{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T01:50:42Z","timestamp":1790819442536,"version":"4.1.0"},"reference-count":187,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2015,8,26]],"date-time":"2015-08-26T00:00:00Z","timestamp":1440547200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000738","name":"Department of Veterans Affairs","doi-asserted-by":"publisher","award":["1I01BX001957"],"award-info":[{"award-number":["1I01BX001957"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01CA163499"],"award-info":[{"award-number":["1R01CA163499"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Despite significant progress in cancer treatments, tumor induced bone disease continues to cause significant morbidities. While tumors show distinct mutations and clinical characteristics, they behave similarly once they establish in bone. Tumors can metastasize to bone from distant sites (breast, prostate, lung), directly invade into bone (head and neck) or originate from the bone (melanoma, chondrosarcoma) where they cause pain, fractures, hypercalcemia, and ultimately, poor prognoses and outcomes. Tumors in bone secrete factors (interleukins and parathyroid hormone-related protein) that induce RANKL expression from osteoblasts, causing an increase in osteoclast mediated bone resorption. While the mechanisms involved varies slightly between tumor types, many tumors display an increase in Hedgehog signaling components that lead to increased tumor growth, therapy failure, and metastasis. The work of multiple laboratories has detailed Hh signaling in several tumor types and revealed that tumor establishment in bone can be controlled by both canonical and non-canonical Hh signaling in a cell type specific manner. This review will explore the role of Hh signaling in the modulation of tumor induced bone disease, and will shed insight into possible therapeutic interventions for blocking Hh signaling in these tumors.<\/jats:p>","DOI":"10.3390\/cancers7030856","type":"journal-article","created":{"date-parts":[[2015,8,26]],"date-time":"2015-08-26T10:23:31Z","timestamp":1440584611000},"page":"1658-1683","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["The Role of Hedgehog Signaling in Tumor Induced Bone Disease"],"prefix":"10.3390","volume":"7","author":[{"given":"Shellese","family":"Cannonier","sequence":"first","affiliation":[{"name":"Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37235, USA"},{"name":"Vanderbilt Center for Bone Biology, Department of Medicine, Division of Clinical Pharmacology Vanderbilt University, Nashville, TN 372335, USA"},{"name":"Department of Cancer Biology, Vanderbilt University, Nashville, TN 37235, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Sterling","sequence":"additional","affiliation":[{"name":"Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37235, USA"},{"name":"Vanderbilt Center for Bone Biology, Department of Medicine, Division of Clinical Pharmacology Vanderbilt University, Nashville, TN 372335, USA"},{"name":"Department of Cancer Biology, Vanderbilt University, Nashville, TN 37235, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2015,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3445","DOI":"10.1242\/dev.083691","article-title":"Roles for hedgehog signaling in adult organ homeostasis and repair","volume":"141","author":"Petrova","year":"2014","journal-title":"Development"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1038\/nature02009","article-title":"Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis","volume":"425","author":"Thayer","year":"2003","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7859","DOI":"10.1073\/pnas.1114718109","article-title":"Hedgehog pathway inhibitor saridegib (ipi-926) increases lifespan in a mouse medulloblastoma model","volume":"109","author":"Lee","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"567","DOI":"10.18632\/oncoscience.80","article-title":"An old friend with new skills: Imiquimod as novel inhibitor of hedgehog signaling in basal cell carcinoma","volume":"1","author":"Gruber","year":"2014","journal-title":"Oncoscience"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1038\/287795a0","article-title":"Mutations affecting segment number and polarity in drosophila","volume":"287","author":"Wieschaus","year":"1980","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1038\/nrn1990","article-title":"Morphogen to mitogen: The multiple roles of hedgehog signalling in vertebrate neural development","volume":"7","author":"Fuccillo","year":"2006","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2489","DOI":"10.1242\/dev.009324","article-title":"Pattern formation in the vertebrate neural tube: A sonic hedgehog morphogen-regulated transcriptional network","volume":"135","author":"Dessaud","year":"2008","journal-title":"Development"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.devcel.2013.10.008","article-title":"The purkinje neuron acts as a central regulator of spatially and functionally distinct cerebellar precursors","volume":"27","author":"Fleming","year":"2013","journal-title":"Dev. Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1242\/dev.00182","article-title":"Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors","volume":"130","author":"Kenney","year":"2003","journal-title":"Development"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"21389","DOI":"10.1074\/jbc.M112.443440","article-title":"Activation of the transcription factor gli1 by wnt signaling underlies the role of sulfatase 2 as a regulator of tissue regeneration","volume":"288","author":"Nakamura","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6981","DOI":"10.1158\/0008-5472.CAN-07-0491","article-title":"Induction of sonic hedgehog mediators by transforming growth factor-beta: Smad3-dependent activation of gli2 and gli1 expression in vitro and in vivo","volume":"67","author":"Dennler","year":"2007","journal-title":"Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9924","DOI":"10.1074\/jbc.M112.409342","article-title":"Hedgehog-gli activators direct osteo-chondrogenic function of bone morphogenetic protein toward osteogenesis in the perichondrium","volume":"288","author":"Hojo","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1111\/dgd.12187","article-title":"Decoding ci: From partial degradation to inhibition","volume":"57","author":"Xiong","year":"2015","journal-title":"Dev. Growth Differ."