Novel Targets for the Treatment of Pancreatic Cancer II: The Hedgehog Signaling Pathway

  • Chris H. Takimoto
Part of the M. D. Anderson Solid Tumor Oncology Series book series (MDA)

Another very promising target for the treatment of pancreatic cancer is the Hedgehog signaling pathway. Currently, a large body of research is focused on modulating solid tumor stem cells as a means to selectively target malignant disease. This strategy is dependent upon the hypothesis that a small, discrete population of stem cells is present in solid tumors that posses an immortal self-renewal capacity with the potential for diverse differentiation. Regulation of cancer stem cells is modulated by a group of signaling molecules with important functions in embryonic development; these include Hedgehog, Notch, Wnt, and bone morphogenic protein/transforming growth factor-β (BMP/TGF-β). Altered regulation of these proteins may occur in a variety of cancer types. One target with particular promise for treating pancreatic cancer is the Hedgehog (Hh) signaling pathway (1, 2).

The Hedgehog signaling pathway is comprised of three creatively named secretory proteins, Sonic Hedgehog (SHH), Indian Hedgehog (IHH), and Desert Hedgehog (DHH). All can modulate cell-cell signaling and are involved in the control of tissue formation or “patterning” during normal embryonic development ( 2 ). In some systems, activation of Hh signaling promotes cell proliferation, whereas in others it can induce differentiation. In tumor cells, aberrant Hh signaling may contribute to the expression of an aggressive malignant phenotype. Recently, it has been a focus for new therapeutic strategies for treating various cancers, including pancreatic tumors ( 3 ).


Pancreatic Cancer Hedgehog Signaling Hedgehog Signaling Pathway Indian Hedgehog Gorlin Syndrome 


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  1. 1.
    Evangelista M, Tian H, de Sauvage FJ. The hedgehog signaling pathway in cancer. Clin Cancer Res 2006, 12:5924–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Rubin LL, de Sauvage FJ, 2006, Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov 5:1026–1033.CrossRefPubMedGoogle Scholar
  3. 3.
    Kayed H, Kleeff J, Osman T, 2006, Hedgehog signaling in the normal and diseased pancreas. Pancreas 32:119–129.CrossRefPubMedGoogle Scholar
  4. 4.
    Roessler E, Belloni E, Gaudenz K, 1997, Mutations in the C-terminal domain of Sonic Hedgehog cause holoprosencephaly. Hum Mol Genet 6:1847–1853.CrossRefPubMedGoogle Scholar
  5. 5.
    Pathi S, Pagan-Westphal S, Baker DP, 2001, Comparative biological responses to human Sonic, Indian, and Desert hedgehog. Mech Dev 106:107–117.CrossRefPubMedGoogle Scholar
  6. 6.
    Sacedon R, Varas A, Hernandez-Lopez C, 2003, Expression of hedgehog proteins in the human thymus. J Histochem Cytochem 51:1557–1566.PubMedGoogle Scholar
  7. 7.
    Kayed H, Kleeff J, Esposito I, 2005, Localization of the human hedgehog-interacting protein (Hip) in the normal and diseased pancreas. Mol Carcinog 42:183–192.CrossRefPubMedGoogle Scholar
  8. 8.
    Gorlin RJ, 2004, Nevoid basal cell carcinoma (Gorlin) syndrome. Genet Med 6:530–539.CrossRefPubMedGoogle Scholar
  9. 9.
    Lindstrom E, Shimokawa T, Toftgard R, 2006, PTCH mutations: distribution and analyses. Hum Mutat 27:215–219.CrossRefPubMedGoogle Scholar
  10. 10.
    Adolphe C, Hetherington R, Ellis T, 2006, Patched1 functions as a gatekeeper by promoting cell cycle progression. Cancer Res 66:2081–2088.CrossRefPubMedGoogle Scholar
  11. 11.
    Watkins DN, Berman DM, Baylin SB, 2003, Hedgehog signaling: progenitor phenotype in small-cell lung cancer. Cell Cycle 2:196–198.PubMedGoogle Scholar
  12. 12.
    Watkins DN, Berman DM, Burkholder SG, 2003, Hedgehog signalling within airway epithe-lial progenitors and in small-cell lung cancer. Nature 422:313–317.CrossRefPubMedGoogle Scholar
  13. 13.
    Berman DM, Karhadkar SS, Maitra A, 2003, Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425:846–851.CrossRefPubMedGoogle Scholar
  14. 14.
    Pasca di Magliano M, Sekine S, Ermilov A, 2006, Hedgehog/Ras interactions regulate early stages of pancreatic cancer. Genes Dev 20:3161–3173.CrossRefPubMedGoogle Scholar
  15. 15.
    Feldmann G, Dhara S, Fendrich V, 2007, Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res 67:2187–2196.CrossRefPubMedGoogle Scholar
  16. 16.
    Ji Z, Mei FC, Xie J, 2007, Oncogenic kras suppresses GLI1 degradation and activates hedge-hog signaling pathway in pancreatic cancer cells. J Biol Chem 278:38254–38259.Google Scholar
  17. 17.
    Williams JA, Guicherit OM, Zaharian BI, 2003, Identification of a small molecule inhibitor of the hedgehog signaling pathway: effects on basal cell carcinoma-like lesions. Proc Natl Acad Sci U S A 100:4616–4121.CrossRefPubMedGoogle Scholar

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© Springer Science + Business Media, LLC 2008

Authors and Affiliations

  • Chris H. Takimoto
    • 1
    • 2
  1. 1.University of Texas Health Science CenterSan Antonio
  2. 2.Accelerated Research TherapeuticsSan AntonioUSA

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