INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Animal model; Cancer; Clinical trials; Hedgehog; Ptch1; Signal transduction; Smoothened

Indexed keywords

ANTINEOPLASTIC AGENT; BMS 833923; DOCETAXEL; GEMCITABINE; LEQ 506; LY 2940680; PF 04449913; PROTEIN PATCHED 1; SARIDEGIB; SMOOTHENED PROTEIN; SONIC HEDGEHOG PROTEIN; SONIDEGIB; TAK 441; TAMOXIFEN; TRANSCRIPTION FACTOR GLI1; UNCLASSIFIED DRUG; VISMODEGIB;

ADVANCED CANCER; BASAL CELL CARCINOMA; BASAL CELL NEVUS SYNDROME; BREAST CANCER; CANCER RADIOTHERAPY; CANCER RECURRENCE; CANCER RESEARCH; CANCER STEM CELL; CARCINOGENESIS; CHEMORADIOTHERAPY; DRUG TARGETING; GENE MUTATION; HEAD AND NECK SQUAMOUS CELL CARCINOMA; HUMAN; LEUKEMIA; LUNG SMALL CELL CANCER; LYMPH NODE METASTASIS; MEDULLOBLASTOMA; METASTASIS; NONHUMAN; PANCREAS CANCER; PROSTATE CANCER; REVIEW; SIGNAL TRANSDUCTION; SOLID TUMOR; TUMOR MICROENVIRONMENT; TUMOR PROMOTION; TUMOR RECURRENCE;

EID: 84886879974     PISSN: 11786930     EISSN: None     Source Type: Journal    
DOI: 10.2147/OTT.S34678     Document Type: Review

References (200)

1. Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature. 1980;287(5785):795-801.
2. Krauss S, Concordet JP, Ingham PW. A functionally conserved homolog of the Drosophila segment polarity gene hh is expressed in tissues with polarizing activity in zebrafish embryos. Cell. 1993;75(7):1431-1444.
3. Echelard Y, Epstein DJ, St-Jacques B, et al. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell. 1993;75(7):1417-1430.
4. Riddle RD, Johnson RL, Laufer E, Tabin C. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell. 1993;75(7):1401-1416.
5. Chang DT, López A, von Kessler DP, et al. Products, genetic linkage and limb patterning activity of a murine hedgehog gene. Development. 1994;120(11):3339-3353.
6. Roelink H, Augsburger A, Heemskerk J, et al. Floor plate and motor neuron induction by vhh-1, a vertebrate homolog of hedgehog expressed by the notochord. Cell. 1994;76(4):761-775.
7. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008;8(10):743-754.
8. Xie J. Hedgehog signaling in prostate cancer. Future Oncol. 2005;1(3): 331-338.
9. Xie J. Hedgehog signaling pathway: development of antagonists for cancer therapy. Curr Oncol Rep. 2008;10(2):107-113.
10. Xie J. Molecular biology of basal and squamous cell carcinomas. Adv Exp Med Biol. 2008;624:241-251.
11. Jiang J, Hui CC. Hedgehog signaling in development and cancer. Dev Cell. 2008;15(6):801-812.
12. Ingham PW, Placzek M. Orchestrating ontogenesis: variations on a theme by sonic hedgehog. Nat Rev Genet. 2006;7(11):841-850.
13. Sasaki H, Hui C, Nakafuku M, Kondoh H. A binding site for Gli proteins is essential for HNF-3beta floor plate enhancer activity in transgenics and can respond to Shh in vitro. Development. 1997;124(7):1313-1322.
14. Kinzler KW, Vogelstein B. The Gli gene encodes a nuclear protein which binds specific sequences in the human genome. Mol Cell Biol. 1990;10(2):634-642.
15. McMahon AP, Ingham PW, Tabin CJ. Developmental roles and clinical significance of hedgehog signaling. Curr Top Dev Biol. 2003;53:1-114.
16. Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 2001;15(23):3059-3087.
17. Taipale J, Beachy PA. The hedgehog and Wnt signalling pathways in cancer. Nature. 2001;411(6835):349-354.
18. Lee JJ, Ekker SC, von Kessler DP, Porter JA, Sun BI, Beachy PA. Autoproteolysis in hedgehog protein biogenesis. Science. 1994; 266(5190):1528-1537.
19. Porter JA, Young KE, Beachy PA. Cholesterol modification of hedgehog signaling proteins in animal development. Science. 1996;274(5285):255-259.
20. Porter JA, von Kessler DP, Ekker SC, et al. The product of hedgehog autoproteolytic cleavage active in local and long-range signalling. Nature. 1995;374(6520):363-366.
21. Buglino JA, Resh MD. Hhat is a palmitoylacyltransferase with specificity for N-palmitoylation of sonic hedgehog. J Biol Chem. 2008;283(32):22076-22088.
22. Kawakami T, Kawcak T, Li YJ, Zhang W, Hu Y, Chuang PT. Mouse dispatched mutants fail to distribute hedgehog proteins and are defective in hedgehog signaling. Development. 2002;129(24):5753-5765.