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1038\/nrg1969","article-title":"Orchestrating ontogenesis: Variations on a theme by sonic hedgehog","volume":"7","author":"Ingham","year":"2006","journal-title":"Nat. Rev. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Alman, B.A. (2015). The role of hedgehog signalling in skeletal health and disease. Nat. Rev. Rheumatol.","DOI":"10.1038\/nrrheum.2015.84"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1126\/science.1139740","article-title":"Patched1 regulates hedgehog signaling at the primary cilium","volume":"317","author":"Rohatgi","year":"2007","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1242\/dev.124.13.2537","article-title":"Gli1 is a target of sonic hedgehog that induces ventral neural tube development","volume":"124","author":"Lee","year":"1997","journal-title":"Development"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/S0092-8674(00)80678-9","article-title":"Hedgehog-regulated processing of gli3 produces an anterior\/posterior repressor gradient in the developing vertebrate limb","volume":"100","author":"Wang","year":"2000","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3365","DOI":"10.1128\/MCB.26.9.3365-3377.2006","article-title":"Sonic hedgehog signaling regulates gli2 transcriptional activity by suppressing its processing and degradation","volume":"26","author":"Pan","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.3892\/ol.2015.3032","article-title":"Effects and mechanisms of blocking the hedgehog signaling pathway in human gastric cancer cells","volume":"9","author":"Gu","year":"2015","journal-title":"Oncol. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1016\/j.bbagen.2015.04.005","article-title":"Hedgehog signaling through gli1 and gli2 is required for epithelial-mesenchymal transition in human trophoblasts","volume":"1850","author":"Tang","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"38356","DOI":"10.1074\/jbc.M112.377382","article-title":"A role for transcription factor stat3 signaling in oncogene smoothened-driven carcinogenesis","volume":"287","author":"Gu","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6063","DOI":"10.1158\/0008-5472.CAN-06-0054","article-title":"Hedgehog signaling and bmi-1 regulate self-renewal of normal and malignant human mammary stem cells","volume":"66","author":"Liu","year":"2006","journal-title":"Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e27941","DOI":"10.1371\/journal.pone.0027941","article-title":"Aberrant hedgehog ligands induce progressive pancreatic fibrosis by paracrine activation of myofibroblasts and ductular cells in transgenic zebrafish","volume":"6","author":"Jung","year":"2011","journal-title":"PLoS ONE"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/nrclinonc.2010.196","article-title":"Targeting cancer stem cells by inhibiting wnt, notch, and hedgehog pathways","volume":"8","author":"Takebe","year":"2011","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1126\/science.1225182","article-title":"Developmental pattern formation: Insights from physics and biology","volume":"338","author":"Kicheva","year":"2012","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2072","DOI":"10.1101\/gad.13.16.2072","article-title":"Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation","volume":"13","author":"Hammerschmidt","year":"1999","journal-title":"Genes Dev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/nature01657","article-title":"Developmental regulation of the growth plate","volume":"423","author":"Kronenberg","year":"2003","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1677\/joe.0.174r001","article-title":"Expression and localization of indian hedgehog (Ihh) and parathyroid hormone related protein (PTHrP) in the human growth plate during pubertal development","volume":"174","author":"Kindblom","year":"2002","journal-title":"J. Endocrinol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1126\/science.273.5275.613","article-title":"Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein","volume":"273","author":"Vortkamp","year":"1996","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1046\/j.1469-7580.2002.00078.x","article-title":"Expression of parathyroid hormone-related peptide (PTHrP) and its receptor (PTH1R) during the histogenesis of cartilage and bone in the chicken mandibular process","volume":"201","author":"Zhao","year":"2002","journal-title":"J. Anat."},{"key":"ref_32","first-page":"599","article-title":"Parathyroid hormone related peptide mRNA expression during murine postimplantation development: Evidence for involvement in multiple differentiation processes","volume":"40","author":"Karperien","year":"1996","journal-title":"Int. J. Dev. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1242\/dev.125.6.1067","article-title":"Regulation of growth region cartilage proliferation and differentiation by perichondrium","volume":"125","author":"Long","year":"1998","journal-title":"Development"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1172\/JCI11706","article-title":"Indian hedgehog couples chondrogenesis to osteogenesis in endochondral bone development","volume":"107","author":"Chung","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1242\/dev.01006","article-title":"Ihh signaling is directly required for the osteoblast lineage in the endochondral skeleton","volume":"131","author":"Long","year":"2004","journal-title":"Development"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4177","DOI":"10.1242\/dev.041624","article-title":"The Gli2 transcriptional activator is a crucial effector for Ihh signaling in osteoblast development and cartilage vascularization","volume":"136","author":"Joeng","year":"2009","journal-title":"Development"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3133","DOI":"10.1242\/dev.002709","article-title":"Regulation of skeletogenic differentiation in cranial dermal bone","volume":"134","author":"Abzhanov","year":"2007","journal-title":"Development"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1002\/dvg.20768","article-title":"Indian hedgehog positively regulates calvarial ossification and modulates bone morphogenetic protein signaling","volume":"49","author":"Lenton","year":"2011","journal-title":"Genesis"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3457","DOI":"10.1093\/hmg\/ddq258","article-title":"Gli3xt-j\/xt-j mice exhibit lambdoid suture craniosynostosis which results from altered osteoprogenitor proliferation and differentiation","volume":"19","author":"Rice","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1086\/518047","article-title":"Rab23 mutations in carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity","volume":"80","author":"Jenkins","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"25103","DOI":"10.1074\/jbc.R109.041087","article-title":"Cellular and molecular mechanisms of bone remodeling","volume":"285","author":"Raggatt","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_42","first-page":"66","article-title":"Modulation of osteoclast differentiation","volume":"13","author":"Suda","year":"1992","journal-title":"Endocr. