Hedgehog Signaling Pathways in Pancreatic Cancer Pathogenesis

  • Marina Pasca di Magliano
  • Matthias Hebrok
Reference work entry


Recent research has identified the Hedgehog signaling pathway as a key player in pancreatic cancer. The pathway is normally silent in the adult pancreas, but it gets activated in precursor lesions of pancreatic cancer as well as in invasive and metastatic pancreatic adenocarcinoma. Interestingly, mutations in the components of Hedgehog signaling have not been identified in pancreatic cancer; instead, the mechanism of activation relies on overexpression of one of the pathway ligands, Sonic Hedgehog, by the tumor cells. It is under investigation whether the secreted Hedgehog ligand mediates interactions among different cell types within the tumor. Our current knowledge indicates that the Hedgehog signaling pathway gets activated downstream of Kras (which is activated through a mutation in the vast majority of pancreatic cancers) and it synergizes with the Kras activity to promote tumor progression. Interestingly, the activity of the Hedgehog pathway appears to regulate processes such as tumor metastasis, one of the factors that preclude treatment in human patients. Current research is aimed at fully understanding the role of the pathway in pancreas cancer formation and progression and at establishing whether inhibition of this pathway might represent a valid approach to treat pancreatic cancer in the clinic.


Pancreatic Cancer Basal Cell Carcinoma Pancreatic Adenocarcinoma Primary Cilium Intraductal Papillary Mucinous Neoplasm 
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  1. 1.
    Jacob L, Lum L: Hedgehog signaling pathway. Sci STKE 2007;2007(407):cm6.Google Scholar
  2. 2.
    Wang Y, McMahon AP, Allen BL: Shifting paradigms in Hedgehog signaling. Curr Opin Cell Biol 2007;19(2):159–165.CrossRefPubMedGoogle Scholar
  3. 3.
    Eggenschwiler JT, Anderson KV: Cilia and developmental signaling. Annu Rev Cell Dev Biol 2007;23:345–373.CrossRefPubMedGoogle Scholar
  4. 4.
    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.CrossRefPubMedGoogle Scholar
  5. 5.
    Huangfu D, Anderson KV: Cilia and Hedgehog responsiveness in the mouse. Proc Natl Acad Sci USA 2005;102(32):11325–11330.CrossRefPubMedGoogle Scholar
  6. 6.
    Ingham PW: The patched gene in development and cancer. Curr Opin Genet Dev 1998;8(1):88–94.CrossRefPubMedGoogle Scholar
  7. 7.
    Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam CW, Hynes M, Goddard A, Rosenthal A, Epstein EH, Jr, de Sauvage FJ. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 1998;391(6662):90–92.CrossRefPubMedGoogle Scholar
  8. 8.
    Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X, Agatep R, Chiappa S, Gao L, Lowrance A, Hao A, Goldstein AM, Stavrou T, Scherer SW, Dura WT, Wainwright B, Squire JA, Rutka JT, Hogg D: Mutations in SUFU predispose to medulloblastoma. Nat Genet 2002;31(3):306–310.CrossRefPubMedGoogle Scholar
  9. 9.
    Reifenberger J, Wolter M, Knobbe CB, Köhler B, Schönicke A, Scharwächter C, Kumar K, Blaschke B, Ruzicka T, Reifenberger G: Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. Br J Dermatol 2005;152(1):43–51.CrossRefPubMedGoogle Scholar
  10. 10.
    Sanchez P, Hernández AM, Stecca B, Kahler AJ, DeGueme AM, Barrett A, Beyna M, Datta MW, Datta S, Ruiz i Altaba A: Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling. Proc Natl Acad Sci USA 2004;101(34):12561–12566.CrossRefPubMedGoogle Scholar
  11. 11.
    Karhadkar SS, Bova GS, Abdallah N, Dhara S, Gardner D, Maitra A, Isaacs JT, Berman DM, Beachy PA: Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 2004;431(7009):707–712.CrossRefPubMedGoogle Scholar
  12. 12.