23. Ma Y, Erkner A, Gong R, et al. Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Cell. 2002;111(1):63-75.
24. Caspary T, García-García MJ, Huangfu D, et al. Mouse dispatched homolog1 is required for long-range, but not juxtacrine, Hh signaling. Curr Biol. 2002;12(18):1628-1632.
25. Dierker T, Dreier R, Petersen A, Bordych C, Grobe K. Heparan sulfate-modulated, metalloprotease-mediated sonic hedgehog release from producing cells. J Biol Chem. 2009;284(12):8013-8022.
26. Beckett K, Franch-Marro X, Vincent JP. Glypican-mediated endocytosis of hedgehog has opposite effects in flies and mice. Trends Cell Biol. 2008;18(8):360-363.
27. Lum L, Yao S, Mozer B, et al. Identification of hedgehog pathway components by RNAi in Drosophila cultured cells. Science. 2003;299(5615):2039-2045.
28. Baena-Lopez LA, Rodriguez I, Baonza A. The tumor suppressor genes dachsous and fat modulate different signalling pathways by regulating dally and dally-like. Proc Natl Acad Sci U S A. 2008;105(28): 9645-9650.
29. Toyoda H, Kinoshita-Toyoda A, Fox B, Selleck SB. Structural analysis of glycosaminoglycans in animals bearing mutations in sugarless, sulfateless, and tout-velu. Drosophila homologues of vertebrate genes encoding glycosaminoglycan biosynthetic enzymes. J Biol Chem. 2000;275(29):21856-21861.
30. Bellaiche Y, The I, Perrimon N. Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion. Nature. 1998;394(6688):85-88.
31. Koziel L, Kunath M, Kelly OG, Vortkamp A. Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Dev Cell. 2004;6(6):801-813.
32. Stone DM, Hynes M, Armanini M, et al. The tumour-suppressor gene patched encodes a candidate receptor for sonic hedgehog. Nature. 1996;384(6605):129-134.
33. Taipale J, Cooper MK, Maiti T, Beachy PA. Patched acts catalytically to suppress the activity of smoothened. Nature. 2002;418(6900): 892-897.
34. Chuang PT, McMahon AP. Vertebrate hedgehog signalling modulated by induction of a hedgehog-binding protein. Nature. 1999;397(6720): 617-621.
35. Martinelli DC, Fan CM. Gas1 extends the range of hedgehog action by facilitating its signaling. Genes Dev. 2007;21(10):1231-1243.
36. Seppala M, Depew MJ, Martinelli DC, Fan CM, Sharpe PT, Cobourne MT. Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog. J Clin Invest. 2007;117(6): 1575-1584.
37. Allen BL, Tenzen T, McMahon AP. The hedgehog-binding proteins Gas1 and Cdo cooperate to positively regulate Shh signaling during mouse development. Genes Dev. 2007;21(10):1244-1257.
38. Okada A, Charron F, Morin S, et al. Boc is a receptor for sonic hedgehog in the guidance of commissural axons. Nature. 2006;444(7117): 369-373.
39. Tenzen T, Allen BL, Cole F, Kang JS, Krauss RS, McMahon AP. The cell surface membrane proteins Cdo and Boc are components and targets of the hedgehog signaling pathway and feedback network in mice. Dev Cell. 2006;10(5):647-656.
40. Zhang W, Kang JS, Cole F, Yi MJ, Krauss RS. Cdo functions at multiple points in the sonic hedgehog pathway, and Cdo-deficient mice accurately model human holoprosencephaly. Dev Cell. 2006;10(5): 657-665.
41. Yao S, Lum L, Beachy P. The ihog cell-surface proteins bind hedgehog and mediate pathway activation. Cell. 2006;125(2):343-357.
42. Capurro MI, 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(5):700-711.
43. Li F, Shi W, Capurro M, Filmus J. Glypican-5 stimulates rhabdomyosarcoma cell proliferation by activating hedgehog signaling. J Cell Biol. 2011;192(4):691-704.
44. Witt RM, Hecht ML, Pazyra-Murphy MF, et al. Heparan sulfate proteoglycans containing a glypican 5 core and 2-O-sulfo-iduronic acid function as sonic hedgehog co-receptors to promote proliferation. J Biol Chem. 2013;288(36):26275-26288.
45. Sanchez-Hernandez D, Sierra J, Ortigao-Farias JR, Guerrero I. The WIF domain of the human and Drosophila Wif-1 secreted factors confers specificity for Wnt or hedgehog. Development. 2012;139(20): 3849-3858.
46. Avanesov A, Honeyager SM, Malicki J, Blair SS. The role of glypicans in Wnt inhibitory factor-1 activity and the structural basis of Wif1's effects on Wnt and hedgehog signaling. PLoS Genetics. 2012;8(2):e1002503.