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1126\/science.289.5484.1504","article-title":"Bone resorption by osteoclasts","volume":"289","author":"Teitelbaum","year":"2000","journal-title":"Science"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Tyrovola, J.B. (2015). The \u201cmechanostat theory\u201d of frost and the OPG\/Rankl\/RANK system. J. Cell. Biochem.","DOI":"10.1002\/jcb.25265"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/j.devcel.2008.03.007","article-title":"Patched1 haploinsufficiency increases adult bone mass and modulates Gli3 repressor activity","volume":"14","author":"Ohba","year":"2008","journal-title":"Dev. Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1016\/j.devcel.2008.02.003","article-title":"Hedgehog signaling in mature osteoblasts regulates bone formation and resorption by controlling PTHrP and RANKL expression","volume":"14","author":"Mak","year":"2008","journal-title":"Dev. Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1006\/bbrc.1999.1197","article-title":"Hedgehog signaling molecules in bone marrow cells at the initial stage of fracture repair","volume":"262","author":"Ito","year":"1999","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/s00418-003-0501-z","article-title":"Expression and distribution of transcripts for sonic hedgehog in the early phase of fracture repair","volume":"119","author":"Miyaji","year":"2003","journal-title":"Histochem. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e76785","DOI":"10.1371\/journal.pone.0076785","article-title":"Sonic hedgehog regulates osteoblast function by focal adhesion kinase signaling in the process of fracture healing","volume":"8","author":"Horikiri","year":"2013","journal-title":"PLoS ONE"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.tips.2009.03.007","article-title":"Mechanisms of hedgehog pathway activation in cancer and implications for therapy","volume":"30","author":"Scales","year":"2009","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"12125","DOI":"10.1074\/jbc.271.21.12125","article-title":"A mammalian patched homolog is expressed in target tissues of sonic hedgehog and maps to a region associated with developmental abnormalities","volume":"271","author":"Hahn","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1126\/science.272.5268.1668","article-title":"Human homolog of patched, a candidate gene for the basal cell nevus syndrome","volume":"272","author":"Johnson","year":"1996","journal-title":"Science"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/ng0996-78","article-title":"The role of the human homologue of drosophila patched in sporadic basal cell carcinomas","volume":"14","author":"Gailani","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1046\/j.1523-1747.2001.01315.x","article-title":"Activation of expression of hedgehog target genes in basal cell carcinomas","volume":"116","author":"Bonifas","year":"2001","journal-title":"J. Investig. Dermatol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1097\/00005792-198703000-00002","article-title":"Nevoid basal-cell carcinoma syndrome","volume":"66","author":"Gorlin","year":"1987","journal-title":"Medicine (Baltimore)"},{"key":"ref_56","unstructured":"Pagon, R.A., Adam, M.P., Ardinger, H.H., Wallace, S.E., Amemiya, A., Bean, L.J.H., Bird, T.D., Dolan, C.R., Fong, C.T., and Smith, R.J.H. (1993). GeneReviews\u00ae, University of Washington."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1002\/ajmg.a.34216","article-title":"Microdeletion 9q22.3 syndrome includes metopic craniosynostosis, hydrocephalus, macrosomia, and developmental delay","volume":"158A","author":"Muller","year":"2012","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/nm0598-619","article-title":"Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of gorlin syndrome","volume":"4","author":"Hahn","year":"1998","journal-title":"Nat. Med."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Nitzki, F., Becker, M., Frommhold, A., Schulz-Schaeffer, W., and Hahn, H. (2012). Patched knockout mouse models of basal cell carcinoma. J. Skin Cancer, 2012.","DOI":"10.1155\/2012\/907543"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.jdermsci.2015.02.007","article-title":"Hedgehog signaling in basal cell carcinoma","volume":"78","author":"Otsuka","year":"2015","journal-title":"J. Dermatol. Sci."},{"key":"ref_61","first-page":"167","article-title":"Basal cell carcinoma: Pathogenesis, epidemiology, clinical features, diagnosis, histopathology, and management","volume":"88","author":"Marzuka","year":"2015","journal-title":"Yale J. Biol. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0733-8635(18)30114-1","article-title":"Nevoid basal cell carcinoma syndrome","volume":"13","author":"Gorlin","year":"1995","journal-title":"Dermatol. Clin."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1111\/j.1365-2133.2005.06353.x","article-title":"Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas","volume":"152","author":"Reifenberger","year":"2005","journal-title":"Br. J. Dermatol."},{"key":"ref_64","first-page":"2085","article-title":"Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of drosophila patched","volume":"57","author":"Pietsch","year":"1997","journal-title":"Cancer Res."},{"key":"ref_65","first-page":"842","article-title":"Sporadic medulloblastomas contain PTCH mutations","volume":"57","author":"Raffel","year":"1997","journal-title":"Cancer Res."