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Hedgehog Signaling Plays a Dual Role in Pancreatic Carcinogenesis

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Pancreatic Cancer

Abstract

The hedgehog (Hh) pathway plays an important role in a wide variety of developmental processes including cellular differentiation and tissue patterning. While Hh signaling is a critical component of embryonic development, this pathway is not typically active in most adult tissues. Inappropriate Hh signaling has been associated with several types of malignancies including pancreatic ductal adenocarcinoma (PDAC). In PDAC, the Hh pathway is activated by two distinct mechanisms in the tumor epithelial and stromal compartments. In the stroma, the Hh pathway activity is induced by its ligands in a canonical fashion; in tumor epithelial cells its activity is regulated in a ligand-independent manner by known PDAC oncogenic cascades including KRAS, TGFβ, and EGFR signaling. Initial preclinical studies demonstrated that the Hh pathway may be a promising therapeutic target for PDAC. However, Hh inhibition has not been successful in clinical trials of PDAC patients with advanced metastatic disease. Recent reports indicate the Hh pathway may play a dual role in carcinogenesis, acting as an oncogene in early tumorigenesis while switching to a tumor suppressor as the cancer progresses. Current research efforts are aimed at further understanding the role of the Hh pathway in all stages of carcinogenesis and defining the translational value of Hh inhibition in PDAC.

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References

  1. Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature. 1980;287(5785):795–801.

    Article  CAS  PubMed  Google Scholar 

  2. Bitgood MJ, Shen L, McMahon AP. Sertoli cell signaling by Desert hedgehog regulates the male germline. Curr Biol. 1996;6(3):298–304.

    Article  CAS  PubMed  Google Scholar 

  3. Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, Westphal H, et al. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature. 1996;383(6599):407–13.

    Article  CAS  PubMed  Google Scholar 

  4. St-Jacques B, Dassule HR, Karavanova I, Botchkarev VA, Li J, Danielian PS, et al. Sonic hedgehog signaling is essential for hair development. Curr Biol. 1998;8(19):1058–68.

    Article  CAS  PubMed  Google Scholar 

  5. Apelqvist A, Ahlgren U, Edlund H. Sonic hedgehog directs specialised mesoderm differentiation in the intestine and pancreas. Curr Biol. 1997;7(10):801–4.

    Article  CAS  PubMed  Google Scholar 

  6. Kayed H, Kleeff J, Keleg S, Buchler MW, Friess H. Distribution of Indian hedgehog and its receptors patched and smoothened in human chronic pancreatitis. J Endocrinol. 2003;178(3):467–78.

    Article  CAS  PubMed  Google Scholar 

  7. Pasca di Magliano M, Sekine S, Ermilov A, Ferris J, Dlugosz AA, Hebrok M. Hedgehog/Ras interactions regulate early stages of pancreatic cancer. Genes Dev. 2006.; 07/18/received09/25/accepted20(22):3161–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rajurkar M, De Jesus-Monge WE, Driscoll DR, Appleman VA, Huang H, Cotton JL, et al. The activity of Gli transcription factors is essential for Kras-induced pancreatic tumorigenesis. Proc Natl Acad Sci U S A. 2012;109(17):E1038–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 2003;425(6960):851–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Eberl M, Klingler S, Mangelberger D, Loipetzberger A, Damhofer H, Zoidl K, 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):218–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mills LD, Zhang Y, Marler RJ, Herreros-Villanueva M, Zhang L, Almada LL, et al. Loss of the transcription factor GLI1 identifies a signaling network in the tumor microenvironment mediating KRAS oncogene-induced transformation. J Biol Chem. 2013;288(17):11786–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Haycraft CJ, Banizs B, Aydin-Son Y, Zhang Q, Michaud EJ, Yoder BK. Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet. 2005;1(4):e53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Corbit KC, Aanstad P, Singla V, Norman AR, Stainier DY, Reiter JF. Vertebrate Smoothened functions at the primary cilium. Nature. 2005;437(7061):1018–21.

    Article  CAS  PubMed  Google Scholar 

  14. Rohatgi R, Milenkovic L, Scott MP. Patched1 regulates hedgehog signaling at the primary cilium. Science. 2007;317(5836):372–6.