47. Yavari A, Nagaraj R, Owusu-Ansah E, et al. Role of lipid metabolism in smoothened derepression in hedgehog signaling. Dev Cell. 2010;19(1):54-65.
48. Khaliullina H, Panakova D, Eugster C, Riedel F, Carvalho M, Eaton S. Patched regulates smoothened trafficking using lipoprotein-derived lipids. Development. 2009;136(24):4111-4121.
49. Callejo A, Culi J, Guerrero I. Patched, the receptor of hedgehog, is a lipoprotein receptor. Proc Natl Acad Sci U S A. 2008;105(3):912-917.
50. Bijlsma MF, Spek CA, Zivkovic D, van de Water S, Rezaee F, Peppelenbosch MP. Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion. PLoS Biol. 2006;4(8):e232.
51. Wang Y, Davidow L, Arvanites AC, et al. Glucocorticoid compounds modify smoothened localization and hedgehog pathway activity. Chem Bio. 2012;19(8):972-982.
52. Philipp M, Fralish GB, Meloni AR, et al. Smoothened signaling in vertebrates is facilitated by a G protein-coupled receptor kinase. Mol Biol Cell. 2008;19(12):5478-5489.
53. Ogden SK, Fei DL, Schilling NS, Ahmed YF, Hwa J, Robbins DJ. G protein Galphai functions immediately downstream of smoothened in hedgehog signalling. Nature. 2008;456(7224):967-970.
54. Molnar C, Holguin H, Mayor F Jr, Ruiz-Gomez A, de Celis JF. The G protein-coupled receptor regulatory kinase GPRK2 participates in hedgehog signaling in Drosophila. Proc Natl Acad Sci U S A. 2007;104(19):7963-7968.
55. Riobo NA, Saucy B, Dilizio C, Manning DR. Activation of heterotrimeric G proteins by smoothened. Proc Natl Acad Sci U S A. 2006;103(33):12607-12612.
56. Douglas AE, Heim JA, Shen F, et al. The alpha subunit of the G protein G13 regulates activity of one or more Gli transcription factors independently of smoothened. J Biol Chem. 2011;286(35):30714-30722.
57. Zhao Y, Tong C, Jiang J. Hedgehog regulates smoothened activity by inducing a conformational switch. Nature. 2007;450(7167):252-258.
58. Corbit KC, Aanstad P, Singla V, Norman AR, Stainier DY, Reiter JF. Vertebrate smoothened functions at the primary cilium. Nature. 2005;437(7061):1018-1021.
59. Huangfu D, Liu A, Rakeman AS, Murcia NS, Niswander L, Anderson KV. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature. 2003;426(6962):83-87.
60. May SR, Ashique AM, Karlen M, et al. Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli. Dev Biol. 2005;287(2):378-389.
61. Huangfu D, Anderson KV. Cilia and hedgehog responsiveness in the mouse. Proc Natl Acad Sci U S A. 2005;102(32):11325-11330.
62. Zhang Q, Davenport JR, Croyle MJ, Haycraft CJ, Yoder BK. Disruption of IFT results in both exocrine and endocrine abnormalities in the pancreas of Tg737(orpk) mutant mice. Lab Invest. 2005;85(1):45-64.
63. Hoover AN, Wynkoop A, Zeng H, Jia J, Niswander LA, Liu A. C2cd3 is required for cilia formation and hedgehog signaling in mouse. Development. 2008;135(24):4049-4058.
64. Hillman RT, Feng BY, Ni J, et al. Neuropilins are positive regulators of hedgehog signal transduction. Genes Dev. 2011;25(22):2333-2346.
65. Snuderl M, Batista A, Kirkpatrick ND, et al. Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell. 2013;152(5):1065-1076.
66. Cao Y, Wang L, Nandy D, et al. Neuropilin-1 upholds dedifferentiation and propagation phenotypes of renal cell carcinoma cells by activating Akt and sonic hedgehog axes. Cancer Res. 2008;68(21):8667-8672.
67. Parra LM, Zou Y. Sonic hedgehog induces response of commissural axons to Semaphorin repulsion during midline crossing. Nat Neurosci. 2010;13(1):29-35.
68. Cheung HO, Zhang X, Ribeiro A, et al. The kinesin protein Kif7 is a critical regulator of Gli transcription factors in mammalian hedgehog signaling. Sci Signal. 2009;2(76):ra29.
69. Endoh-Yamagami S, Evangelista M, Wilson D, et al. The mammalian Cos2 homolog Kif7 plays an essential role in modulating Hh signal transduction during development. Curr Biol. 2009;19(15):1320-1326.
70. Law KK, Makino S, Mo R, Zhang X, Puviindran V, Hui CC. Antagonistic and cooperative actions of Kif7 and Sufu define graded intracellular Gli activities in hedgehog signaling. PLoS One. 2012;7(11):e50193.
71. Li ZJ, Nieuwenhuis E, Nien W, et al. Kif7 regulates Gli2 through Sufu-dependent and -independent functions during skin development and tumorigenesis. Development. 2012;139(22):4152-4161.
