Hedgehog signaling pathway as a new therapeutic target in pancreatic cancer

World Journal of Gastroenterology

Volumn 20, Issue 9, 2014, Pages 2335-2342

  Onishi, Hideya ^a   Katano, Mitsuo ^a  

^a KYUSHU UNIVERSITY   (Japan)

Author keywords

Cancer stem cells; Hedgehog signaling pathway; Hypoxic condition; Pancreatic cancer; Therapeutic target

Indexed keywords

CANCER GROWTH FACTOR; CD24 ANTIGEN; CYCLIN D1; EPIDERMAL GROWTH FACTOR RECEPTOR; HERMES ANTIGEN; HYPOXIA INDUCIBLE FACTOR PROLINE DIOXYGENASE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; MITOGEN ACTIVATED PROTEIN KINASE; PROTEIN P21; SARIDEGIB; SONIC HEDGEHOG PROTEIN; SONIDEGIB; TRANSCRIPTION FACTOR GLI1; TRANSIENT RECEPTOR POTENTIAL CHANNEL M2; URELUMAB; VISMODEGIB; ANTINEOPLASTIC AGENT;

ANGIOGENESIS; APOPTOSIS; ARTICLE; CANCER GROWTH; CANCER STEM CELL; CELL HYPOXIA; CELL INVASION; CELL PROLIFERATION; GROWTH REGULATION; HUMAN; ONCOGENE C MYB; PANCREAS CANCER; PARACRINE SIGNALING; PHASE 2 CLINICAL TRIAL (TOPIC); PROTEIN EXPRESSION; THERAPY RESISTANCE; ANIMAL; DRUG DESIGN; DRUG EFFECTS; METABOLISM; MOLECULARLY TARGETED THERAPY; PANCREATIC NEOPLASMS; PATHOLOGY; PHENOTYPE; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL HYPOXIA; DRUG DESIGN; HEDGEHOG PROTEINS; HUMANS; MOLECULAR TARGETED THERAPY; NEOPLASTIC STEM CELLS; PANCREATIC NEOPLASMS; PHENOTYPE; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT;

EID: 84895858874     PISSN: 10079327     EISSN: 22192840     Source Type: Journal    
DOI: 10.3748/wjg.v20.i9.2335     Document Type: Article

References (82)