    Article  CAS  PubMed  Google Scholar 

  15. Rosenbaum JL, Witman GB. Intraflagellar transport. Nat Rev Mol Cell Biol. 2002;3(11):813–25.

    Article  CAS  PubMed  Google Scholar 

  16. Stone DM, Hynes M, Armanini M, Swanson TA, Gu Q, Johnson RL, et al. The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature. 1996;384(6605):129–34.

    Article  CAS  PubMed  Google Scholar 

  17. Taipale J, Cooper MK, Maiti T, Beachy PA. Patched acts catalytically to suppress the activity of Smoothened. Nature. 2002;418(6900):892–7.

    Article  CAS  PubMed  Google Scholar 

  18. Nachtergaele S, Mydock LK, Krishnan K, Rammohan J, Schlesinger PH, Covey DF, et al. Oxysterols are allosteric activators of the oncoprotein smoothened. Nat Chem Biol. 2012;8(2):211–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yue S, Tang LY, Tang Y, Tang Y, Shen QH, Ding J, et al. Requirement of Smurf-mediated endocytosis of Patched1 in sonic hedgehog signal reception. Elife. 2014;3:e02555.

    Google Scholar 

  20. Ruiz i Altaba A, Sanchez P, Dahmane N. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer. 2002;2(5):361–72.

    Article  CAS  PubMed  Google Scholar 

  21. 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):647–56.

    Article  CAS  PubMed  Google Scholar 

  22. 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):1244–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Martinelli DC, Fan CM. Gas1 extends the range of Hedgehog action by facilitating its signaling. Genes Dev. 2007;21(10):1231–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chuang PT, McMahon AP. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature. 1999;397(6720):617–21.

    Article  CAS  PubMed  Google Scholar 

  25. Katritch V, Cherezov V, Stevens RC. Structure-function of the G protein-coupled receptor superfamily. Annu Rev Pharmacol Toxicol. 2013;53:531–56.

    Article  CAS  PubMed  Google Scholar 

  26. Wang C, Wu H, Katritch V, Han GW, Huang XP, Liu W, et al. Structure of the human smoothened receptor bound to an antitumour agent. Nature. 2013;497(7449):338–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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):12607–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chen W, Ren XR, Nelson CD, Barak LS, Chen JK, Beachy PA, et al. Activity-dependent internalization of smoothened mediated by beta-arrestin 2 and GRK2. Science. 2004;306(5705):2257–60.

    Article  CAS  PubMed  Google Scholar 

  29. Kovacs JJ, Whalen EJ, Liu R, Xiao K, Kim J, Chen M, et al. Beta-arrestin-mediated localization of smoothened to the primary cilium. Science. 2008;320(5884):1777–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Svard J, Heby-Henricson K, Persson-Lek M, Rozell B, Lauth M, Bergstrom A, et al. Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Dev Cell. 2006;10(2):187–97.

    Article  PubMed  CAS  Google Scholar 

  31. 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):2001–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen Y, Yue S, Xie L, Pu XH, Jin T, Cheng SY. Dual Phosphorylation of suppressor of fused (Sufu) by PKA and GSK3beta regulates its stability and localization in the primary cilium. J Biol Chem. 2011;286(15):13502–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tempe D, Casas M, Karaz S, Blanchet-Tournier MF, Concordet JP. Multisite protein kinase A and glycogen synthase kinase 3beta phosphorylation leads to Gli3 ubiquitination by SCFbetaTrCP. Mol Cell Biol. 2006;26(11):4316–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kaesler S, Luscher B, Ruther U. Transcriptional activity of GLI1 is negatively regulated by protein kinase A. Biol Chem. 2000;381(7):545–51.

    Article  CAS  PubMed  Google Scholar 

  35. Tukachinsky H, Lopez LV, Salic A. A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes. J Cell Biol. 2010;191(2):415–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Riobo NA, Lu K, Ai X, Haines GM, Emerson Jr CP. Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling. Proc Natl Acad Sci U S A. 2006;103(12):4505–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hsu SH, Zhang X, Yu C, Li ZJ, Wunder JS, Hui CC, et al. Kif7 promotes hedgehog signaling in growth plate chondrocytes by restricting the inhibitory function of Sufu. Development. 2011;138(17):3791–801.