72. Hsu SH, Zhang X, Yu C, et al. Kif7 promotes hedgehog signaling in growth plate chondrocytes by restricting the inhibitory function of Sufu. Development. 2011;138(17):3791-3801.
73. Wilson CW, Nguyen CT, Chen MH, et al. Fused has evolved divergent roles in vertebrate hedgehog signalling and motile ciliogenesis. Nature. 2009;459(7243):98-102.
74. Merchant M, Evangelista M, Luoh SM, et al. Loss of the serine/threonine kinase fused results in postnatal growth defects and lethality due to progressive hydrocephalus. Mol Cell Biol. 2005;25(16):7054-7068.
75. Chen MH, Gao N, Kawakami T, Chuang PT. Mice deficient in the fused homolog do not exhibit phenotypes indicative of perturbed hedgehog signaling during embryonic development. Mol Cell Biol. 2005;25(16): 7042-7053.
76. Eggenschwiler JT, Espinoza E, Anderson KV. Rab23 is an essential negative regulator of the mouse sonic hedgehog signalling pathway. Nature. 2001;412(6843):194-198.
77. Reiter JF, Skarnes WC. Tectonic, a novel regulator of the hedgehog pathway required for both activation and inhibition. Genes Dev. 2006;20(1):22-27.
78. Li C, Chi S, Xie J. Hedgehog signaling in skin cancers. Cell Signal. 2011;23(8):1235-1243.
79. Huang S, Yang L, An Y, et al. Expression of hedgehog signaling molecules in lung cancer. Acta Histochem. 2011;113(5):564-569.
80. Kinzler KW, Ruppert JM, Bigner SH, Vogelstein B. The Gli gene is a member of the Kruppel family of zinc finger proteins. Nature. 1988;332(6162):371-374.
81. Ruppert JM, Kinzler KW, Wong AJ, et al. The Gli-Kruppel family of human genes. Mol Cell Biol. 1988;8(8):3104-3113.
82. Barnfield PC, Zhang X, Thanabalasingham V, Yoshida M, Hui CC. Negative regulation of Gli1 and Gli2 activator function by suppressor of fused through multiple mechanisms. Differentiation. 2005;73(8): 397-405.
83. Sheng T, Chi S, Zhang X, Xie J. Regulation of Gli1 localization by the cAMP/protein kinase A signaling axis through a site near the nuclear localization signal. J Biol Chem. 2006;281(1):9-12.
84. Kogerman P, Grimm T, Kogerman L, et al. Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1. Nat Cell Biol. 1999;1(5):312-319.
85. Stecca B, Mas C, Clement V, et al. Melanomas require hedghog-Gli signaling regulated by interactions between Gli1 and the RAS-MEK/AKT pathways. Proc Natl Acad Sci U S A. 2007;104(14): 5895-5900.
86. Pan Y, Bai CB, Joyner AL, Wang B. Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. Mol Cell Biol. 2006;26(9):3365-3377.
87. Huntzicker EG, Estay IS, Zhen H, Lokteva LA, Jackson PK, Oro AE. Dual degradation signals control Gli protein stability and tumor formation. Genes Dev. 2006;20(3):276-281.
88. Wang B, Li Y. Evidence for the direct involvement of βTrCP in Gli3 protein processing. Proc Natl Acad Sci U S A. 2006;103(1):33-38.
89. Di Marcotullio L, Ferretti E, Greco A, et al. Numb is a suppressor of hedgehog signalling and targets Gli1 for Itch-dependent ubiquitination. Nat Cell Biol. 2006;8(12):1415-1423.
90. Jiang J. Regulation of Hh/Gli signaling by dual ubiquitin pathways. Cell Cycle. 2006;5(21):2457-2463.
91. Canettieri G, Di Marcotullio L, Greco A, et al. Histone deacetylase and Cullin3-REN(KCTD11) ubiquitin ligase interplay regulates hedgehog signalling through Gli acetylation. Nat Cell Biol. 2010;12(2): 132-142.
92. Coni S, Antonucci L, D'Amico D, et al. Gli2 acetylation at lysine 757 regulates hedgehog-dependent transcriptional output by preventing its promoter occupancy. PLoS One. 2013;8(6):e65718.
93. Han L, Pan Y, Wang B. Small ubiquitin-like modifier (SUMO) modification inhibits Gli2 protein transcriptional activity in vitro and in vivo. J Biol Chem. 2012;287(24):20483-20489.
94. Zhang Q, Shi Q, Chen Y, et al. Multiple Ser/Thr-rich degrons mediate the degradation of Ci/Gli by the Cul3-HIB/SPOP E3 ubiquitin ligase. Proc Natl Acad Sci U S A. 2009;106(50):21191-21196.
95. Cheng SY, Bishop JM. Suppressor of fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex. Proc Natl Acad Sci U S A. 2002;99(8):5442-5447.
