title: Prevention of Barrett esophagus and esophageal adenocarcinoma by smoothened inhibitor in a rat model of gastroesophageal reflux disease.
abstract: BACKGROUND
  Activated hedgehog (Hh) pathway is associated with development of both Barrett esophagus (BE) and esophageal adenocarcinoma (EAC). We hypothesize that blockade of the Hh pathway with smoothened (Smo) inhibitor can prevent the development of BE/EAC in the Levrat model, in which induced gastroduodenoesophageal reflux (GDER) leads to esophageal carcinogenesis.
  
  
  METHODS
  GDER was induced in 6- to 8-week-old male Sprague-Dawley rats. The Smo inhibitor (10 mg/kg/d) was given orally on postoperative weeks 10 to 16, 18 to 22, and 24 to 28, and rats were killed on week 28. The primary outcome measure was the incidence of BE and EAC. To examine potential therapeutic effects of Smo inhibition on tumor tissue, semiquantitative immunohistochemistry for Ki-67 and caspase 3 was performed. In treated animals that developed cancer, gene expression was analyzed.
  
  
  RESULTS
  Thirty-eight of 48 controls and 32 of 46 treated animals survived to 28 weeks. messenger ribonucleic acid (mRNA) expression of Indian Hh, a ligand of transmembrane receptor patched 1, was 184× higher in BE and 99× higher in EAC compared with normal esophageal tissue (P = 0.0239 and P = 0.0004, respectively). Compared with controls, the incidence of BE and EAC was decreased in treated animals by 35.7% (relative risk reduction, 36%; P = 0.0015) and 36% (relative risk reduction, 62%; P = 0.0033), respectively. Compared with untreated EAC, Ki-67 was downregulated (P = 0.04) and cleaved caspase 3 was no different in treated EAC (P = 0.398). Of the 84 well-known genes involved in cancer drug resistance, 50 were dysregulated in treated EAC (P < 0.05 for each gene).
  
  
  CONCLUSIONS
  Smo inhibitor prevents the development of BE and EAC in an in vivo model of GDER.
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Gibson
authors.forename: Ali H
authors.initials: AH
authors.lastname: Zaidi
authors.forename: Jon M
authors.initials: JM
authors.lastname: Davison
authors.forename: Alejandro F
authors.initials: AF
authors.lastname: Sanz
authors.forename: Bruce
authors.initials: B
authors.lastname: Hough
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Komatsu
authors.forename: Juliann E
authors.initials: JE
authors.lastname: Kosovec
authors.forename: Astha
authors.initials: A
authors.lastname: Bhatt
authors.forename: Usha
authors.initials: U
authors.lastname: Malhotra
authors.forename: Tyler
authors.initials: T
authors.lastname: Foxwell
authors.forename: Christina L
authors.initials: CL
authors.lastname: Rotoloni
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Hoppo
authors.forename: Blair A
authors.initials: BA
authors.lastname: Jobe
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology* / Q000517:prevention & control*; D000818:Animals; D001471:Barrett Esophagus / Q000209:etiology* / Q000517:prevention & control*; D001549:Benzamides / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000209:etiology* / Q000517:prevention & control*; D005764:Gastroesophageal Reflux / Q000150:complications*; D015870:Gene Expression; D053823:Hedgehog Proteins / Q000378:metabolism; D007124:Immunoenzyme Techniques; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D000072086:Smoothened Receptor
chemical_list: C583051:BMS-833923; D001549:Benzamides; D053823:Hedgehog Proteins; D019394:Ki-67 Antigen; D011799:Quinazolines; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C498555:Smo protein, rat; D000072086:Smoothened Receptor; D053148:Caspase 3