    Article  CAS  PubMed  Google Scholar 

  38. Chen MH, Wilson CW, Li YJ, Law KK, Lu CS, Gacayan R, et al. Cilium-independent regulation of Gli protein function by Sufu in Hedgehog signaling is evolutionarily conserved. Genes Dev. 2009;23(16):1910–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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):5442–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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):83–7.

    Article  CAS  PubMed  Google Scholar 

  41. Huangfu D, Anderson KV. Cilia and hedgehog responsiveness in the mouse. Proc Natl Acad Sci U S A. 2005;102(32):11325–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Liu A, Wang B, Niswander LA. Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development. 2005;132(13):3103–11.

    Article  CAS  PubMed  Google Scholar 

  43. Dennler S, Andre J, Alexaki I, Li A, Magnaldo T, ten Dijke P, et al. Induction of sonic hedgehog mediators by transforming growth factor-beta: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo. Cancer Res. 2007;67(14):6981–6.

    Article  CAS  PubMed  Google Scholar 

  44. Hui CC, Angers S. Gli proteins in development and disease. Annu Rev Cell Dev Biol. 2011;27:513–37.

    Article  CAS  PubMed  Google Scholar 

  45. Vokes SA, Ji H, McCuine S, Tenzen T, Giles S, Zhong S, et al. Genomic characterization of Gli-activator targets in sonic hedgehog-mediated neural patterning. Development. 2007;134(10):1977–89.

    Article  CAS  PubMed  Google Scholar 

  46. Ikram MS, Neill GW, Regl G, Eichberger T, Frischauf AM, Aberger F, et al. GLI2 is expressed in normal human epidermis and BCC and induces GLI1 expression by binding to its promoter. J Invest Dermatol. 2004;122(6):1503–9.

    Article  CAS  PubMed  Google Scholar 

  47. Mao J, Maye P, Kogerman P, Tejedor FJ, Toftgard R, Xie W, et al. Regulation of Gli1 transcriptional activity in the nucleus by Dyrk1. J Biol Chem. 2002;277(38):35156–61.

    Article  CAS  PubMed  Google Scholar 

  48. Riobo NA, Haines GM, Emerson Jr CP. Protein kinase C-delta and mitogen-activated protein/extracellular signal-regulated kinase-1 control GLI activation in hedgehog signaling. Cancer Res. 2006;66(2):839–45.

    Article  CAS  PubMed  Google Scholar 

  49. 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):484–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jenkins D. Hedgehog signalling: emerging evidence for non-canonical pathways. Cell Signal. 2009;21(7):1023–34.

    Article  CAS  PubMed  Google Scholar 

  51. Mille F, Thibert C, Fombonne J, Rama N, Guix C, Hayashi H, et al. The patched dependence receptor triggers apoptosis through a DRAL-caspase-9 complex. Nat Cell Biol. 2009;11(6):739–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chinchilla P, Xiao L, Kazanietz MG, Riobo NA. Hedgehog proteins activate pro-angiogenic responses in endothelial cells through non-canonical signaling pathways. Cell Cycle. 2010;9(3):570–9.

    Article  CAS  PubMed  Google Scholar 

  53. Polizio AH, Chinchilla P, Chen X, Manning DR, Riobo NA. Sonic Hedgehog activates the GTPases Rac1 and RhoA in a Gli-independent manner through coupling of smoothened to Gi proteins. Sci Signal 2011;4(200):pt7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Bijlsma MF, Borensztajn KS, Roelink H, Peppelenbosch MP, Spek CA. Sonic hedgehog induces transcription-independent cytoskeletal rearrangement and migration regulated by arachidonate metabolites. Cell Signal. 2007;19(12):2596–604.

    Article  CAS  PubMed  Google Scholar 

  55. Yauch RL, Gould SE, Scales SJ, Tang T, Tian H, Ahn CP, et al. A paracrine requirement for hedgehog signalling in cancer. Nature. 2008;455(7211):406–10.