1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin 2009; 59: 225-249 [PMID: 19474385 DOI: 10.3322/caac.20006]
2. Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, Qi YP, Gysin S, Fernández-del Castillo C, Yajnik V, Antoniu B, McMahon M, Warshaw AL, Hebrok M. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003; 425: 851-856 [PMID: 14520413 DOI: 10.1038/nature02009]
3. Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev 2001; 15: 3059-3087 [PMID: 11731473 DOI: 10.1101/gad.938601]
4. McMahon AP, Ingham PW, Tabin CJ. Developmental roles and clinical significance of hedgehog signaling. Curr Top Dev Biol 2003; 53: 1-114 [PMID: 12509125 DOI: 10.1016/ S0070-2153(03)53002-2]
5. Hooper JE, Scott MP. Communicating with Hedgehogs. Nat Rev Mol Cell Biol 2005; 6: 306-317 [PMID: 15803137 DOI: 10.1038/nrm1622]
6. Mukherjee S, Frolova N, Sadlonova A, Novak Z, Steg A, Page GP, Welch DR, Lobo-Ruppert SM, Ruppert JM, Johnson MR, Frost AR. Hedgehog signaling and response to cyclopamine differ in epithelial and stromal cells in benign breast and breast cancer. Cancer Biol Ther 2006; 5: 674-683 [PMID: 16855373 DOI: 10.4161/cbt.5.6.2906]
7. Cohen MM. The hedgehog signaling network. Am J Med Genet A 2003; 123A: 5-28 [PMID: 14556242]
8. Onishi H, Katano M. Hedgehog signaling pathway as a therapeutic target in various types of cancer. Cancer Sci 2011; 102: 1756-1760 [PMID: 21679342 DOI: 10.1111/ j.1349-7006.2011.02010.x]
9. Jiang J, Hui CC. Hedgehog signaling in development and cancer. Dev Cell 2008; 15: 801-812 [PMID: 19081070 DOI: 10.1016/j.devcel]
10. Bai CB, Stephen D, Joyner AL. All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3. Dev Cell 2004; 6: 103-115 [PMID: 14723851 DOI: 10.1016/S1534-5807(03)00394-0]
11. Kasper M, Regl G, Frischauf AM, Aberger F. GLI transcription factors: mediators of oncogenic Hedgehog signalling. Eur J Cancer 2006; 42: 437-445 [PMID: 16406505 DOI: 10.1016/j.ejca.2005.08.039]
12. Stecca B, Ruiz I Altaba A. Context-dependent regulation of the GLI code in cancer by HEDGEHOG and non-HEDGEHOG signals. J Mol Cell Biol 2010; 2: 84-95 [PMID: 20083481 DOI: 10.1093/jmcb/mjp052]
13. Wang B, Fallon JF, Beachy PA. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 2000; 100: 423-434 [PMID: 10693759 DOI: 10.1016/S0092-8674(00)80678-9]
14. 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: 3365-3377 [PMID: 16611981 DOI: 10.1128/MCB.26.9.3365-3377.2006]
15. Corbit KC, Aanstad P, Singla V, Norman AR, Stainier DY, Reiter JF. Vertebrate Smoothened functions at the primary cilium. Nature 2005; 437: 1018-1021 [PMID: 16136078 DOI: 10.1038/nature04117]
16. Freeman M. Feedback control of intercellular signalling in development. Nature 2000; 408: 313-319 [PMID: 11099031 DOI: 10.1038/35042500]
17. Pasca di Magliano M, Hebrok M. Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer 2003; 3: 903-911 [PMID: 14737121 DOI: 10.1038/nrc1229]
18. Gill PS, Rosenblum ND. Control of murine kidney development by sonic hedgehog and its GLI effectors. Cell Cycle 2006; 5: 1426-1430 [PMID: 16855389 DOI: 10.4161/cc.5.13.2928]
19. Kinzler KW, Bigner SH, Bigner DD, Trent JM, Law ML, O' Brien SJ, Wong AJ, Vogelstein B. Identification of an amplified, highly expressed gene in a human glioma. Science 1987; 236: 70-73 [PMID: 3563490 DOI: 10.1126/science.3563490]
20. Gailani MR, Bale AE. Developmental genes and cancer: role of patched in basal cell carcinoma of the skin. J Natl Cancer Inst 1997; 89: 1103-1109 [PMID: 9262247 DOI: 10.1093/ jnci/89.15.1103]
21. Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam CW, Hynes M, Goddard A, Rosenthal A, Epstein EH, de Sauvage FJ. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 1998; 391: 90-92 [PMID: 9422511 DOI: 10.1038/34201]