},{"key":"ref_66","first-page":"2581","article-title":"Mutations in the human homologue of the drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system","volume":"57","author":"Wolter","year":"1997","journal-title":"Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/ng916","article-title":"Mutations in SUFU predispose to medulloblastoma","volume":"31","author":"Taylor","year":"2002","journal-title":"Nat. Genet."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s00401-011-0846-7","article-title":"Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct","volume":"122","author":"Northcott","year":"2011","journal-title":"Acta Neuropathol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1126\/science.3563490","article-title":"Identification of an amplified, highly expressed gene in a human glioma","volume":"236","author":"Kinzler","year":"1987","journal-title":"Science"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/labinvest.3780280","article-title":"Detection of multiple gene amplifications in glioblastoma multiforme using array-based comparative genomic hybridization","volume":"81","author":"Hui","year":"2001","journal-title":"Lab. Investig."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/S0165-4608(00)00278-8","article-title":"Molecular and cytogenetic analysis of glioblastoma multiforme","volume":"122","author":"Mao","year":"2000","journal-title":"Cancer Genet. Cytogenet."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1038\/ng.2734","article-title":"The integrated landscape of driver genomic alterations in glioblastoma","volume":"45","author":"Frattini","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.cub.2006.11.033","article-title":"Hedgehog-gli1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity","volume":"17","author":"Clement","year":"2007","journal-title":"Curr. Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"5752","DOI":"10.1038\/sj.onc.1210359","article-title":"Ligand-dependent activation of the hedgehog pathway in glioma progenitor cells","volume":"26","author":"Ehtesham","year":"2007","journal-title":"Oncogene"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2524","DOI":"10.1634\/stemcells.2007-0166","article-title":"Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma","volume":"25","author":"Bar","year":"2007","journal-title":"Stem Cells"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1093\/neuonc\/nou217","article-title":"Targeting the SMO oncogene by miR-326 inhibits glioma biological behaviors and stemness","volume":"17","author":"Du","year":"2015","journal-title":"Neuro Oncol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"4002","DOI":"10.1158\/0008-5472.CAN-10-3738","article-title":"Hedgehog overexpression is associated with stromal interactions and predicts for poor outcome in breast cancer","volume":"71","author":"Machalek","year":"2011","journal-title":"Cancer Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"79","DOI":"10.2147\/OTT.S54702","article-title":"High expression of sonic hedgehog signaling pathway genes indicates a risk of recurrence of breast carcinoma","volume":"7","author":"Jeng","year":"2013","journal-title":"Onco Targets Ther."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1186\/1471-2407-9-298","article-title":"Expression of the glioma-associated oncogene homolog (gli) 1 in human breast cancer is associated with unfavourable overall survival","volume":"9","author":"Bektas","year":"2009","journal-title":"BMC Cancer"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/1476-4598-3-29","article-title":"Activation of the hedgehog pathway in advanced prostate cancer","volume":"3","author":"Sheng","year":"2004","journal-title":"Mol. Cancer"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1038\/nature02962","article-title":"Hedgehog signalling in prostate regeneration, neoplasia and metastasis","volume":"431","author":"Karhadkar","year":"2004","journal-title":"Nature"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"12561","DOI":"10.1073\/pnas.0404956101","article-title":"Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling","volume":"101","author":"Sanchez","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"4505","DOI":"10.1073\/pnas.0504337103","article-title":"Phosphoinositide 3-kinase and AKT are essential for sonic hedgehog signaling","volume":"103","author":"Riobo","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1158\/0008-5472.CAN-05-2539","article-title":"Protein kinase C-delta and mitogen-activated protein\/extracellular signal-regulated kinase-1 control GLI activation in hedgehog signaling","volume":"66","author":"Riobo","year":"2006","journal-title":"Cancer Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"6283","DOI":"10.1128\/MCB.02317-05","article-title":"Selective modulation of Hedgehog\/GLI target gene expression by epidermal growth factor signaling in human keratinocytes","volume":"26","author":"Kasper","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1158\/0008-5472.CAN-08-2331","article-title":"Epidermal growth factor receptor signaling synergizes with Hedgehog\/Gli in oncogenic transformation via activation of the MEK\/ERK\/JUN pathway","volume":"69","author":"Schnidar","year":"2009","journal-title":"Cancer Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2150","DOI":"10.1074\/jbc.M803235200","article-title":"Protein kinase Cdelta negatively regulates hedgehog signaling by inhibition of Gli1 activity","volume":"284","author":"Cai","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3282","DOI":"10.1038\/sj.onc.1210991","article-title":"The EWS\/FLI1 oncogenic transcription factor deregulates gli1","volume":"27","author":"Zwerner","year":"2008","journal-title":"Oncogene"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.febslet.2012.12.028","article-title":"A feedback regulation between kindlin-2 and GLI1 in prostate cancer cells","volume":"587","author":"Gao","year":"2013","journal-title":"FEBS Lett."