    Article  CAS  PubMed  Google Scholar 

  56. Ji Z, Mei FC, Xie J, Cheng X. Oncogenic KRAS activates hedgehog signaling pathway in pancreatic cancer cells. J Biol Chem. 2007;282(19):14048–55.

    Article  CAS  PubMed  Google Scholar 

  57. Nolan-Stevaux O, Lau J, Truitt ML, Chu GC, Hebrok M, Fernandez-Zapico ME, et al. GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev. 2009;23(1):24–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Thomas MK, Lee JH, Rastalsky N, Habener JF. Hedgehog signaling regulation of homeodomain protein islet duodenum homeobox-1 expression in pancreatic beta-cells. Endocrinology. 2001;142(3):1033–40.

    Article  CAS  PubMed  Google Scholar 

  59. Fendrich V, Esni F, Garay MV, Feldmann G, Habbe N, Jensen JN, et al. Hedgehog signaling is required for effective regeneration of exocrine pancreas. Gastroenterology. 2008;135(2):621–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Syn WK, Jung Y, Omenetti A, Abdelmalek M, Guy CD, Yang L, et al. Hedgehog-mediated epithelial-to-mesenchymal transition and fibrogenic repair in nonalcoholic fatty liver disease. Gastroenterology. 2009;137(4):1478–88. e8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Strobel O, Rosow DE, Rakhlin EY, Lauwers GY, Trainor AG, Alsina J, et al. Pancreatic duct glands are distinct ductal compartments that react to chronic injury and mediate Shh-induced metaplasia. Gastroenterology. 2010;138(3):1166–77.

    Article  PubMed  Google Scholar 

  62. Jensen JN, Cameron E, Garay MV, Starkey TW, Gianani R, Jensen J. Recapitulation of elements of embryonic development in adult mouse pancreatic regeneration. Gastroenterology. 2005;128(3):728–41.

    Article  CAS  PubMed  Google Scholar 

  63. Kayed H, Kleeff J, Esposito I, Giese T, Keleg S, Giese N, et al. Localization of the human hedgehog-interacting protein (Hip) in the normal and diseased pancreas. Mol Carcinog. 2005;42(4):183–92.

    Article  CAS  PubMed  Google Scholar 

  64. Wang LW, Lin H, Lu Y, Xia W, Gao J, Li ZS. Sonic hedgehog expression in a rat model of chronic pancreatitis. World J Gastroenterol. 2014;20(16):4712–7.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Mathew E, Collins MA, Fernandez-Barrena MG, Holtz AM, Yan W, Hogan JO, et al. The transcription factor GLI1 modulates the inflammatory response during pancreatic tissue remodeling. J Biol Chem. 2014;289(40):27727–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Cano DA, Sekine S, Hebrok M. Primary cilia deletion in pancreatic epithelial cells results in cyst formation and pancreatitis. Gastroenterology. 2006;131(6):1856–69.

    Article  CAS  PubMed  Google Scholar 

  67. Seeley ES, Carriere C, Goetze T, Longnecker DS, Korc M. Pancreatic cancer and precursor pancreatic intraepithelial neoplasia lesions are devoid of primary cilia. Cancer Res. 2009;69(2):422–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cervantes S, Lau J, Cano DA, Borromeo-Austin C, Hebrok M. Primary cilia regulate Gli/Hedgehog activation in pancreas. Proc Natl Acad Sci U S A. 2010;107(22):10109–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Wong SY, Seol AD, So PL, Ermilov AN, Bichakjian CK, Epstein Jr EH, et al. Primary cilia can both mediate and suppress Hedgehog pathway-dependent tumorigenesis. Nat Med. 2009;15(9):1055–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Pasca di Magliano M, Hebrok M. Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer. 2003;3(12):903–11.

    Article  PubMed  Google Scholar 

  71. Liu M-S, Yang P-Y, Yeh T-S. Sonic Hedgehog signaling pathway in pancreatic cystic neoplasms and ductal adenocarcinoma. Pancreas. 2007;34(3):340–6.

    Article  CAS  PubMed  Google Scholar 

  72. Berman DM, Karhadkar SS, Maitra A, Montes De Oca R, Gerstenblith MR, Briggs K, et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature. 2003;425(6960):846–51.