22. Berman DM, Karhadkar SS, Maitra A, Montes De Oca R, Gerstenblith MR, Briggs K, Parker AR, Shimada Y, Eshleman JR, Watkins DN, Beachy PA. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 2003; 425: 846-851 [PMID: 14520411 DOI: 10.1038/nature01972]
23. Garcea G, Dennison AR, Steward WP, Berry DP. Role of inflammation in pancreatic carcinogenesis and the implications for future therapy. Pancreatology 2005; 5: 514-529 [PMID: 16110250 DOI: 10.1159/000087493]
24. Farrow B, Evers BM. Inflammation and the development of pancreatic cancer. Surg Oncol 2002; 10: 153-169 [PMID: 12020670 DOI: 10.1016/S0960-7404(02)00015-4]
25. Jura N, Archer H, Bar-Sagi D. Chronic pancreatitis, pancreatic adenocarcinoma and the black box in-between. Cell Res 2005; 15: 72-77 [PMID: 15686632 DOI: 10.1038/sj.cr.7290269]
26. Luo JL, Maeda S, Hsu LC, Yagita H, Karin M. Inhibition of NF-kappaB in cancer cells converts inflammation-induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression. Cancer Cell 2004; 6: 297-305 [PMID: 15380520 DOI: 10.1016/j.ccr.2004.08.012]
27. Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, Kagnoff MF, Karin M. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 2004; 118: 285-296 [PMID: 15294155 DOI: 10.1016/ j.cell.2004.07.013]
28. Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 2005; 5: 749-759 [PMID: 16175180 DOI: 10.1038/ nri1703]
29. Nakashima H, Nakamura M, Yamaguchi H, Yamanaka N, Akiyoshi T, Koga K, Yamaguchi K, Tsuneyoshi M, Tanaka M, Katano M. Nuclear factor-kappaB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer. Cancer Res 2006; 66: 7041-7049 [PMID: 16849549]
30. Kasperczyk H, Baumann B, Debatin KM, Fulda S. Characterization of sonic hedgehog as a novel NF-kappaB target gene that promotes NF-kappaB-mediated apoptosis resistance and tumor growth in vivo. FASEB J 2009; 23: 21-33 [PMID: 18772349 DOI: 10.1096/fj.08-111096]
31. Yauch RL, Gould SE, Scales SJ, Tang T, Tian H, Ahn CP, Marshall D, Fu L, Januario T, Kallop D, Nannini-Pepe M, Kotkow K, Marsters JC, Rubin LL, de Sauvage FJ. A paracrine requirement for hedgehog signalling in cancer. Nature 2008; 455: 406-410 [PMID: 18754008 DOI: 10.1038/nature07275]
32. Tian H, Callahan CA, DuPree KJ, Darbonne WC, Ahn CP, Scales SJ, de Sauvage FJ. Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc Natl Acad Sci USA 2009; 106: 4254-4259 [PMID: 19246386 DOI: 10.1073/pnas.0813203106]
33. Yamasaki A, Kameda C, Xu R, Tanaka H, Tasaka T, Chikazawa N, Suzuki H, Morisaki T, Kubo M, Onishi H, Tanaka M, Katano M. Nuclear factor kappaB-activated monocytes contribute to pancreatic cancer progression through the production of Shh. Cancer Immunol Immunother 2010; 59: 675-686 [PMID: 19862523 DOI: 10.1007/s00262-009-0783-7]
34. Hwang RF, Moore TT, Hattersley MM, Scarpitti M, Yang B, Devereaux E, Ramachandran V, Arumugam T, Ji B, Logsdon CD, Brown JL, Godin R. Inhibition of the hedgehog pathway targets the tumor-associated stroma in pancreatic cancer. Mol Cancer Res 2012; 10: 1147-1157 [PMID: 22859707]
35. Lonardo E, Frias-Aldeguer J, Hermann PC, Heeschen C. Pancreatic stellate cells form a niche for cancer stem cells and promote their self-renewal and invasiveness. Cell Cycle 2012; 11: 1282-1290 [PMID: 22421149 DOI: 10.4161/cc.19679]
36. Singh AP, Arora S, Bhardwaj A, Srivastava SK, Kadakia MP, Wang B, Grizzle WE, Owen LB, Singh S. CXCL12/CXCR4 protein signaling axis induces sonic hedgehog expression in pancreatic cancer cells via extracellular regulated kinase-and Akt kinase-mediated activation of nuclear factor κB: implications for bidirectional tumor-stromal interactions. J Biol Chem 2012; 287: 39115-39124 [PMID: 22995914 DOI: 10.1074/jbc. M112.409581]