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"5895","DOI":"10.1073\/pnas.0700776104","article-title":"Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK\/AKT pathways","volume":"104","author":"Stecca","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/nature11889","article-title":"GLI activation by atypical protein kinase C iota\/lambda regulates the growth of basal cell carcinomas","volume":"494","author":"Atwood","year":"2013","journal-title":"Nature"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1186\/1476-4598-13-137","article-title":"Estrogen promotes stemness and invasiveness of ER-positive breast cancer cells through Gli1 activation","volume":"13","author":"Sun","year":"2014","journal-title":"Mol. Cancer"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"5048","DOI":"10.1158\/0008-5472.CAN-12-1248","article-title":"Hedgehog signaling is a novel therapeutic target in tamoxifen-resistant breast cancer aberrantly activated by PI3K\/AKT pathway","volume":"72","author":"Ramaswamy","year":"2012","journal-title":"Cancer Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"674","DOI":"10.4161\/cbt.5.6.2906","article-title":"Hedgehog signaling and response to cyclopamine differ in epithelial and stromal cells in benign breast and breast cancer","volume":"5","author":"Mukherjee","year":"2006","journal-title":"Cancer Biol. Ther."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"3370","DOI":"10.1038\/onc.2011.496","article-title":"Increased vascularity and spontaneous metastasis of breast cancer by hedgehog signaling mediated upregulation of cyr61","volume":"31","author":"Harris","year":"2012","journal-title":"Oncogene"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3961","DOI":"10.1210\/en.2004-0079","article-title":"Hedgehog signaling promotes prostate xenograft tumor growth","volume":"145","author":"Fan","year":"2004","journal-title":"Endocrinology"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1002\/pros.22720","article-title":"Hedgehog signaling is active in human prostate cancer stroma and regulates proliferation and differentiation of adjacent epithelium","volume":"73","author":"Wilkinson","year":"2013","journal-title":"Prostate"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1002\/pros.21388","article-title":"Active sonic hedgehog signaling between androgen independent human prostate cancer cells and normal\/benign but not cancer-associated prostate stromal cells","volume":"71","author":"Shigemura","year":"2011","journal-title":"Prostate"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1002\/pros.22550","article-title":"Integrated hedgehog signaling is induced following castration in human and murine prostate cancers","volume":"73","author":"Efstathiou","year":"2013","journal-title":"Prostate"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1002\/path.2427","article-title":"Comparative expression of hedgehog ligands at different stages of prostate carcinoma progression","volume":"216","author":"Azoulay","year":"2008","journal-title":"J. Pathol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"149","DOI":"10.4161\/cc.8.1.7532","article-title":"Androgenic regulation of hedgehog signaling pathway components in prostate cancer cells","volume":"8","author":"Chen","year":"2009","journal-title":"Cell Cycle"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/1476-4598-9-89","article-title":"Hedgehog\/GLI supports androgen signaling in androgen deprived and androgen independent prostate cancer cells","volume":"9","author":"Chen","year":"2010","journal-title":"Mol. Cancer"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"e5","DOI":"10.1017\/erm.2015.3","article-title":"Cooperative integration between HEDGEHOG-GLI signalling and other oncogenic pathways: Implications for cancer therapy","volume":"17","author":"Pandolfi","year":"2015","journal-title":"Expert Rev. Mol. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1002\/cncr.11132","article-title":"Mechanisms of osteolytic bone metastases in breast carcinoma","volume":"97","author":"Kakonen","year":"2003","journal-title":"Cancer"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Mavrogenis, A.F., Angelini, A., Vottis, C., Pala, E., Calabro, T., Papagelopoulos, P.J., and Ruggieri, P. (2015). Modern palliative treatments for metastatic bone disease: Awareness of merits, demerits and guidance. Clin. J. Pain.","DOI":"10.1097\/AJP.0000000000000255"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1002\/(SICI)1097-0142(19971015)80:8+<1546::AID-CNCR4>3.0.CO;2-I","article-title":"Mechanisms of bone metastasis","volume":"80","author":"Mundy","year":"1997","journal-title":"Cancer"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"15","DOI":"10.4236\/abb.2013.410A4003","article-title":"Role of TGF-\u03b2 in breast cancer bone metastases","volume":"4","author":"Chiechi","year":"2013","journal-title":"Adv. Biosci. Biotechnol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.biomaterials.2015.06.026","article-title":"Matrix rigidity regulates the transition of tumor cells to a bone-destructive phenotype through integrin beta3 and TGF-beta receptor type II","volume":"64","author":"Page","year":"2015","journal-title":"Biomaterials"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.bone.2014.01.015","article-title":"Circulating interleukin-8 levels explain breast cancer osteolysis in mice and humans","volume":"61","author":"Kamalakar","year":"2014","journal-title":"Bone"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1007\/s10585-014-9682-1","article-title":"Wnt signaling induces gene expression of factors associated with bone destruction in lung and breast cancer","volume":"31","author":"Johnson","year":"2014","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"e60983","DOI":"10.1371\/journal.pone.0060983","article-title":"Activation of NF-kappa B signaling promotes growth of prostate cancer cells in bone","volume":"8","author":"Jin","year":"2013","journal-title":"PLoS ONE"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1158\/0008-5472.CAN-10-2993","article-title":"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","volume":"71","author":"Johnson","year":"2011","journal-title":"Cancer Res."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"7548","DOI":"10.1158\/0008-5472.CAN-06-0452","article-title":"The hedgehog signaling molecule Gli2 induces parathyroid hormone-related peptide expression and osteolysis in metastatic human breast cancer cells","volume":"66","author":"Sterling","year":"2006","journal-title":"Cancer Res."