96. Wang C, Pan Y, Wang B. Suppressor of fused and Spop regulate the stability, processing and function of Gli2 and Gli3 full-length activators but not their repressors. Development. 2010;137(12):2001-2009.
97. Li ZJ, Mack SC, Mak TH, Angers S, Taylor MD, Hui CC. Evasion of p53 and G/M checkpoints are characteristic of Hh-driven basal cell carcinoma. Oncogene. Epub June 10, 2013.
98. Jagani Z, Mora-Blanco EL, Sansam CG, et al. Loss of the tumor suppressor Snf5 leads to aberrant activation of the hedgehog-Gli pathway. Nat Med. 2010;16(12):1429-1433.
99. Atwood SX, Li M, Lee A, Tang JY, Oro AE. Gli activation by atypical protein kinase C iota/lambda regulates the growth of basal cell carcinomas. Nature. 2013;494(7438):484-488.
100. Yang L, Xie G, Fan Q, Xie J. Activation of the hedgehog-signaling pathway in human cancer and the clinical implications. Oncogene. 2010;29(4):469-481.
101. Hahn H, Wicking C, Zaphiropoulous PG, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996;85(6):841-851.
102. Johnson RL, Rothman AL, Xie J, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 1996;272(5268):1668-1671.
103. Epstein E Jr. Genetic determinants of basal cell carcinoma risk. Med Pediatr Oncol. 2001;36(5):555-558.
104. Gorlin RJ. Nevoid basal-cell carcinoma syndrome. Medicine. 1987; 66(2):98-113.
105. Xie J, Murone M, Luoh SM, et al. Activating smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998;391(6662):90-92.
106. Lam CW, Xie J, To KF, et al. A frequent activated smoothened mutation in sporadic basal cell carcinomas. Oncogene. 1999;18(3):833-836.
107. Reifenberger J, Wolter M, Knobbe CB, et al. Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. Br J Dermatol. 2005;152(1):43-51.
108. Reifenberger J, Wolter M, Weber RG, et al. 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(9):1798-1803.
109. Couve-Privat S, Bouadjar B, Avril MF, Sarasin A, Daya-Grosjean L. Significantly high levels of ultraviolet-specific mutations in the smoothened gene in basal cell carcinomas from DNA repair-deficient xeroderma pigmentosum patients. Cancer Res. 2002;62(24):7186-7189.
110. Tostar U, Malm CJ, Meis-Kindblom JM, Kindblom LG, Toftgard R, Unden AB. 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(1):17-25.
111. Pressey JG, Anderson JR, Crossman DK, Lynch JC, Barr FG. Hedgehog pathway activity in pediatric embryonal rhabdomyosarcoma and undifferentiated sarcoma: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2011;57(6):930-938.
112. Clark VE, Erson-Omay EZ, Serin A, et al. Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science. 2013;339(6123):1077-1080.
113. Aavikko M, Li SP, Saarinen S, et al. Loss of SUFU function in familial multiple meningioma. Am J Hum Genet. 2012;91(3):520-526.
114. Kijima C, Miyashita T, Suzuki M, Oka H, Fujii K. Two cases of nevoid basal cell carcinoma syndrome associated with meningioma caused by a PTCH1 or SUFU germline mutation. Fam Cancer. 2012;11(4): 565-570.
115. Fei DL, Sanchez-Mejias A, Wang Z, et al. Hedgehog signaling regulates bladder cancer growth and tumorigenicity. Cancer Res. 2012;72(17):4449-4458.
116. Rodriguez-Blanco J, Schilling NS, Tokhunts R, et al. The hedgehog processing pathway is required for NSCLC growth and survival. Oncogene. 2013;32(18):2335-2345.
117. Shin K, Lee J, Guo N, et al. Hedgehog/Wnt feedback supports regenerative proliferation of epithelial stem cells in bladder. Nature. 2011;472(7341):110-114.
118. Hahn H, Wojnowski L, Zimmer AM, Hall J, Miller G, Zimmer A. Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome. Nat Med. 1998;4(5):619-622.
119. Hatley ME, Tang W, Garcia MR, et al. A mouse model of rhabdomyosarcoma originating from the adipocyte lineage. Cancer Cell. 2012;22(4):536-546.
120. Ignatius MS, Chen E, Elpek NM, et al. In vivo imaging of tumor-propagating cells, regional tumor heterogeneity, and dynamic cell movements in embryonal rhabdomyosarcoma. Cancer Cell. 2012;21(5):680-693.
121. Nitzki F, Zibat A, Frommhold A, et al. Uncommitted precursor cells might contribute to increased incidence of embryonal rhabdomyosarcoma in heterozygous patched1-mutant mice. Oncogene. 2011;30(43):4428-4436.
122. Pelczar P, Zibat A, van Dop WA, et al. Inactivation of patched1 in mice leads to development of gastrointestinal stromal-like tumors that express PDGFRα but not kit. Gastroenterology. 2013;144(1):134-144.
123. Park KS, Martelotto LG, Peifer M, et al. A crucial requirement for hedgehog signaling in small cell lung cancer. Nat Med. 2011;17(11): 1504-1508.