37. Onishi H, Morifuji Y, Kai M, Suyama K, Iwasaki H, Katano M. Hedgehog inhibitor decreases chemosensitivity to 5-fluorouracil and gemcitabine under hypoxic conditions in pancreatic cancer. Cancer Sci 2012; 103: 1272-1279 [PMID: 22486854 DOI: 10.1111/j.1349-7006.2012.02297.x]
38. Onishi H, Kai M, Odate S, Iwasaki H, Morifuji Y, Ogino T, Morisaki T, Nakashima Y, Katano M. Hypoxia activates the hedgehog signaling pathway in a ligand-independent manner by upregulation of Smo transcription in pancreatic cancer. Cancer Sci 2011; 102: 1144-1150 [PMID: 21338440 DOI: 10.1111/j.1349-7006.2011.01912.x]
39. Onishi H, Morisaki T, Nakao F, Odate S, Morisaki T, Katano M. Protein-bound polysaccharide decreases invasiveness and proliferation in pancreatic cancer by inhibition of hedgehog signaling and HIF-1α pathways under hypoxia. Cancer Lett 2013; 335: 289-298 [PMID: 23485726 DOI: 10.1016/ j.canlet.2013.02.041]
40. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100: 3983-3988 [PMID: 12629218]
41. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM. Identification of pancreatic cancer stem cells. Cancer Res 2007; 67: 1030-1037 [PMID: 17283135 DOI: 10.1158/0008-5472.CAN-06-2030]
42. Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, Heeschen C. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 2007; 1: 313-323 [PMID: 18371365 DOI: 10.1016/j.stem.2007.06.002]
43. Bar EE, Chaudhry A, Lin A, Fan X, Schreck K, Matsui W, Piccirillo S, Vescovi AL, DiMeco F, Olivi A, Eberhart CG. Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells 2007; 25: 2524-2533 [PMID: 17628016 DOI: 10.1634/stemcells. 2007-0166]
44. Mueller MT, Hermann PC, Witthauer J, Rubio-Viqueira B, Leicht SF, Huber S, Ellwart JW, Mustafa M, Bartenstein P, D'Haese JG, Schoenberg MH, Berger F, Jauch KW, Hidalgo M, Heeschen C. Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer. Gastroenterology 2009; 137: 1102-1113 [PMID: 19501590 DOI: 10.1053/j.gastro.2009.05.053]
45. Di J, Duiveman-de Boer T, Figdor CG, Torensma R. Eradicating cancer cells: struggle with a chameleon. Oncotarget 2011; 2: 99-101 [PMID: 21378413]
46. Lee CJ, Dosch J, Simeone DM. Pancreatic cancer stem cells. J Clin Oncol 2008; 26: 2806-2812 [PMID: 18539958 DOI: 10.1200/JCO.2008.16.6702]
47. Huang FT, Zhuan-Sun YX, Zhuang YY, Wei SL, Tang J, Chen WB, Zhang SN. Inhibition of hedgehog signaling depresses self-renewal of pancreatic cancer stem cells and reverses chemoresistance. Int J Oncol 2012; 41: 1707-1714 [PMID: 22923052 DOI: 10.3892/ijo.2012.1597]
48. 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: 30-40 [PMID: 21796625 DOI: 10.1002/ijc.26323]
49. Li SH, Fu J, Watkins DN, Srivastava RK, Shankar S. Sulforaphane regulates self-renewal of pancreatic cancer stem cells through the modulation of Sonic hedgehog-GLI pathway. Mol Cell Biochem 2013; 373: 217-227 [PMID: 23129257 DOI: 10.1007/s11010-012-1493-6]
50. Rodova M, Fu J, Watkins DN, Srivastava RK, Shankar S. Sonic hedgehog signaling inhibition provides opportunities for targeted therapy by sulforaphane in regulating pancreatic cancer stem cell self-renewal. PLoS One 2012; 7: e46083 [PMID: 23029396 DOI: 10.1371/journal.pone.0046083]
51. Han JB, Sang F, Chang JJ, Hua YQ, Shi WD, Tang LH, Liu LM. Arsenic trioxide inhibits viability of pancreatic cancer stem cells in culture and in a xenograft model via binding to SHH-Gli. Onco Targets Ther 2013; 6: 1129-1138 [PMID: 23990729 DOI: 10.2147/OTT.S49148.]
52. Kristiansen G, Sammar M, Altevogt P. Tumour biological aspects of CD24, a mucin-like adhesion molecule. J Mol Histol 2004; 35: 255-262 [PMID: 15339045]
53. Aigner S, Sthoeger ZM, Fogel M, Weber E, Zarn J, Ruppert M, Zeller Y, Vestweber D, Stahel R, Sammar M, Altevogt P. CD24, a mucin-type glycoprotein, is a ligand for P-selectin on human tumor cells. Blood 1997; 89: 3385-3395 [PMID: 9129046]