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1093\/jnci\/djq257","article-title":"GLI2-mediated melanoma invasion and metastasis","volume":"102","author":"Alexaki","year":"2010","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"321","DOI":"10.2353\/ajpath.2006.050001","article-title":"Constitutive hedgehog signaling in chondrosarcoma up-regulates tumor cell proliferation","volume":"168","author":"Tiet","year":"2006","journal-title":"Am. J. Pathol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1038\/labinvest.3780202","article-title":"Up-regulation of PTHrP and BCL-2 expression characterizes the progression of osteochondroma towards peripheral chondrosarcoma and is a late event in central chondrosarcoma","volume":"80","author":"Bovee","year":"2000","journal-title":"Lab. Investig."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1002\/path.1501","article-title":"Expression of cartilage growth plate signalling molecules in chondroblastoma","volume":"202","author":"Romeo","year":"2004","journal-title":"J. Pathol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1097\/00003086-200210000-00029","article-title":"Parathyroid hormone-related peptide expression in cartilaginous tumors","volume":"403","author":"Pateder","year":"2002","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1080\/003130201201117936","article-title":"Co-expression of parathyroid hormone-related protein (PTHrP) and PTH\/PTHrP receptor in cartilaginous tumours: A marker for malignancy?","volume":"34","author":"Kunisada","year":"2002","journal-title":"Pathology"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1002\/hed.21958","article-title":"Expression of hedgehog signaling molecules as a prognostic indicator of oral squamous cell carcinoma","volume":"34","author":"Wang","year":"2012","journal-title":"Head Neck"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/j.oraloncology.2011.03.027","article-title":"HH\/GLI signalling as a new therapeutic target for patients with oral squamous cell carcinoma","volume":"47","author":"Yan","year":"2011","journal-title":"Oral Oncol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1002\/hed.20036","article-title":"The influence of the pattern of mandibular invasion on recurrence and survival in oral squamous cell carcinoma","volume":"26","author":"Shaw","year":"2004","journal-title":"Head Neck"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1002\/hed.10062","article-title":"Patterns of invasion and routes of tumor entry into the mandible by oral squamous cell carcinoma","volume":"24","author":"Brown","year":"2002","journal-title":"Head Neck"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.oraloncology.2011.08.026","article-title":"Sonic hedgehog signaling promotes growth of oral squamous cell carcinoma cells associated with bone destruction","volume":"48","author":"Honami","year":"2012","journal-title":"Oral Oncol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"13899","DOI":"10.18632\/oncotarget.4224","article-title":"Targeting the hedgehog signaling pathway in cancer: Beyond smoothened","volume":"6","author":"Gonnissen","year":"2015","journal-title":"Oncotarget"},{"key":"ref_126","first-page":"62","article-title":"Digging a hole under hedgehog: Downstream inhibition as an emerging anticancer strategy","volume":"1856","author":"Coni","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.tips.2015.05.006","article-title":"Targeting GLI factors to inhibit the hedgehog pathway","volume":"36","author":"Infante","year":"2015","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.1101\/gad.1025302","article-title":"Inhibition of hedgehog signaling by direct binding of cyclopamine to smoothened","volume":"16","author":"Chen","year":"2002","journal-title":"Genes Dev."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"8607","DOI":"10.1039\/C5NR01084E","article-title":"Hyaluronic acid functional amphipathic and redox-responsive polymer particles for the co-delivery of doxorubicin and cyclopamine to eradicate breast cancer cells and cancer stem cells","volume":"7","author":"Hu","year":"2015","journal-title":"Nanoscale"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"2350","DOI":"10.1021\/mp3002792","article-title":"Micellar delivery of cyclopamine and gefitinib for treating pancreatic cancer","volume":"9","author":"Chitkara","year":"2012","journal-title":"Mol. Pharmcol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1038\/nature01972","article-title":"Widespread requirement for hedgehog ligand stimulation in growth of digestive tract tumours","volume":"425","author":"Berman","year":"2003","journal-title":"Nature"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1126\/science.1073733","article-title":"Medulloblastoma growth inhibition by hedgehog pathway blockade","volume":"297","author":"Berman","year":"2002","journal-title":"Science"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/nature01493","article-title":"Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer","volume":"422","author":"Watkins","year":"2003","journal-title":"Nature"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1093\/toxsci\/kfn076","article-title":"Dose- and route-dependent teratogenicity, toxicity, and pharmacokinetic profiles of the hedgehog signaling antagonist cyclopamine in the mouse","volume":"104","author":"Lipinski","year":"2008","journal-title":"Toxicol. Sci."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"3878","DOI":"10.1158\/1535-7163.MCT-08-0476","article-title":"In vivo characterization of a polymeric nanoparticle platform with potential oral drug delivery capabilities","volume":"7","author":"Bisht","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"4400","DOI":"10.1021\/jm900305z","article-title":"Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926)","volume":"52","author":"Tremblay","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1038\/nm.3389","article-title":"Unraveling the therapeutic potential of the hedgehog pathway in cancer","volume":"19","author":"Amakye","year":"2013","journal-title":"Nat. Med."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"4616","DOI":"10.1073\/pnas.0732813100","article-title":"Identification of a small molecule inhibitor of the hedgehog signaling pathway: Effects on basal cell carcinoma-like lesions","volume":"100","author":"Williams","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.ccr.2004.08.019","article-title":"Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+\/\u2212)p53(\u2212\/\u2212) mice","volume":"6","author":"Romer","year":"2004","journal-title":"Cancer Cell"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.ccr.2010.02.027","article-title":"Itraconazole, a commonly used antifungal that inhibits hedgehog pathway activity and cancer growth","volume":"17","author":"Kim","year":"2010","journal-title":"Cancer Cell"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"51ra70","DOI":"10.1126\/scitranslmed.3001599","article-title":"Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma","volume":"2","author":"Buonamici","year":"2010","journal-title":"Sci. Transl. Med."