124. Wang DH, Clemons NJ, Miyashita T, et al. Aberrant epithelial-mesenchymal hedgehog signaling characterizes Barrett's metaplasia. Gastroenterology. 2010;138(5):1810-1822.
125. Yang L, Wang LS, Chen XL, et al. Hedgehog signaling activation in the development of squamous cell carcinoma and adenocarcinoma of esophagus. Int J Biochem Mol Biol. 2012;3(1):46-57.
126. Tian H, Callahan CA, DuPree KJ, et al. Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc Natl Acad Sci U S A. 2009;106(11):4254-4259.
127. Mao J, Ligon KL, Rakhlin EY, et al. A novel somatic mouse model to survey tumorigenic potential applied to the hedgehog pathway. Cancer Res. 2006;66(20):10171-10178.
128. Aszterbaum M, Epstein J, Oro A, et al. Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice. Nat Med. 1999;5(11):1285-1291.
129. Goodrich LV, Milenkovic L, Higgins KM, Scott MP. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science. 1997;277(5329):1109-1113.
130. Feldmann G, Dhara S, Fendrich V, et al. Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res. 2007;67(5): 2187-2196.
131. Bailey JM, Swanson BJ, Hamada T, et al. Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin Cancer Res. 2008;14(19): 5995-6004.
132. Chang Q, Foltz WD, Chaudary N, Hill RP, Hedley DW. Tumor-stroma interaction in orthotopic primary pancreatic cancer xenografts during hedgehog pathway inhibition. Int J Cancer. 2013;133(1):225-234.
133. Tang SN, Fu J, Nall D, Rodova M, Shankar S, Srivastava RK. Inhibition of sonic hedgehog pathway and pluripotency maintaining factors regulate human pancreatic cancer stem cell characteristics. Int J Cancer. 2012;131(1):30-40.
134. Feldmann G, Fendrich V, McGovern K, et al. An orally bioavailable small-molecule inhibitor of hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer. Mol Cancer Ther. 2008;7(9): 2725-2735.
135. Gu D, Liu H, Su GH, et al. Combining hedgehog signaling inhibition with focal irradiation on reduction of pancreatic cancer metastasis. Mol Cancer Ther. 2013;12(6):1038-1048.
136. Bailey JM, Mohr AM, Hollingsworth MA. Sonic hedgehog paracrine signaling regulates metastasis and lymphangiogenesis in pancreatic cancer. Oncogene. 2009;28(40):3513-3525.
137. Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324(5933):1457-1461.
138. Zhao C, Chen A, Jamieson CH, et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature. 2009;458(7239):776-779.
139. Boyd AL, Salci KR, Shapovalova Z, McIntyre BA, Bhatia M. Nonhematopoietic cells represent a more rational target of in vivo hedgehog signaling affecting normal or acute myeloid leukemia progenitors. Exp Hematol. Epub June 6, 2013.
140. Romer JT, Kimura H, Magdaleno S, et al. Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/-)p53(-/-) mice. Cancer Cell. 2004;6(3):229-240.
141. Gu D, Fan Q, Zhang X, Xie J. A role for transcription factor STAT3 signaling in oncogene smoothened-driven carcinogenesis. J Biol Chem. 2012;287(45):38356-38366.
142. Xie J, Aszterbaum M, Zhang X, et al. A role of PDGFRalpha in basal cell carcinoma proliferation. Proc Natl Acad Sci U S A. 2001;98(16):9255-9259.
143. Johnson RW, Nguyen MP, Padalecki SS, et al. TGF-beta promotion of Gli2-induced expression of parathyroid hormone-related protein, an important osteolytic factor in bone metastasis, is independent of canonical hedgehog signaling. Cancer Res. 2011;71(3):822-831.
144. Keysar SB, Le PN, Anderson RT, et al. Hedgehog signaling alters reliance on EGF receptor signaling and mediates anti-EGFR therapeutic resistance in head and neck cancer. Cancer Res. 2013;73(11): 3381-3392.
145. Eberl M, Klingler S, Mangelberger D, et al. Hedgehog-EGFR cooperation response genes determine the oncogenic phenotype of basal cell carcinoma and tumour-initiating pancreatic cancer cells. EMBO Mol Med. 2012;4(3):218-233.
146. Fan Q, He M, Sheng T, et al. Requirement of TGFbeta signaling for SMO-mediated carcinogenesis. J Biol Chem. 2010;285(47):36570-36576.
147. Wang Y, Ding Q, Yen CJ, et al. The crosstalk of mTOR/S6K1 and hedgehog pathways. Cancer Cell. 2012;21(3):374-387.
148. Shi S, Deng YZ, Zhao JS, et al. RACK1 promotes non-small-cell lung cancer tumorigenicity through activating sonic hedgehog signaling pathway. J Biol Chem. 2012;287(11):7845-7858.