54. Cao X, Geradts J, Dewhirst MW, Lo HW. Upregulation of VEGF-A and CD24 gene expression by the tGLI1 transcription factor contributes to the aggressive behavior of breast cancer cells. Oncogene 2012; 31: 104-115 [PMID: 21666711 DOI: 10.1038/onc.2011.219]
55. Ringel J, Jesnowski R, Schmidt C, Ringel J, Köhler HJ, Rychly J, Batra SK, Löhr M. CD44 in normal human pancreas and pancreatic carcinoma cell lines. Teratog Carcinog Mutagen 2001; 21: 97-106 [PMID: 11135324]
56. Koong AC, Mehta VK, Le QT, Fisher GA, Terris DJ, Brown JM, Bastidas AJ, Vierra M. Pancreatic tumors show high levels of hypoxia. Int J Radiat Oncol Biol Phys 2000; 48: 919-922 [PMID: 11072146]
57. Caldwell CC, Kojima H, Lukashev D, Armstrong J, Farber M, Apasov SG, Sitkovsky MV. Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions. J Immunol 2001; 167: 6140-6149 [PMID: 11714773]
58. Höckel S, Schlenger K, Vaupel P, Höckel M. Association between host tissue vascularity and the prognostically relevant tumor vascularity in human cervical cancer. Int J Oncol 2001; 19: 827-832 [PMID: 11562762]
59. Lei J, Ma J, Ma Q, Li X, Liu H, Xu Q, Duan W, Sun Q, Xu J, Wu Z, Wu E. Hedgehog signaling regulates hypoxia induced epithelial to mesenchymal transition and invasion in pancreatic cancer cells via a ligand-independent manner. Mol Cancer 2013; 12: 66 [PMID: 23786654 DOI: 10.1186/1476-4598-12-66]
60. Spivak-Kroizman TR, Hostetter G, Posner R, Aziz M, Hu C, Demeure MJ, Von Hoff D, Hingorani SR, Palculict TB, Izzo J, Kiriakova GM, Abdelmelek M, Bartholomeusz G, James BP, Powis G. Hypoxia triggers hedgehog-mediated tumorstromal interactions in pancreatic cancer. Cancer Res 2013; 73: 3235-3247 [PMID: 23633488 DOI: 10.1158/0008-5472. CAN-11-1433]
61. Bahra M, Kamphues C, Boas-Knoop S, Lippert S, Esendik U, Schüller U, Hartmann W, Waha A, Neuhaus P, Heppner F, Pietsch T, Koch A. Combination of hedgehog signaling blockage and chemotherapy leads to tumor reduction in pancreatic adenocarcinomas. Pancreas 2012; 41: 222-229 [PMID: 22076568 DOI: 10.1097/MPA.0b013e31822896dd]
62. Qin CF, Hao K, Tian XD, Xie XH, Yang YM. Combined effects of EGFR and Hedgehog signaling pathway inhibition on the proliferation and apoptosis of pancreatic cancer cells. Oncol Rep 2012; 28: 519-526 [PMID: 22581058 DOI: 10.3892/ or.2012.1808]
63. Eberl M, Klingler S, Mangelberger D, Loipetzberger A, Damhofer H, Zoidl K, Schnidar H, Hache H, Bauer HC, Solca F, Hauser-Kronberger C, Ermilov AN, Verhaegen ME, Bichakjian CK, Dlugosz AA, Nietfeld W, Sibilia M, Lehrach H, Wierling C, Aberger F. Hedgehog-EGFR cooperation response genes determine the oncogenic phenotype of basal cell carcinoma and tumour-initiating pancreatic cancer cells. EMBO Mol Med 2012; 4: 218-233 [PMID: 22294553 DOI: 10.1002/emmm.201100201]
64. Chitkara D, Singh S, Kumar V, Danquah M, Behrman SW, Kumar N, Mahato RI. Micellar delivery of cyclopamine and gefitinib for treating pancreatic cancer. Mol Pharm 2012; 9: 2350-2357 [PMID: 22780906]
65. Gu D, Liu H, Su GH, Zhang X, Chin-Sinex H, Hanenberg H, Mendonca MS, Shannon HE, Chiorean EG, Xie J. Combining hedgehog signaling inhibition with focal irradiation on reduction of pancreatic cancer metastasis. Mol Cancer Ther 2013; 12: 1038-1048 [PMID: 23468532 DOI: 10.1158/1535-7163. MCT-12-1030]
66. Onishi H, Morisaki T, Kiyota A, Koya N, Tanaka H, Umebayashi M, Katano M. The Hedgehog inhibitor cyclopamine impairs the benefits of immunotherapy with activated T and NK lymphocytes derived from patients with advanced cancer. Cancer Immunol Immunother 2013; 62: 1029-1039 [PMID: 23591983 DOI: 10.1007/s00262-013-1419-5]
