Hedgehog Signaling Plays a Dual Role in Pancreatic Carcinogenesis

  • Tara L. Hogenson
  • Rachel L. O. Olson
  • Martin E. Fernandez-Zapico
Reference work entry

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.

Keywords

Hedgehog GLI1 GLI2 GLI3 KRAS TGFβ EGFR Tumor microenvironment Vismodegib 

Notes

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.

References

  1. 1.
    Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature. 1980;287(5785):795–801.PubMedCrossRefGoogle Scholar
  2. 2.
    Bitgood MJ, Shen L, McMahon AP. Sertoli cell signaling by Desert hedgehog regulates the male germline. Curr Biol. 1996;6(3):298–304.PubMedCrossRefGoogle Scholar
  3. 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.PubMedCrossRefGoogle Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. 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.PubMedCrossRefGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 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.CrossRefPubMedGoogle Scholar
  14. 14.
    Rohatgi R, Milenkovic L, Scott MP. Patched1 regulates hedgehog signaling at the primary cilium. Science. 2007;317(5836):372–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Rosenbaum JL, Witman GB. Intraflagellar transport. Nat Rev Mol Cell Biol. 2002;3(11):813–25.CrossRefPubMedGoogle Scholar
  16. 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.PubMedCrossRefGoogle Scholar
  17. 17.
    Taipale J, Cooper MK, Maiti T, Beachy PA. Patched acts catalytically to suppress the activity of Smoothened. Nature. 2002;418(6900):892–7.PubMedCrossRefGoogle Scholar
  18. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 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. 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.PubMedCrossRefGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Martinelli DC, Fan CM. Gas1 extends the range of Hedgehog action by facilitating its signaling. Genes Dev. 2007;21(10):1231–43.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Chuang PT, McMahon AP. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature. 1999;397(6720):617–21.PubMedCrossRefGoogle Scholar
  25. 25.
    Katritch V, Cherezov V, Stevens RC. Structure-function of the G protein-coupled receptor superfamily. Annu Rev Pharmacol Toxicol. 2013;53:531–56.PubMedCrossRefGoogle Scholar
  26. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 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.PubMedCrossRefGoogle Scholar
  31. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 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.PubMedCrossRefGoogle Scholar
  35. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 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.PubMedCrossRefGoogle Scholar
  38. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 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.CrossRefPubMedGoogle Scholar
  41. 41.
    Huangfu D, Anderson KV. Cilia and hedgehog responsiveness in the mouse. Proc Natl Acad Sci U S A. 2005;102(32):11325–30.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 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.CrossRefPubMedGoogle Scholar
  43. 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.PubMedCrossRefGoogle Scholar
  44. 44.
    Hui CC, Angers S. Gli proteins in development and disease. Annu Rev Cell Dev Biol. 2011;27:513–37.PubMedCrossRefGoogle Scholar
  45. 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.PubMedCrossRefGoogle Scholar
  46. 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.PubMedCrossRefGoogle Scholar
  47. 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.PubMedCrossRefGoogle Scholar
  48. 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.PubMedCrossRefGoogle Scholar
  49. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Jenkins D. Hedgehog signalling: emerging evidence for non-canonical pathways. Cell Signal. 2009;21(7):1023–34.PubMedCrossRefGoogle Scholar
  51. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 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.PubMedCrossRefGoogle Scholar
  53. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 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.PubMedCrossRefGoogle Scholar
  55. 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.PubMedCrossRefGoogle Scholar
  56. 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.PubMedCrossRefGoogle Scholar
  57. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 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.PubMedCrossRefGoogle Scholar
  59. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 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. e8PubMedPubMedCentralCrossRefGoogle Scholar
  61. 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.PubMedCrossRefGoogle Scholar
  62. 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.PubMedCrossRefGoogle Scholar
  63. 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.PubMedCrossRefGoogle Scholar
  64. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 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.PubMedCrossRefGoogle Scholar
  67. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Pasca di Magliano M, Hebrok M. Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer. 2003;3(12):903–11.PubMedCrossRefGoogle Scholar