    Sheng T, Li C, Zhang X, Chi S, He N, Chen K, McCormick F, Gatalica Z, Xie J: Activation of the hedgehog pathway in advanced prostate cancer. Mol Cancer 2004;3:29.CrossRefPubMedGoogle Scholar
  13. 13.
    Dierks C, Grbic J, Zirlik K, Beigi R, Englund NP, Guo GR, Veelken H, Engelhardt M, Mertelsmann R, Kelleher JF, Schultz P, Warmuth M: Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nat Med 2007;13(8):944–951.CrossRefPubMedGoogle Scholar
  14. 14.
    Hruban RH, Adsay NV, Albores-Saavedra J, Compton C, Garrett ES, Goodman SN, Kern SE, Klimstra DS, Klöppel G, Longnecker DS, Lüttges J, Offerhaus GJ: Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol 2001;25(5):579–586.CrossRefPubMedGoogle Scholar
  15. 15.
    Hingorani SR: Location, location, location: precursors and prognoses for pancreatic cancer. Gastroenterology 2007;133(1):345–350.CrossRefPubMedGoogle Scholar
  16. 16.
    Hruban RH, van Mansfeld AD, Offerhaus GJ, van Weering DH, Allison DC, Goodman SN, Kensler TW, Bose KK, Cameron JL, Bos JL: K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol 1993;143(2):545–554.PubMedGoogle Scholar
  17. 17.
    Hruban RH, Wilentz RE, Kern SE: Genetic progression in the pancreatic ducts. Am J Pathol 2000;156(6):1821–1825.PubMedGoogle Scholar
  18. 18.
    Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, Ross S, Conrads TP, Veenstra TD, Hitt BA, Kawaguchi Y, Johann D, Liotta LA, Crawford HC, Putt ME, Jacks T, Wright CV, Hruban RH, Lowy AM, Tuveson DA: Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 2003;4(6):437–450.CrossRefPubMedGoogle Scholar
  19. 19.
    Tada M, Ohashi M, Shiratori Y, Okudaira T, Komatsu Y, Kawabe T, Yoshida H, Machinami R, Kishi K, Omata M: Analysis of K-ras gene mutation in hyperplastic duct cells of the pancreas without pancreatic disease. Gastroenterology 1996;110(1):227–231.CrossRefPubMedGoogle Scholar
  20. 20.
    Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, Rustgi AK, Chang S, Tuveson DA: Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005;7(5):469–483.CrossRefPubMedGoogle Scholar
  21. 21.
    Aguirre AJ, Bardeesy N, Sinha M, Lopez L, Tuveson DA, Horner J, Redston MS, DePinho RA: Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev 2003;17(24):3112–3126.CrossRefPubMedGoogle Scholar
  22. 22.
    Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA: Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 2006;20(10):1218–1249.CrossRefPubMedGoogle Scholar
  23. 23.
    Fendrich V, Esni F, Garay MV, Feldmann G, Habbe N, Jensen JN, Dor Y, Stoffers D, Jensen J, Leach SD, Maitra A: Hedgehog signaling is required for effective regeneration of exocrine pancreas. Gastroenterology 2008;135(2):621–631.CrossRefPubMedGoogle Scholar
  24. 24.
    Thayer SP, Pasca di Magliano M, 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(6960):851–856.CrossRefPubMedGoogle Scholar
  25. 25.
    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(6960):846–851.CrossRefPubMedGoogle Scholar
  26. 26.
    Apelqvist A, Ahlgren U, Edlund H: Sonic hedgehog directs specialised mesoderm differentiation in the intestine and pancreas. Curr Biol 1997;7(10):801–814.CrossRefPubMedGoogle Scholar
  27. 27.
    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;20(22):3161–3173.CrossRefPubMedGoogle Scholar
  28. 28.