67. Onishi H, Morisaki T, Kiyota A, Koya N, Tanaka H, Umebayashi M, Katano M. The Hedgehog inhibitor suppresses the function of monocyte-derived dendritic cells from patients with advanced cancer under hypoxia. Biochem Biophys Res Commun 2013; 436: 53-59 [PMID: 23707943 DOI: 10.1016/ j.bbrc.2013.05.057]
68. Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, Solomon JA, Yoo S, Arron ST, Friedlander PA, Marmur E, Rudin CM, Chang AL, Low JA, Mackey HM, Yauch RL, Graham RA, Reddy JC, Hauschild A. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012; 366: 2171-2179 [PMID: 22670903 DOI: 10.1056/NEJMoa1113713]
69. Kelleher FC. Hedgehog signaling and therapeutics in pancreatic cancer. Carcinogenesis 2011; 32: 445-451 [PMID: 21186299 DOI: 10.1093/carcin/bgq280]
70. Sandhiya S, Melvin G, Kumar SS, Dkhar SA. The dawn of hedgehog inhibitors: Vismodegib. J Pharmacol Pharmacother 2013; 4: 4-7 [PMID: 23662017 DOI: 10.4103/0976-500X.107628]
71. Fendrich V, Wiese D, Waldmann J, Lauth M, Heverhagen AE, Rehm J, Bartsch DK. Hedgehog inhibition with the orally bioavailable Smo antagonist LDE225 represses tumor growth and prolongs survival in a transgenic mouse model of islet cell neoplasms. Ann Surg 2011; 254: 818-823; discussion 823 [PMID: 22042473 DOI: 10.1097/ SLA.0b013e318236bc0f]
72. Fu J, Rodova M, Roy SK, Sharma J, Singh KP, Srivastava RK, Shankar S. GANT-61 inhibits pancreatic cancer stem cell growth in vitro and in NOD/SCID/IL2R gamma null mice xenograft. Cancer Lett 2013; 330: 22-32 [PMID: 23200667 DOI: 10.1016/j.canlet.2012.11.018]
73. Mo W, Xu X, Xu L, Wang F, Ke A, Wang X, Guo C. Resveratrol inhibits proliferation and induces apoptosis through the hedgehog signaling pathway in pancreatic cancer cell. Pancreatology 2011; 11: 601-609 [PMID: 22301921 DOI: 10.1159/000333542]
74. Sun XD, Liu XE, Huang DS. Curcumin reverses the epithelial-mesenchymal transition of pancreatic cancer cells by inhibiting the Hedgehog signaling pathway. Oncol Rep 2013; 29: 2401-2407 [PMID: 23563640 DOI: 10.3892/or.2013.2385]
75. Bi X, Han X, Zhang F, He M, Zhang Y, Zhi XY, Zhao H. Triparanol suppresses human tumor growth in vitro and in vivo. Biochem Biophys Res Commun 2012; 425: 613-618 [PMID: 22877755 DOI: 10.1016/j.bbrc.2012.07.136]
76. Nolan-Stevaux O, Lau J, Truitt ML, Chu GC, Hebrok M, Fernández-Zapico ME, Hanahan D. GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev 2009; 23: 24-36 [PMID: 19136624 DOI: 10.1101/gad.1753809]
77. An Y, Cai B, Chen J, Lv N, Yao J, Xue X, Tu M, Tang D, Wei J, Jiang K, Wu J, Li Q, Gao W, Miao Y. MAP3K10 promotes the proliferation and decreases the sensitivity of pancreatic cancer cells to gemcitabine by upregulating Gli-1 and Gli-2. Cancer Lett 2013; 329: 228-235 [PMID: 23178452 DOI: 10.1016/ j.canlet.2012.11.005]
78. Li X, Ma Q, Xu Q, Liu H, Lei J, Duan W, Bhat K, Wang F, Wu E, Wang Z. SDF-1/CXCR4 signaling induces pancreatic cancer cell invasion and epithelial-mesenchymal transition in vitro through non-canonical activation of Hedgehog pathway. Cancer Lett 2012; 322: 169-176 [PMID: 22450749 DOI: 10.1016/j.canlet.2012.02.035]
79. Low JA, de Sauvage FJ. Clinical experience with Hedgehog pathway inhibitors. J Clin Oncol 2010; 28: 5321-5326 [PMID: 21041712 DOI: 10.1200/JCO.2010.27.9943]
80. Merchant AA, Matsui W. Targeting Hedgehog--a cancer stem cell pathway. Clin Cancer Res 2010; 16: 3130-3140 [PMID: 20530699 DOI: 10.1158/1078-0432.CCR-09-2846]
81. Sahebjam S, Siu LL, Razak AA. The utility of hedgehog signaling pathway inhibition for cancer. Oncologist 2012; 17: 1090-1099 [PMID: 22851551 DOI: 10.1634/theoncologist. 2011-0450]
82. Atwood SX, Chang AL, Oro AE. Hedgehog pathway inhibition and the race against tumor evolution. J Cell Biol 2012; 199: 193-197 [PMID: 23071148 DOI: 10.1083/jcb.201207140]