    Article  CAS  PubMed  Google Scholar 

  73. Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 2011;25(7):717–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lo Re AE, Fernandez-Barrena MG, Almada LL, Mills LD, Elsawa SF, Lund G, et al. Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells. J Biol Chem. 2012;287(30):25325–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Lauth M, Bergstrom A, Shimokawa T, Tostar U, Jin Q, Fendrich V, et al. DYRK1B-dependent autocrine-to-paracrine shift of Hedgehog signaling by mutant RAS. Nat Struct Mol Biol. 2010;17(6):718–25.

    Article  CAS  PubMed  Google Scholar 

  76. Dennler S, Andre J, Verrecchia F, Mauviel A. Cloning of the human GLI2 Promoter: transcriptional activation by transforming growth factor-beta via SMAD3/beta-catenin cooperation. J Biol Chem. 2009;284(46):31523–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Nye MD, Almada LL, Fernandez-Barrena MG, Marks DL, Elsawa SF, Vrabel A, et al. The transcription factor GLI1 interacts with SMAD proteins to modulate transforming growth factor beta-induced gene expression in a p300/CREB-binding protein-associated factor (PCAF)-dependent manner. J Biol Chem. 2014;289(22):15495–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Javelaud D, Pierrat MJ, Mauviel A. Crosstalk between TGF-beta and hedgehog signaling in cancer. FEBS Lett. 2012;586(14):2016–25.

    Article  CAS  PubMed  Google Scholar 

  79. Joost S, Almada LL, Rohnalter V, Holz PS, Vrabel AM, Fernandez-Barrena MG, et al. GLI1 inhibition promotes epithelial-to-mesenchymal transition in pancreatic cancer cells. Cancer Res. 2012;72(1):88–99.

    Article  CAS  PubMed  Google Scholar 

  80. 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):714–23.

    Article  CAS  PubMed  Google Scholar 

  81. Martinez-Bosch N, Fernandez-Barrena MG, Moreno M, Ortiz-Zapater E, Munne-Collado J, Iglesias M, et al. Galectin-1 drives pancreatic carcinogenesis through stroma remodeling and Hedgehog signaling activation. Cancer Res. 2014;74(13):3512–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lee CJ, Dosch J, Simeone DM. Pancreatic cancer stem cells. J Clin Oncol. 2008;26(17):2806–12.

    Article  PubMed  Google Scholar 

  83. Dembinski JL, Krauss S. Characterization and functional analysis of a slow cycling stem cell-like subpopulation in pancreas adenocarcinoma. Clin Exp Metastasis. 2009;26(7):611–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Huang FT, Zhuan-Sun YX, Zhuang YY, Wei SL, Tang J, Chen WB, et al. Inhibition of hedgehog signaling depresses self-renewal of pancreatic cancer stem cells and reverses chemoresistance. Int J Oncol. 2012;41(5):1707–14.

    Article  CAS  PubMed  Google Scholar 

  85. 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.

    Article  CAS  PubMed  Google Scholar 

  86. 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.

    Article  CAS  PubMed  Google Scholar 

  87. Gu D, Liu H, Su GH, Zhang X, Chin-Sinex H, Hanenberg H, et al. Combining hedgehog signaling inhibition with focal irradiation on reduction of pancreatic cancer metastasis. Mol Cancer Ther. 2013;12(6):1038–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Douglas AE, Heim JA, Shen F, Almada LL, Riobo NA, Fernandez-Zapico ME, 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):30714–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Schneider P, Bayo-Fina JM, Singh R, Kumar Dhanyamraju P, Holz P, Baier A, et al. Identification of a novel actin-dependent signal transducing module allows for the targeted degradation of GLI1. Nat Commun. 2015;6:8023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. He S, Wang F, Yang L, Guo C, Wan R, Ke A, et al. Expression of DNMT1 and DNMT3a are regulated by GLI1 in human pancreatic cancer. PLoS One. 2011;6(11):e27684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Huang Y, Nahar S, Nakagawa A, Fernandez de Barrena MG, Mertz JA, Bryant BM, et al. Regulation of GLI underlies a role for BET bromodomains in pancreatic cancer growth and the tumor microenvironment. Clin Cancer Res. 2016;22:4259–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Erkan M, Michalski CW, Rieder S, Reiser-Erkan C, Abiatari I, Kolb A, et al. The activated stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma. Clin Gastroenterol Hepatol. 2008;6(10):1155–61.