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"47","DOI":"10.2147\/OTT.S21957","article-title":"Hedgehog pathway as a drug target: Smoothened inhibitors in development","volume":"5","author":"Lin","year":"2012","journal-title":"Onco Targets Ther."},{"key":"ref_143","first-page":"707","article-title":"Vismodegib, a small-molecule inhibitor of the hedgehog pathway for the treatment of advanced cancers","volume":"11","author":"Ferretti","year":"2010","journal-title":"Curr. Opin. Investig. Drugs"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"2766","DOI":"10.1158\/1078-0432.CCR-12-3654","article-title":"Phase I study of the hedgehog pathway inhibitor IPI-926 in adult patients with solid tumors","volume":"19","author":"Jimeno","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1038\/bjc.2014.421","article-title":"Inhibition of hedgehog signalling by NVP-LDE225 (Erismodegib) interferes with growth and invasion of human renal cell carcinoma cells","volume":"111","author":"Rosa","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1158\/1078-0432.CCR-14-0507","article-title":"Molecular pathways: Novel approaches for improved therapeutic targeting of hedgehog signaling in cancer stem cells","volume":"21","author":"Justilien","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1158\/1078-0432.CCR-14-1116","article-title":"A phase I study of PF-04449913, an oral hedgehog inhibitor, in patients with advanced solid tumors","volume":"21","author":"Wagner","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1002\/ijc.28193","article-title":"Tak-441, a novel investigational smoothened antagonist, delays castration-resistant progression in prostate cancer by disrupting paracrine hedgehog signaling","volume":"133","author":"Ibuki","year":"2013","journal-title":"Int. J. Cancer"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"2502","DOI":"10.1158\/1078-0432.CCR-10-2745","article-title":"Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors","volume":"17","author":"LoRusso","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1056\/NEJMoa1113713","article-title":"Efficacy and safety of vismodegib in advanced basal-cell carcinoma","volume":"366","author":"Sekulic","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"1900","DOI":"10.1158\/1078-0432.CCR-13-1710","article-title":"A phase I, multicenter, open-label, first-in-human, dose-escalation study of the oral smoothened inhibitor sonidegib (LDE225) in patients with advanced solid tumors","volume":"20","author":"Rodon","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1200\/JCO.2013.49.9525","article-title":"Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma","volume":"32","author":"Kim","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.ccr.2011.12.028","article-title":"The crosstalk of mTOR\/S6K1 and hedgehog pathways","volume":"21","author":"Wang","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1056\/NEJMoa1113538","article-title":"Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome","volume":"366","author":"Tang","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"6509","DOI":"10.1158\/1078-0432.CCR-12-1796","article-title":"A phase II, randomized, placebo-controlled study of vismodegib as maintenance therapy in patients with ovarian cancer in second or third complete remission","volume":"18","author":"Kaye","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"2922","DOI":"10.1093\/annonc\/mdt391","article-title":"GDC-0449 in patients with advanced chondrosarcomas: A French Sarcoma Group\/US and French National Cancer Institute single-arm phase II collaborative study","volume":"24","author":"Italiano","year":"2013","journal-title":"Ann. Oncol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1126\/science.1179386","article-title":"Smoothened mutation confers resistance to a hedgehog pathway inhibitor in medulloblastoma","volume":"326","author":"Yauch","year":"2009","journal-title":"Science"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1158\/0008-5472.CAN-10-2876","article-title":"Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance","volume":"71","author":"Dijkgraaf","year":"2011","journal-title":"Cancer Res."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1002\/cmdc.201300217","article-title":"Discovery of NVP-LEQ506, a second-generation inhibitor of smoothened","volume":"8","author":"Peukert","year":"2013","journal-title":"ChemMedChem"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"e101969","DOI":"10.1371\/journal.pone.0101969","article-title":"Repurposing the FDA-approved pinworm drug pyrvinium as a novel chemotherapeutic agent for intestinal polyposis","volume":"9","author":"Li","year":"2014","journal-title":"PLoS ONE"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"8455","DOI":"10.1073\/pnas.0609699104","article-title":"Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists","volume":"104","author":"Lauth","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"200","DOI":"10.15252\/embj.201489213","article-title":"GLI1\/DNA interaction is a druggable target for hedgehog-dependent tumors","volume":"34","author":"Infante","year":"2015","journal-title":"EMBO J."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"4492","DOI":"10.18632\/oncotarget.2046","article-title":"Mode and specificity of binding of the small molecule GANT61 to GLI determines inhibition of GLI-DNA binding","volume":"5","author":"Agyeman","year":"2014","journal-title":"Oncotarget"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"12151","DOI":"10.18632\/oncotarget.2569","article-title":"GLI inhibitor GANT-61 diminishes embryonal and alveolar rhabdomyosarcoma growth by inhibiting Shh\/AKT-mTOR axis","volume":"5","author":"Srivastava","year":"2014","journal-title":"Oncotarget"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1248\/bpb.b13-00920","article-title":"The GANT61, a GLI inhibitor, induces caspase-independent apoptosis of SK-N-LO cells","volume":"37","author":"Matsumoto","year":"2014","journal-title":"Biol. Pharm. Bull."