Dosage-dependent regulation of pancreatic cancer growth and angiogenesis by hedgehog signaling

Cell Rep. 2014 Oct 23;9(2):484-94. doi: 10.1016/j.celrep.2014.09.010. Epub 2014 Oct 9.


Pancreatic cancer, a hypovascular and highly desmoplastic cancer, is characterized by tumor expression of Hedgehog (HH) ligands that signal to fibroblasts in the surrounding stroma that in turn promote tumor survival and growth. However, the mechanisms and consequences of stromal HH pathway activation are not well understood. Here, we show that the HH coreceptors GAS1, BOC, and CDON are expressed in cancer-associated fibroblasts. Deletion of two coreceptors (Gas1 and Boc) in fibroblasts reduces HH responsiveness. Strikingly, these fibroblasts promote greater tumor growth in vivo that correlates with increased tumor-associated vascularity. In contrast, deletion of all three coreceptors (Gas1, Boc, and Cdon) results in the near complete abrogation of HH signaling and a corresponding failure to promote tumorigenesis and angiogenesis. Collectively, these data identify a role for HH dosage in pancreatic cancer promotion and may explain the clinical failure of HH pathway blockade as a therapeutic approach in pancreatic cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cells, Cultured
  • Fibroblasts / metabolism
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / metabolism
  • Gene Deletion
  • Gene Dosage*
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Immunoglobulin G / genetics
  • Immunoglobulin G / metabolism
  • Mice
  • Neovascularization, Pathologic / genetics*
  • Neovascularization, Pathologic / metabolism
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Signal Transduction*


  • Boc protein, mouse
  • Cdon protein, mouse
  • Cell Adhesion Molecules
  • Cell Cycle Proteins
  • GPI-Linked Proteins
  • Gas1 protein, mouse
  • Hedgehog Proteins
  • Immunoglobulin G
  • Receptors, Cell Surface