    Article  PubMed  Google Scholar 

  93. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324(5933):1457–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331(6024):1612–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014;25(6):735–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Lee JJ, Perera RM, Wang H, Wu DC, Liu XS, Han S, et al. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc Natl Acad Sci U S A. 2014;111(30):E3091–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ozdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014;25(6):719–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Mahadevan D, Von Hoff DD. Tumor-stroma interactions in pancreatic ductal adenocarcinoma. Mol Cancer Ther. 2007;6(4):1186–97.

    Article  CAS  PubMed  Google Scholar 

  99. Singh AP, Arora S, Bhardwaj A, Srivastava SK, Kadakia MP, Wang B, et al. 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 kappaB: implications for bidirectional tumor-stromal interactions. J Biol Chem. 2012;287(46):39115–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Bailey JM, Mohr AM, Hollingsworth MA. Sonic hedgehog paracrine signaling regulates metastasis and lymphangiogenesis in pancreatic cancer. Oncogene. 2009;28(40):3513–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Bailey JM, Swanson BJ, Hamada T, Eggers JP, Singh PK, Caffery T, et al. Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin Cancer Res. 2008;14(19):5995–6004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Apte MV, Pirola RC, Wilson JS. Battle-scarred pancreas: role of alcohol and pancreatic stellate cells in pancreatic fibrosis. J Gastroenterol Hepatol. 2006;21(Suppl 3):S97–S101.

    Article  CAS  PubMed  Google Scholar 

  103. Yen TW, Aardal NP, Bronner MP, Thorning DR, Savard CE, Lee SP, et al. Myofibroblasts are responsible for the desmoplastic reaction surrounding human pancreatic carcinomas. Surgery. 2002;131(2):129–34.

    Article  PubMed  Google Scholar 

  104. Faouzi S, Le Bail B, Neaud V, Boussarie L, Saric J, Bioulac-Sage P, et al. Myofibroblasts are responsible for collagen synthesis in the stroma of human hepatocellular carcinoma: an in vivo and in vitro study. J Hepatol. 1999;30(2):275–84.

    Article  CAS  PubMed  Google Scholar 

  105. Koong AC, Mehta VK, Le QT, Fisher GA, Terris DJ, Brown JM, et al. Pancreatic tumors show high levels of hypoxia. Int J Radiat Oncol Biol Phys. 2000;48(4):919–22.

    Article  CAS  PubMed  Google Scholar 

  106. Erkan M, Reiser-Erkan C, Michalski CW, Deucker S, Sauliunaite D, Streit S, et al. Cancer-stellate cell interactions perpetuate the hypoxia-fibrosis cycle in pancreatic ductal adenocarcinoma. Neoplasia. 2009;11(5):497–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Chang Q, Jurisica I, Do T, Hedley DW. Hypoxia predicts aggressive growth and spontaneous metastasis formation from orthotopically grown primary xenografts of human pancreatic cancer. Cancer Res. 2011;71(8):3110–20.

    Article  CAS  PubMed  Google Scholar 

  108. Spivak-Kroizman TR, Hostetter G, Posner R, Aziz M, Hu C, Demeure MJ, et al. Hypoxia triggers hedgehog-mediated tumor-stromal interactions in pancreatic cancer. Cancer Res. 2013;73(11):3235–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Lei J, Ma J, Ma Q, Li X, Liu H, Xu Q, et al. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW, Lankisch PG, Andersen JR, et al. Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med. 1993;328(20):1433–7.

    Article  CAS  PubMed  Google Scholar 

  111. Ebrahimi B, Tucker SL, Li D, Abbruzzese JL, Kurzrock R. Cytokines in pancreatic carcinoma: correlation with phenotypic characteristics and prognosis. Cancer. 2004;101(12):2727–36.

