Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma

  • Cancer Cell. 2014 Jun 16;25(6):735-47. doi: 10.1016/j.ccr.2014.04.021.
Andrew D Rhim  1 ,  Paul E Oberstein  2 ,  Dafydd H Thomas  3 ,  Emily T Mirek  4 ,  Carmine F Palermo  3 ,  Stephen A Sastra  3 ,  Erin N Dekleva  4 ,  Tyler Saunders  5 ,  Claudia P Becerra  6 ,  Ian W Tattersall  6 ,  C Benedikt Westphalen  7 ,  Jan Kitajewski  6 ,  Maite G Fernandez-Barrena  8 ,  Martin E Fernandez-Zapico  8 ,  Christine Iacobuzio-Donahue  5 ,  Kenneth P Olive  9 ,  Ben Z Stanger  10
Affiliations
  • 1. Division of Gastroenterology, Department of Internal Medicine and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Gastroenterology Division, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 2. Division of Hematology and Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
  • 3. Division of Digestive and Liver Diseases in the Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
  • 4. Gastroenterology Division, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 5. Sol Goldman Pancreatic Cancer Research Center and Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA.
  • 6. Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
  • 7. Division of Digestive and Liver Diseases in the Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
  • 8. Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
  • 9. Division of Digestive and Liver Diseases in the Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: [email protected].
  • 10. Gastroenterology Division, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: [email protected].
PMID: 24856585 DOI: 10.1016/j.ccr.2014.04.021
Abstract

Sonic Hedgehog (Shh), a soluble ligand overexpressed by neoplastic cells in Pancreatic Ductal Adenocarcinoma (PDAC), drives formation of a fibroblast-rich desmoplastic stroma. To better understand its role in malignant progression, we deleted Shh in a well-defined mouse model of PDAC. As predicted, Shh-deficient Tumors had reduced stromal content. Surprisingly, such Tumors were more aggressive and exhibited undifferentiated histology, increased vascularity, and heightened proliferation--features that were fully recapitulated in control mice treated with a Smoothened inhibitor. Furthermore, administration of VEGFR blocking antibody selectively improved survival of Shh-deficient Tumors, indicating that Hedgehog-driven stroma suppresses tumor growth in part by restraining tumor angiogenesis. Together, these data demonstrate that some components of the tumor stroma can act to restrain tumor growth.