Influence of acid reflux on stromal epithelial interaction in Barrett?s esophagus

Summary

Principal Investigator: GANAPATHY PRASAD
Abstract: DESCRIPTION (provided by applicant): Barrett's esophagus (BE) is an important risk factor for esophageal adenocarcinoma. Duodenogastric reflux leads to chronic inflammation and the development of BE in a subset of patients1, 2. Chronic inflammation may activate fibroblasts which can promote carcinogenesis in the gastrointestinal tract by secreting growth factors 4. Myofibroblast derived growth factors are known to promote proliferation of epithelial neoplasms 5-7. Although acid and bile promote proliferation of Barrett's epithelium, control of reflux decreases proliferation and promotes differentiation 8 and control of acid reflux is associated with lower risk of dysplasia in BE 9, the precise mechanisms, the degree of reflux control needed and the influence of acid reflux on BE stroma is unknown. Based on these concepts, it is our hypothesis that gastroduodenal reflux results in stromal fibroblast activation which promotes oncogenesis via growth factor secretion. The first aim of this proposal will be to compare stromal activation in patients with known BE without dysplasia, who have controlled and persistent acid reflux. Patients with BE without dysplasia will undergo endoscopy with biopsies and a 24 hour pH study on treatment with proton pump inhibitors (PPIs). Patients will then be divided into Group A (GER): with acid reflux (characterized by either presence of esophagitis (as determined by the Los Angeles classification) 10 on endoscopy, and/or a positive pH study defined by standard criteria 11 and Group B (NGER): with controlled acid reflux (negative endoscopy and pH study on treatment). We will compare the presence of myofibroblasts and expression of COX-2, assessed by immunohistochemistry between the 2 groups. We will also assess the influence of acid and bile on esophageal fibroblast proliferation and apoptosis in vitro. The second aim of this application will be to assess and compare the presence of stromal derived growth factors (EGF, HGF) and their receptors (EGFR, HER2 for EGF and c-Met for HGF) in BE biopsies of subjects with persistent and controlled acid reflux using immunohistochemistry and quantitative PCR. In addition we will also assess stromal epithelial interaction in BE using co-culture models and attempt to block this interaction by using inhibitors of stromal derived growth factors. The goal of our research program is to identify and ultimately study with clinical trials novel chemopreventive agents in Barrett's esophagus. This translational proposal aims to identify novel targets for chemoprevention by studying the mechanisms of and the influence of acid reflux on stromal-epithelial interaction in Barrett's esophagus. Successful completion of this study will help further define the role of acid reflux control in modulating stromal activation and carcinogenesis in BE. Preliminary data gathered from these experiments would allow us to further investigate mechanisms of stromal epithelial interaction in BE as well as identify evidence based molecular targets for the chemoprevention of neoplasia in BE and launch clinical trials for chemopreventive agents. Project Narrative The purpose of this study is to determine the association between acid reflux and cell changes in Barrett's esophagus.
Funding Period: 2008-07-01 - 2010-06-30
more information: NIH RePORT

Top Publications

  1. pmc Endoscopic and surgical treatment of mucosal (T1a) esophageal adenocarcinoma in Barrett's esophagus
    Ganapathy A Prasad
    Barrett s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
    Gastroenterology 137:815-23. 2009
  2. pmc Depth of submucosal invasion does not predict lymph node metastasis and survival of patients with esophageal carcinoma
    Rami J Badreddine
    Barrett s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
    Clin Gastroenterol Hepatol 8:248-53. 2010
  3. pmc Prevalence and predictors of recurrent neoplasia after ablation of Barrett's esophagus
    Rami J Badreddine
    Barrett s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
    Gastrointest Endosc 71:697-703. 2010
  4. pmc Predictors of progression in Barrett's esophagus: current knowledge and future directions
    Ganapathy A Prasad
    Division of Gastroenterology and Hepatology, Barrett s Esophagus Unit, Mayo Clinic, Rochester, MN 55905, USA
    Am J Gastroenterol 105:1490-1502. 2010
  5. pmc Endoscopic mucosal resection in the management of esophageal neoplasia: current status and future directions
    Vikneswaran Namasivayam
    Barrett s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA
    Clin Gastroenterol Hepatol 8:743-54; quiz e96. 2010
  6. pmc Epidemiology and natural history of intestinal metaplasia of the gastroesophageal junction and Barrett's esophagus: a population-based study
    Kee Wook Jung
    Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
    Am J Gastroenterol 106:1447-55; quiz 1456. 2011

Scientific Experts

  • Ganapathy A Prasad
  • Kenneth K Wang
  • Rami J Badreddine
  • Lori S Lutzke
  • Kelly T Dunagan
  • Kee Wook Jung
  • Vikneswaran Namasivayam
  • Lynn S Borkenhagen
  • G Richard Locke
  • Cathy D Schleck
  • David A Katzka
  • Alan R Zinsmeister
  • Debra M Geno
  • Nicholas J Talley
  • Mary Frederickson
  • Tsung Teh Wu
  • Yvonne Romero
  • Navtej S Buttar
  • Jason T Lewis
  • Louis M Wong Kee Song

Detail Information

Publications6

  1. pmc Endoscopic and surgical treatment of mucosal (T1a) esophageal adenocarcinoma in Barrett's esophagus
    Ganapathy A Prasad
    Barrett s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
    Gastroenterology 137:815-23. 2009
    ..Long-term outcomes of patients treated endoscopically and surgically for mucosal EAC are unknown. We compared long-term outcomes of patients with mucosal EAC treated endoscopically and surgically...
  2. pmc Depth of submucosal invasion does not predict lymph node metastasis and survival of patients with esophageal carcinoma
    Rami J Badreddine
    Barrett s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
    Clin Gastroenterol Hepatol 8:248-53. 2010
    ..We evaluated the impact of depth of submucosal invasion on the presence of metastatic lymphadenopathy and survival in patients with esophageal adenocarcinoma...
  3. pmc Prevalence and predictors of recurrent neoplasia after ablation of Barrett's esophagus
    Rami J Badreddine
    Barrett s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
    Gastrointest Endosc 71:697-703. 2010
    ..The incidence and risk factors for recurrence of dysplasia after ablation of Barrett's esophagus (BE) have not been well defined...
  4. pmc Predictors of progression in Barrett's esophagus: current knowledge and future directions
    Ganapathy A Prasad
    Division of Gastroenterology and Hepatology, Barrett s Esophagus Unit, Mayo Clinic, Rochester, MN 55905, USA
    Am J Gastroenterol 105:1490-1502. 2010
    ..Although it would be challenging, creation of such a score has the potential to improve outcomes and make the management of patients with BE more cost-effective...
  5. pmc Endoscopic mucosal resection in the management of esophageal neoplasia: current status and future directions
    Vikneswaran Namasivayam
    Barrett s Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA
    Clin Gastroenterol Hepatol 8:743-54; quiz e96. 2010
    ..Training requirements to achieve proficiency in endoscopic mucosal resection as well as potential quality measures to assess competence also are proposed in this review...
  6. pmc Epidemiology and natural history of intestinal metaplasia of the gastroesophageal junction and Barrett's esophagus: a population-based study
    Kee Wook Jung
    Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
    Am J Gastroenterol 106:1447-55; quiz 1456. 2011
    ....