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"14132","DOI":"10.1073\/pnas.0907134106","article-title":"Small-molecule inhibitors reveal multiple strategies for hedgehog pathway blockade","volume":"106","author":"Hyman","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"5574","DOI":"10.1038\/onc.2013.343","article-title":"Imiquimod directly inhibits hedgehog signalling by stimulating adenosine receptor\/protein kinase A-mediated GLI phosphorylation","volume":"32","author":"Wolff","year":"2013","journal-title":"Oncogene"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"13432","DOI":"10.1073\/pnas.1006822107","article-title":"Arsenic antagonizes the hedgehog pathway by preventing ciliary accumulation and reducing stability of the GLI2 transcriptional effector","volume":"107","author":"Kim","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1002\/cbic.200700511","article-title":"Naturally occurring small-molecule inhibitors of hedgehog\/GLI-mediated transcription","volume":"9","author":"Hosoya","year":"2008","journal-title":"Chembiochem"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1038\/onc.2013.164","article-title":"Targeting GLI transcription activation by small molecule suppresses tumor growth","volume":"33","author":"Zhang","year":"2014","journal-title":"Oncogene"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/s11060-007-9505-1","article-title":"Response of preclinical medulloblastoma models to combination therapy with 13-cis retinoic acid and suberoylanilide hydroxamic acid (SAHA)","volume":"87","author":"Spiller","year":"2008","journal-title":"J. Neurooncol."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/s11060-006-9142-0","article-title":"Suberoylanilide hydroxamic acid is effective in preclinical studies of medulloblastoma","volume":"79","author":"Spiller","year":"2006","journal-title":"J. Neurooncol."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1158\/1535-7163.MCT-14-0481","article-title":"Histone deacetylase 6 represents a novel drug target in the oncogenic hedgehog signaling pathway","volume":"14","author":"Dhanyamraju","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1038\/nature09504","article-title":"Selective inhibition of bet bromodomains","volume":"468","author":"Filippakopoulos","year":"2010","journal-title":"Nature"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/nm.3613","article-title":"Epigenetic targeting of hedgehog pathway transcriptional output through bet bromodomain inhibition","volume":"20","author":"Tang","year":"2014","journal-title":"Nat. Med."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.juro.2010.03.007","article-title":"Gli2 expression and human bladder transitional carcinoma cell invasiveness","volume":"184","author":"Mechlin","year":"2010","journal-title":"J. Urol."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"4885","DOI":"10.1038\/onc.2010.243","article-title":"Inhibition of GLI, but not smoothened, induces apoptosis in chronic lymphocytic leukemia cells","volume":"29","author":"Desch","year":"2010","journal-title":"Oncogene"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"5904","DOI":"10.1158\/0008-5472.CAN-10-4173","article-title":"Blocking hedgehog survival signaling at the level of the GLI genes induces DNA damage and extensive cell death in human colon carcinoma cells","volume":"71","author":"Mazumdar","year":"2011","journal-title":"Cancer Res."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1016\/j.leukres.2012.02.012","article-title":"Gli inhibitor GANT61 causes apoptosis in myeloid leukemia cells and acts in synergy with rapamycin","volume":"36","author":"Pan","year":"2012","journal-title":"Leuk. Res."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"3381","DOI":"10.1158\/0008-5472.CAN-12-4047","article-title":"Hedgehog signaling alters reliance on EGF receptor signaling and mediates anti-EGFR therapeutic resistance in head and neck cancer","volume":"73","author":"Keysar","year":"2013","journal-title":"Cancer Res."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1038\/cdd.2013.41","article-title":"Interaction between the TP63 and SHH pathways is an important determinant of epidermal homeostasis","volume":"20","author":"Chari","year":"2013","journal-title":"Cell Death Differ."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1053\/j.gastro.2009.05.053","article-title":"Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer","volume":"137","author":"Mueller","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"e66371","DOI":"10.1371\/journal.pone.0066371","article-title":"Multimodal treatment eliminates cancer stem cells and leads to long-term survival in primary human pancreatic cancer tissue xenografts","volume":"8","author":"Hermann","year":"2013","journal-title":"PLoS ONE"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.ccr.2012.07.016","article-title":"Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch- and hedgehog-dependent tumor-initiating cells","volume":"22","author":"Vidal","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"E33","DOI":"10.1002\/ijc.27349","article-title":"In vitro and in vivo characterization of a novel hedgehog signaling antagonist in human glioblastoma cell lines","volume":"131","author":"Ferruzzi","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"6310","DOI":"10.1158\/0008-5472.CAN-12-4258","article-title":"Targeting sonic hedgehog-associated medulloblastoma through inhibition of Aurora and Polo-like kinases","volume":"73","author":"Markant","year":"2013","journal-title":"Cancer Res."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.1158\/0008-5472.CAN-06-3281","article-title":"Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: A new paradigm for combination therapy in solid cancers","volume":"67","author":"Feldmann","year":"2007","journal-title":"Cancer Res."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/7\/3\/856\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:47:28Z","timestamp":1760215648000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/7\/3\/856"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,8,26]]},"references-count":187,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2015,9]]}},"alternative-id":["cancers7030856"],"URL":"https:\/\/doi.org\/10.3390\/cancers7030856","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,8,26]]}}}