    Desai BM, Oliver-Krasinski J, De Leon DD, Farzad C, Hong N, Leach SD, Stoffers DA: Preexisting pancreatic acinar cells contribute to acinar cell, but not islet beta cell, regeneration. J Clin Invest 2007;117(4):971–977.CrossRefPubMedGoogle Scholar
  29. 29.
    Means AL, Xu Y, Zhao A, Ray KC, Gu G: A CK19(CreERT) knockin mouse line allows for conditional DNA recombination in epithelial cells in multiple endodermal organs. Genesis 2008;46(6):318–323.CrossRefPubMedGoogle Scholar
  30. 30.
    Murtaugh LC, Law AC, Dor Y, Melton DA: Beta-catenin is essential for pancreatic acinar but not islet development. Development 2005;132(21):4663–4674.CrossRefPubMedGoogle Scholar
  31. 31.
    Park SW, Davison JM, Rhee J, Hruban RH, Maitra A, Leach SD: Oncogenic KRAS induces progenitor cell expansion and malignant transformation in  zebrafish exocrine pancreas. Gastroenterology 2008;134(7):2080–2090.CrossRefPubMedGoogle Scholar
  32. 32.
    Prasad NB, Biankin AV, Fukushima N, Maitra A, Dhara S, Elkahloun AG, Hruban RH, Goggins M, Leach SD: Gene expression profiles in pancreatic intraepithelial neoplasia reflect the effects of Hedgehog signaling on pancreatic ductal epithelial cells. Cancer Res 2005;65(5):1619–1626.CrossRefPubMedGoogle Scholar
  33. 33.
    Guerra C, Schuhmacher AJ, Cañamero M, Grippo PJ, Verdaguer L, Pérez-Gallego L, Dubus P, Sandgren EP, Barbacid M: Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 2007;11(3):291–302.CrossRefPubMedGoogle Scholar
  34. 34.
    Steinle AU, Weidenbach H, Wagner M, Adler G, Schmid RM: NF-kappaB/Rel activation in cerulein pancreatitis. Gastroenterology 1999;116(2):420–430.CrossRefPubMedGoogle Scholar
  35. 35.
    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(14):7041–7049.CrossRefPubMedGoogle Scholar
  36. 36.
    Pola R, Ling LE, Silver M, Corbley MJ, Kearney M, Blake Pepinsky R, Shapiro R, Taylor FR, Baker DP, Asahara T, Isner JM: The morphogen Sonic hedgehog is an indirect angiogenic agent upregulating two families of angiogenic growth factors. Nat Med 2001;7(6):706–711.CrossRefPubMedGoogle Scholar
  37. 37.
    Kanda S, Mochizuki Y, Suematsu T, Miyata Y, Nomata K, Kanetake H: Sonic hedgehog induces capillary morphogenesis by endothelial cells through phosphoinositide 3-kinase. J Biol Chem. 2003;278(10):8244–8249.CrossRefPubMedGoogle Scholar
  38. 38.
    Yamazaki M, Nakamura K, Mizukami Y, Ii M, Sasajima J, Sugiyama Y, Nishikawa T, Nakano Y, Yanagawa N, Sato K, Maemoto A, Tanno S, Okumura T, Karasaki H, Kono T, Fujiya M, Ashida T, Chung DC, Kohgo Y: Sonic hedgehog derived from human pancreatic cancer cells augments angiogenic function of endothelial progenitor cells. Cancer Sci 2008;99(6):1131–1138.CrossRefPubMedGoogle Scholar
  39. 39.
    Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, Mullendore M, Karikari C, Alvarez H, Iacobuzio-Donahue C, Jimeno A, Gabrielson KL, Matsui W, Maitra A: Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res 2007;67(5):2187–2196.CrossRefPubMedGoogle Scholar
  40. 40.