  71. 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.PubMedCrossRefGoogle Scholar
  72. 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.CrossRefPubMedGoogle Scholar
  73. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 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.PubMedCrossRefGoogle Scholar
  76. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Javelaud D, Pierrat MJ, Mauviel A. Crosstalk between TGF-beta and hedgehog signaling in cancer. FEBS Lett. 2012;586(14):2016–25.PubMedCrossRefGoogle Scholar
  79. 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.PubMedCrossRefGoogle Scholar
  80. 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.PubMedCrossRefGoogle Scholar
  81. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Lee CJ, Dosch J, Simeone DM. Pancreatic cancer stem cells. J Clin Oncol. 2008;26(17):2806–12.PubMedCrossRefGoogle Scholar
  83. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 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.PubMedCrossRefGoogle Scholar
  85. 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.PubMedCrossRefGoogle Scholar
  86. 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.PubMedCrossRefGoogle Scholar
  87. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 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.PubMedCrossRefGoogle Scholar
  93. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Mahadevan D, Von Hoff DD. Tumor-stroma interactions in pancreatic ductal adenocarcinoma. Mol Cancer Ther. 2007;6(4):1186–97.PubMedCrossRefGoogle Scholar
  99. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Bailey JM, Mohr AM, Hollingsworth MA. Sonic hedgehog paracrine signaling regulates metastasis and lymphangiogenesis in pancreatic cancer. Oncogene. 2009;28(40):3513–25.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 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.PubMedCrossRefGoogle Scholar
  103. 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.CrossRefPubMedGoogle Scholar
  104. 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.PubMedCrossRefGoogle Scholar
  105. 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.PubMedCrossRefGoogle Scholar
  106. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 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.PubMedCrossRefGoogle Scholar
  108. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 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.PubMedCrossRefGoogle Scholar
  111. 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.PubMedCrossRefGoogle Scholar
  112. 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.PubMedCrossRefGoogle Scholar
  113. 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. e12PubMedCrossRefGoogle Scholar
  114. 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.PubMedCrossRefGoogle Scholar
  115. 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.PubMedCrossRefGoogle Scholar
  116. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 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.PubMedCrossRefGoogle Scholar
  122. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 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.PubMedCrossRefGoogle Scholar
  124. 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.PubMedGoogle Scholar
  125. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 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.PubMedCrossRefGoogle Scholar
  127. 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.PubMedCrossRefGoogle Scholar
  128. 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.PubMedCrossRefGoogle Scholar
  129. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 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.PubMedCrossRefGoogle Scholar
  132. 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.PubMedGoogle Scholar
  133. 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.PubMedCrossRefGoogle Scholar
  134. 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.PubMedCrossRefGoogle Scholar
  135. 135.
    Aggarwal BB, Sundaram C, Malani N, Ichikawa H. Curcumin: the Indian solid gold. Adv Exp Med Biol. 2007;595:1–75.PubMedCrossRefGoogle Scholar
  136. 136.
    Strimpakos AS, Sharma RA. Curcumin: preventive and therapeutic properties in laboratory studies and clinical trials. Antioxid Redox Signal. 2008;10(3):511–45.PubMedCrossRefGoogle Scholar
  137. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 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.PubMedCrossRefGoogle Scholar
  139. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Tara L. Hogenson
    • 1
  • Rachel L. O. Olson
    • 1
    • 2
  • Martin E. Fernandez-Zapico
    • 1
  1. 1.Schulze Center for Novel TherapeuticsMayo ClinicRochesterUSA
  2. 2.Center for Learning InnovationUniversity of Minnesota RochesterRochesterUSA

Section editors and affiliations

  • Raul A. Urrutia
    • 1
  • Markus W. Büchler
    • 2
  • John Neoptolemos
    • 3
  1. 1.Mayo Clinic Cancer CenterMayo ClinicRochesterUSA
  2. 2.Department of General, Visceral and Transplantation SurgeryUniversity of HeidelbergHeidelbergGermany
  3. 3.Division of Surgery and OncologyUniversity of LiverpoolLiverpoolUK

Personalised recommendations