149. Hsieh A, Ellsworth R, Hsieh D. Hedgehog/Gli1 regulates IGF dependent malignant behaviors in glioma stem cells. J Cell Physiol. 2011;226(4):1118-1127.
150. Mainwaring LA, Kenney AM. Divergent functions for eIF4E and S6 kinase by sonic hedgehog mitogenic signaling in the developing cerebellum. Oncogene. 2011;30(15):1784-1797.
151. Fernandez LA, Squatrito M, Northcott P, et al. Oncogenic YAP promotes radioresistance and genomic instability in medulloblastoma through IGF2-mediated Akt activation. Oncogene. 2012;31(15):1923-1937.
152. Heller E, Hurchla MA, Xiang J, et al. Hedgehog signaling inhibition blocks growth of resistant tumors through effects on tumor microenvironment. Cancer Res. 2012;72(4):897-907.
153. Abbruzzese JL, National Institutes of Health (US). Are there new targets for pancreatic cancer therapeutics?; 2007. Available from: http://videocast.nih.gov/launch.asp?13834. Accessed September 10, 2013.
154. Inaguma S, Kasai K, Ikeda H. Gli1 facilitates the migration and invasion of pancreatic cancer cells through MUC5AC-mediated attenuation of E-cadherin. Oncogene. 2011;30(6):714-723.
155. Joost S, Almada LL, Rohnalter V, et al. Gli1 inhibition promotes epithelial-to-mesenchymal transition in pancreatic cancer cells. Cancer Res. 2012;72(1):88-99.
156. Li X, Deng W, Lobo-Ruppert SM, Ruppert JM. Gli1 acts through snail and E-cadherin to promote nuclear signaling by beta-catenin. Oncogene. 2007;26(31):4489-4498.
157. Javelaud D, Pierrat MJ, Mauviel A. Crosstalk between TGF-beta and hedgehog signaling in cancer. FEBS Lett. 2012;586(14):2016-2025.
158. Von Hoff DD, LoRusso PM, Rudin CM, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med. September 17, 2009;361(12):1164-1172.
159. Graham RA, Lum BL, Cheeti S, et al. Pharmacokinetics of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors: the role of alpha-1-acid glycoprotein binding. Clin Cancer Res. 2011;17(8):2512-2520.
160. LoRusso PM, Rudin CM, Reddy JC, et al. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res. 2011;17(8):2502-2511.
161. Lorusso PM, Jimeno A, Dy G, et al. Pharmacokinetic dose-scheduling study of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors. Clin Cancer Res. 2011;17(17):5774-5782.
162. Metcalfe C, de Sauvage FJ. Hedgehog fights back: mechanisms of acquired resistance against smoothened antagonists. Cancer Res. 2011;71(15):5057-5061.
163. Tang T, Tang JY, Li D, et al. Targeting superficial or nodular basal cell carcinoma with topically formulated small molecule inhibitor of smoothened. Clin Cancer Res. 2011;17(10):3378-3387.
164. Skvara H, Kalthoff F, Meingassner JG, et al. Topical treatment of basal cell carcinomas in nevoid basal cell carcinoma syndrome with a smoothened inhibitor. J Invest Dermatol. 2011;131(8): 1735-1744.
165. Buonamici S, Williams J, Morrissey M, et al. Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci Transl Med. 2010;2(51):51ra70.
166. Dijkgraaf GJ, Alicke B, Weinmann L, et al. Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance. Cancer Res. 2011;71(2): 435-444.
167. Kim J, Aftab BT, Tang JY, et al. Itraconazole and arsenic trioxide inhibit hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer Cell. 2013;23(1):23-34.
168. Kim J, Tang JY, Gong R, et al. Itraconazole, a commonly used antifungal that inhibits hedgehog pathway activity and cancer growth. Cancer Cell. 2010;17(4):388-399.
169. Tang JY, Xiao TZ, Oda Y, et al. Vitamin D3 inhibits hedgehog signaling and proliferation in murine basal cell carcinomas. Cancer Prev Res (Phila). 2011;4(5):744-751.
170. Chenna V, Hu C, Pramanik D, et al. A polymeric nanoparticle encapsulated small-molecule inhibitor of hedgehog signaling (NanoHHI) bypasses secondary mutational resistance to smoothened antagonists. Mol Cancer Ther. 2012;11(1):165-173.
171. Rohner A, Spilker ME, Lam JL, et al. Effective targeting of hedgehog signaling in a medulloblastoma model with PF-5274857, a potent and selective smoothened antagonist that penetrates the blood-brain barrier. Mol Cancer Ther. 2012;11(1):57-65.
172. Lee MJ, Hatton BA, Villavicencio EH, et al. Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model. Proc Natl Acad Sci U S A. 2012;109(20):7859-7864.
173. Rudin CM, Hann CL, Laterra J, et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med. 2009;361(12):1173-1178.
174. Fulda S. Molecular targeted therapies for rhabdomyosarcoma: focus on hedgehog and apoptosis signaling. Klinische Padiatrie. 2013;225(3): 115-119.