    Li X, Deng W, Nail CD, Bailey SK, Kraus MH, Ruppert JM, Lobo-Ruppert SM: Snail induction is an early response to Gli1 that determines the efficiency of epithelial transformation. Oncogene 2006;25(4):609–621.PubMedGoogle Scholar
  41. 41.
    Ohuchida K, Mizumoto K, Fujita H, Yamaguchi H, Konomi H, Nagai E, Yamaguchi K, Tsuneyoshi M, Tanaka M: Sonic hedgehog is an early developmental marker of intraductal papillary mucinous neoplasms: clinical implications of mRNA levels in pancreatic juice. J Pathol 2006;210(1):42–48.CrossRefPubMedGoogle Scholar
  42. 42.
    Satoh K, Kanno A, Hamada S, Hirota M, Umino J, Masamune A, Egawa S, Motoi F, Unno M, Shimosegawa T: Expression of Sonic hedgehog signaling pathway correlates with the tumorigenesis of intraductal papillary mucinous neoplasm of the pancreas. Oncol Rep 2008;19(5):1185–1190.PubMedGoogle Scholar
  43. 43.
    Jang KT, Lee KT, Lee JG, Choi SH, Heo JS, Choi DW, Ahn G: Immunohistochemical expression of Sonic hedgehog in intraductal papillary mucinous tumor of the pancreas. Appl Immunohistochem Mol Morphol 2007;15(3):294–298.CrossRefPubMedGoogle Scholar
  44. 44.
    Liu MS, Yang PY, Yeh TS: Sonic hedgehog signaling pathway in pancreatic cystic neoplasms and ductal adenocarcinoma. Pancreas 2007;34(3):340–346.CrossRefPubMedGoogle Scholar
  45. 45.
    Izeradjene K, Combs C, Best M, Gopinathan A, Wagner A, Grady WM, Deng CX, Hruban RH, Adsay NV, Tuveson DA, Hingorani SR: Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas. Cancer Cell 2007;11(3):229–243.CrossRefPubMedGoogle Scholar
  46. 46.
    Siveke JT, Einwächter H, Sipos B, Lubeseder-Martellato C, Klöppel G, Schmid RM: Concomitant pancreatic activation of Kras(G12D) and Tgfa results in cystic papillary neoplasms reminiscent of human IPMN. Cancer Cell 2007;12(3):266–279.CrossRefPubMedGoogle Scholar
  47. 47.
    Nielsen SK, Møllgård K, Clement CA, Veland IR, Awan A, Yoder BK, Novak I, Christensen ST: Characterization of primary cilia and Hedgehog signaling during development of the human pancreas and in human pancreatic duct cancer cell lines. Dev Dyn 2008;237(8):2039–2052.CrossRefPubMedGoogle Scholar
  48. 48.
    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(3):1030–1037.CrossRefPubMedGoogle Scholar
  49. 49.
    Feldmann G, Habbe N, Dhara S, Bisht S, Alvarez H, Fendrich V, Beaty R, Mullendore M, Karikari C, Bardeesy N, Oullette MM, Yu W, Maitra A: Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer. Gut 2008;57(10):1420–1430.CrossRefPubMedGoogle Scholar
  50. 50.
    Brunton SA, Stibbard JH, Rubin LL, Kruse LI, Guicherit OM, Boyd EA, Price S: Potent inhibitors of the hedgehog signaling pathway. J Med Chem 2008;51(5):1108–1110.CrossRefPubMedGoogle Scholar
  51. 51.
    Lee J, Wu X, Pasca di Magliano M, Peters EC, Wang Y, Hong J, Hebrok M, Ding S, Cho CY, Schultz PG: A small-molecule antagonist of the hedgehog signaling pathway. Chembiochem 2007;8(16):1916–1919.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Marina Pasca di Magliano
    • 1
  • Matthias Hebrok
    • 2
  1. 1.University of MichiganAnn ArborUSA
  2. 2.University of CaliforniaSan FranciscoUSA

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