title: Inhibition of the hedgehog pathway targets the tumor-associated stroma in pancreatic cancer.
abstract: OBJECTIVE
  The Hedgehog (Hh) pathway has emerged as an important pathway in multiple tumor types and is thought to be dependent on a paracrine signaling mechanism. The purpose of this study was to determine the role of pancreatic cancer-associated fibroblasts (human pancreatic stellate cells, HPSCs) in Hh signaling. In addition, we evaluated the efficacy of a novel Hh antagonist, AZD8542, on tumor progression with an emphasis on the role of the stroma compartment.
  
  
  METHODS
  Expression of Hh pathway members and activation of the Hh pathway were analyzed in both HPSCs and pancreatic cancer cells. We tested the effects of Smoothened (SMO) inhibition with AZD8542 on tumor growth in vivo using an orthotopic model of pancreatic cancer containing varying amounts of stroma.
  
  
  RESULTS
  HPSCs expressed high levels of SMO receptor and low levels of Hh ligands, whereas cancer cells showed the converse expression pattern. HPSC proliferation was stimulated by Sonic Hedgehog with upregulation of downstream GLI1 mRNA. These effects were abrogated by AZD8542 treatment. In an orthotopic model of pancreatic cancer, AZD8542 inhibited tumor growth only when HPSCs were present, implicating a paracrine signaling mechanism dependent on stroma. Further evidence of paracrine signaling of the Hh pathway in prostate and colon cancer models is provided, demonstrating the broader applicability of our findings.
  
  
  CONCLUSIONS
  Based on the use of our novel human-derived pancreatic cancer stellate cells, our results suggest that Hh-targeted therapies primarily affect the tumor-associated stroma, rather than the epithelial compartment.
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77230, USA. rhwang@mdanderson.org
authors.forename: Rosa F
authors.initials: RF
authors.lastname: Hwang
authors.forename: Todd T
authors.initials: TT
authors.lastname: Moore
authors.forename: Maureen Mertens
authors.initials: MM
authors.lastname: Hattersley
authors.forename: Meghan
authors.initials: M
authors.lastname: Scarpitti
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
authors.forename: Erik
authors.initials: E
authors.lastname: Devereaux
authors.forename: Vijaya
authors.initials: V
authors.lastname: Ramachandran
authors.forename: Thiruvengadam
authors.initials: T
authors.lastname: Arumugam
authors.forename: Baoan
authors.initials: B
authors.lastname: Ji
authors.forename: Craig D
authors.initials: CD
authors.lastname: Logsdon
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Brown
authors.forename: Robert
authors.initials: R
authors.lastname: Godin
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000502:physiology; D019899:Paracrine Communication / Q000187:drug effects*; D011471:Prostatic Neoplasms / Q000188:drug therapy; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D000072086:Smoothened Receptor; D015854:Up-Regulation
chemical_list: C000591817:AZD8542; D000970:Antineoplastic Agents; D001549:Benzamides; D053823:Hedgehog Proteins; D007093:Imidazoles; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; C491022:Smo protein, mouse; D000072086:Smoothened Receptor