    Article  CAS  PubMed  Google Scholar 

  112. Scholz A, Heinze S, Detjen KM, Peters M, Welzel M, Hauff P, et al. Activated signal transducer and activator of transcription 3 (STAT3) supports the malignant phenotype of human pancreatic cancer. Gastroenterology. 2003;125(3):891–905.

    Article  CAS  PubMed  Google Scholar 

  113. Wormann SM, Song L, Ai J, Diakopoulos KN, Kurkowski MU, Gorgulu K, et al. Loss of P53 function activates JAK2-STAT3 signaling to promote pancreatic tumor growth, stroma modification, and gemcitabine resistance in mice and is associated with patient survival. Gastroenterology. 2016;151(1):180–93. e12

    Article  PubMed  CAS  Google Scholar 

  114. Lesina M, Wormann SM, Neuhofer P, Song L, Algul H. Interleukin-6 in inflammatory and malignant diseases of the pancreas. Semin Immunol. 2014;26(1):80–7.

    Article  CAS  PubMed  Google Scholar 

  115. Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Kloppel G, et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell. 2011;19(4):456–69.

    Article  CAS  PubMed  Google Scholar 

  116. Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, et al. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a Hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol. 2015;33(36):4284–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. LoRusso PM, Rudin CM, Reddy JC, Tibes R, Weiss GJ, Borad MJ, 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):2502–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Mills LD, Zhang L, Marler R, Svingen P, Fernandez-Barrena MG, Dave M, et al. Inactivation of the transcription factor GLI1 accelerates pancreatic cancer progression. J Biol Chem. 2014;289(23):16516–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Mathew E, Zhang Y, Holtz AM, Kane KT, Song JY, Allen BL, et al. Dosage-dependent regulation of pancreatic cancer growth and angiogenesis by hedgehog signaling. Cell Rep. 2014;9(2):484–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Lauth M, Bergstrom A, Shimokawa T, Toftgard R. Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc Natl Acad Sci U S A. 2007;104(20):8455–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Fu J, Rodova M, Roy SK, Sharma J, Singh KP, Srivastava RK, et al. GANT-61 inhibits pancreatic cancer stem cell growth in vitro and in NOD/SCID/IL2R gamma null mice xenograft. Cancer Lett. 2013;330(1):22–32.

    Article  CAS  PubMed  Google Scholar 

  122. Miyazaki Y, Matsubara S, Ding Q, Tsukasa K, Yoshimitsu M, Kosai K, et al. Efficient elimination of pancreatic cancer stem cells by hedgehog/GLI inhibitor GANT61 in combination with mTOR inhibition. Mol Cancer. 2016;15(1):49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Xu Y, An Y, Wang X, Zha W, Li X. Inhibition of the Hedgehog pathway induces autophagy in pancreatic ductal adenocarcinoma cells. Oncol Rep. 2014;31(2):707–12.

    Article  PubMed  CAS  Google Scholar 

  124. Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997;89(9):3354–60.

    CAS  PubMed  Google Scholar 

  125. Kim J, Lee JJ, Kim J, Gardner D, Beachy PA. Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector. Proc Natl Acad Sci U S A. 2010;107(30):13432–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Beauchamp EM, Ringer L, Bulut G, Sajwan KP, Hall MD, Lee YC, et al. Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. J Clin Invest. 2011;121(1):148–60.

    Article  CAS  PubMed  Google Scholar 

  127. Wang W, Adachi M, Zhang R, Zhou J, Zhu D. A novel combination therapy with arsenic trioxide and parthenolide against pancreatic cancer cells. Pancreas. 2009;38(4):e114–23.

    Article  CAS  PubMed  Google Scholar 

  128. Damhofer H, Veenstra VL, Tol JA, van Laarhoven HW, Medema JP, Bijlsma MF. Blocking Hedgehog release from pancreatic cancer cells increases paracrine signaling potency. J Cell Sci. 2015;128(1):129–39.

