title: Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma.
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.
authors.affiliation: 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.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Rhim
authors.affiliation: Division of Hematology and Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Oberstein
authors.affiliation: 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.
authors.forename: Dafydd H
authors.initials: DH
authors.lastname: Thomas
authors.affiliation: Gastroenterology Division, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Emily T
authors.initials: ET
authors.lastname: Mirek
authors.affiliation: 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.
authors.forename: Carmine F
authors.initials: CF
authors.lastname: Palermo
authors.affiliation: 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.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Sastra
authors.affiliation: Gastroenterology Division, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Erin N
authors.initials: EN
authors.lastname: Dekleva
authors.affiliation: Sol Goldman Pancreatic Cancer Research Center and Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Saunders
authors.affiliation: Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Claudia P
authors.initials: CP
authors.lastname: Becerra
authors.affiliation: Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Ian W
authors.initials: IW
authors.lastname: Tattersall
authors.affiliation: 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.
authors.forename: C Benedikt
authors.initials: CB
authors.lastname: Westphalen
authors.affiliation: Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Kitajewski
authors.affiliation: Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Maite G
authors.initials: MG
authors.lastname: Fernandez-Barrena
authors.affiliation: Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernandez-Zapico
authors.affiliation: Sol Goldman Pancreatic Cancer Research Center and Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Iacobuzio-Donahue
authors.affiliation: 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: kenolive@columbia.edu.
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Olive
authors.affiliation: Gastroenterology Division, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: bstanger@exchange.upenn.edu.
authors.forename: Ben Z
authors.initials: BZ
authors.lastname: Stanger
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D055785:Gene Knockdown Techniques; D053823:Hedgehog Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011897:Random Allocation; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*
chemical_list: D000911:Antibodies, Monoclonal; C511761:DC101 monoclonal antibody; D053823:Hedgehog Proteins; D007074:Immunoglobulin G; D040262:Receptors, Vascular Endothelial Growth Factor