175. Dierks C, Beigi R, Guo GR, et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on hedgehog pathway activation. Cancer Cell. 2008;14(3):238-249.
176. Read TA, Fogarty MP, Markant SL, et al. Identification of CD15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma. Cancer Cell. 2009;15(2):135-147.
177. Hofmann I, Stover EH, Cullen DE, et al. Hedgehog signaling is dispensable for adult murine hematopoietic stem cell function and hematopoiesis. Cell Stem Cell. 2009;4(6):559-567.
178. Gao J, Graves S, Koch U, et al. Hedgehog signaling is dispensable for adult hematopoietic stem cell function. Cell Stem Cell. 2009;4(6): 548-558.
179. Siggins SL, Nguyen NY, McCormack MP, et al. The hedgehog receptor patched1 regulates myeloid and lymphoid progenitors by distinct cell-extrinsic mechanisms. Blood. 2009;114(5):995-1004.
180. Merchant A, Joseph G, Wang Q, Brennan S, Matsui W. Gli1 regulates the proliferation and differentiation of HSCs and myeloid progenitors. Blood. 2010;115(12):2391-2396.
181. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105-111.
182. Sims-Mourtada J, Izzo JG, Apisarnthanarax S, et al. Hedgehog: an attribute to tumor regrowth after chemoradiotherapy and a target to improve radiation response. Clin Cancer Res. 2006;12(21):6565-6572.
183. Yoshikawa R, Nakano Y, Tao L, et al. Hedgehog signal activation in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy. Br J Cancer. 2008;98(10):1670-1674.
184. Takebe N, Harris PJ, Warren RQ, Ivy SP. Targeting cancer stem cells by inhibiting Wnt, notch, and hedgehog pathways. Nat Rev Clin Oncol. 2011;8(2):97-106.
185. Song Z, Yue W, Wei B, et al. Sonic hedgehog pathway is essential for maintenance of cancer stem-like cells in human gastric cancer. PLoS One. 2011;6(3):e17687.
186. Tanaka H, Nakamura M, Kameda C, et al. The hedgehog signaling pathway plays an essential role in maintaining the CD44+CD24-/low subpopulation and the side population of breast cancer cells. Anticancer Res. 2009;29(6):2147-2157.
187. Liu S, Dontu G, Mantle ID, et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 2006;66(12):6063-6071.
188. Takahashi T, Kawakami K, Mishima S, et al. Cyclopamine induces eosinophilic differentiation and upregulates CD44 expression in myeloid leukemia cells. Leuk Res. 2011;35(5):638-645.
189. Li C, Heidt DG, Dalerba P, et al. Identification of pancreatic cancer stem cells. Cancer Res. 2007;67(3):1030-1037.
190. Visbal AP, LaMarca HL, Villanueva H, et al. Altered differentiation and paracrine stimulation of mammary epithelial cell proliferation by conditionally activated smoothened. Dev Biol. 2011;352(1):116-127.
191. Bar EE, Chaudhry A, Lin A, et al. Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells. 2007;25(10):2524-2533.
192. Clement V, Sanchez P, de Tribolet N, Radovanovic I, Ruiz i Altaba A. Hedgehog-Gli1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol. 2007;17(2):165-172.
193. Su W, Meng F, Huang L, Zheng M, Liu W, Sun H. Sonic hedgehog maintains survival and growth of chronic myeloid leukemia progenitor cells through β-catenin signaling. Exp Hematol. 2012;40(5): 418-427.
194. Domingo-Domenech J, Vidal SJ, Rodriguez-Bravo V, et al. Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch- and hedgehog-dependent tumor-initiating cells. Cancer Cell. 2012;22(3):373-388.
195. Ramaswamy B, Lu Y, Teng KY, et al. Hedgehog signaling is a novel therapeutic target in tamoxifen-resistant breast cancer aberrantly activated by PI3K/AKT pathway. Cancer Res. 2012;72(19):5048-5059.
196. Steg AD, Bevis KS, Katre AA, et al. Stem cell pathways contribute to clinical chemoresistance in ovarian cancer. Clin Cancer Res. 2012;18(3):869-881.
197. Chaudary N, Pintilie M, Hedley D, et al. Hedgehog pathway signaling in cervical carcinoma and outcome after chemoradiation. Cancer. 2012;118(12):3105-3115.
198. Queiroz KC, Ruela-de-Sousa RR, Fuhler GM, et al. Hedgehog signaling maintains chemoresistance in myeloid leukemic cells. Oncogene. 2010;29(48):6314-6322.
199. Singh RR, Kunkalla K, Qu C, et al. ABCG2 is a direct transcriptional target of hedgehog signaling and involved in stroma-induced drug tolerance in diffuse large B-cell lymphoma. Oncogene. 2011;30(49): 4874-4886.
200. Lin SH, George TJ, Ben-Josef E, et al. Opportunities and challenges in the era of molecularly targeted agents and radiation therapy. J Natl Cancer Inst. 2013;105(10):686-693.