    Article  CAS  PubMed  Google Scholar 

  129. Kim J, Tang JY, Gong R, Kim J, Lee JJ, Clemons KV, et al. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell. 2010;17(4):388–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Liu R, Li J, Zhang T, Zou L, Chen Y, Wang K, et al. Itraconazole suppresses the growth of glioblastoma through induction of autophagy. Autophagy. 2014;10(7):1241–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Chong CR, Xu J, Lu J, Bhat S, Sullivan Jr DJ, Liu JO. Inhibition of angiogenesis by the antifungal drug itraconazole. ACS Chem Biol. 2007;2(4):263–70.

    Article  CAS  PubMed  Google Scholar 

  132. Tsubamoto H, Sonoda T, Ikuta S, Tani S, Inoue K, Yamanaka N. Combination chemotherapy with itraconazole for treating metastatic pancreatic cancer in the second-line or additional setting. Anticancer Res. 2015;35(7):4191–6.

    CAS  PubMed  Google Scholar 

  133. Lockhart NR, Waddell JA, Schrock NE. Itraconazole therapy in a pancreatic adenocarcinoma patient: a case report. J Oncol Pharm Pract. 2016;22(3):528–32.

    Article  CAS  PubMed  Google Scholar 

  134. Block G, Patterson B, Subar A. Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr Cancer. 1992;18(1):1–29.

    Article  CAS  PubMed  Google Scholar 

  135. Aggarwal BB, Sundaram C, Malani N, Ichikawa H. Curcumin: the Indian solid gold. Adv Exp Med Biol. 2007;595:1–75.

    Article  PubMed  Google Scholar 

  136. Strimpakos AS, Sharma RA. Curcumin: preventive and therapeutic properties in laboratory studies and clinical trials. Antioxid Redox Signal. 2008;10(3):511–45.

    Article  CAS  PubMed  Google Scholar 

  137. 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(9):e46083.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Mizugishi K, Aruga J, Nakata K, Mikoshiba K. Molecular properties of Zic proteins as transcriptional regulators and their relationship to GLI proteins. J Biol Chem. 2001;276(3):2180–8.

    Article  CAS  PubMed  Google Scholar 

  139. Koyabu Y, Nakata K, Mizugishi K, Aruga J, Mikoshiba K. Physical and functional interactions between Zic and Gli proteins. J Biol Chem. 2001;276(10):6889–92.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We would like to thank Dr. David L. Marks for critically reading the manuscript. We would also like to thank the contributors to the excellent research studies cited within this chapter and apologize to any researchers whose work was omitted due to space constrains. This work was supported by the CA136526, Mayo Clinic Pancreatic SPORE P50 CA102701, and Mayo Clinic Center for Cell Signaling in Gastroenterology P30 DK84567 to M.E.F.-Z.

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Authors and Affiliations

  1. Schulze Center for Novel Therapeutics, Mayo Clinic, Gonda 19-216, 200 First Street SW, Rochester, MN, 55905, USA

    Tara L. Hogenson, Rachel L. O. Olson & Martin E. Fernandez-Zapico

  2. Center for Learning Innovation, University of Minnesota Rochester, Rochester, MN, USA

    Rachel L. O. Olson

Authors
  1. Tara L. Hogenson
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  2. Rachel L. O. Olson
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  3. Martin E. Fernandez-Zapico
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Corresponding author

Correspondence to Martin E. Fernandez-Zapico .

Editor information

Editors and Affiliations

  1. Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany

    John P. Neoptolemos

  2. Division of Research Department of Surgery and Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, Wisconsin, USA

    Raul Urrutia

  3. Division of Medical Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA

    James L. Abbruzzese

  4. Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany

    Markus W. Büchler

Section Editor information

  1. Mayo Clinic Cancer Center, Mayo Clinic, 200 First Street SW, 55905, Rochester, MN, USA

    Raul A. Urrutia

  2. Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany

    Markus W. Büchler

  3. Division of Surgery and Oncology, University of Liverpool, Daulby Street, Liverpool, UK

    John Neoptolemos

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Hogenson, T.L., Olson, R.L.O., Fernandez-Zapico, M.E. (2018). Hedgehog Signaling Plays a Dual Role in Pancreatic Carcinogenesis. In: Neoptolemos, J., Urrutia, R., Abbruzzese, J., Büchler, M. (eds) Pancreatic Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-7193-0_76

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