title: Insulin/Insulin-Like Growth Factor-1 Pathway in Barrett's Carcinogenesis.
abstract: OBJECTIVE
  Obesity-associated carcinogenesis is postulated to be mediated through the proliferative actions of insulin and the insulin-like growth factor (IGF) family. The aim of this study was to determine whether the insulin/IGF-1 pathway is involved in the sequential progression from metaplastic Barrett's esophagus (BE) to dysplasia to esophageal adenocarcinoma (EAC).
  
  
  METHODS
  Fasting serum levels of insulin, glucose, IGF-1, insulin growth factor binding protein-1 (IGFBP1), and IGFBP3 were measured in 44 non-dysplastic, 9 low-grade dysplasia (LGD), 12 high-grade dysplasia (HGD), and 10 EAC subjects. Immunohistochemistry was performed on paraffin-embedded tissue derived from BE cases using rabbit monoclonal antibodies to p-mammalian target of rapamycin (mTOR) and p-AKT, mouse monoclonal antibody to Ki-67, and rabbit polyclonal antibody to p-insulin receptor substrate 1 (IRS1).
  
  
  RESULTS
  Nineteen of 44 (43.2%) BE, 5/9 (55%) LGD, 8/12 (66.7%) HGD and EAC 7/10 (70%) cases showed strong staining for p-IRS1. A significantly higher proportion of HGD/EAC subjects showed p-IRS1 staining when compared with BE/LGD subjects, 63.6% vs. 41.5%, P<0.05. p-IRS1 immunostaining was moderately correlated with strong immunostaining of the downstream mediators p-AKT and p-mTOR (Spearman correlation coefficient=0.167 and 0.27 for p-IRS1/p-AKT and for p-IRS1/p-mTOR, respectively) and the proliferation marker Ki-67 (Spearman correlation coefficient=0.20, P=0.09). However, systemic levels of insulin, IGF-1, or IGF-2 were not associated with tissue immunostaining of p-IRS1.
  
  
  CONCLUSIONS
  Activation of the insulin/IGF-1 pathway in BE may be associated with cellular proliferation and appears to have a role in the progression from metaplasia to cancer. The activation of the insulin/IGF-1 pathway at the tissue level is likely complex and does not have a simple association with systemic measures of insulin or IGF-1.
authors: Division of Gastroenterology and Liver Disease, University Hospitals of Cleveland, Cleveland, Ohio, USA.
authors: K B
authors: KB
authors: Greer
authors: A
authors: A
authors: Kresak
authors: B
authors: B
authors: Bednarchik
authors: D
authors: D
authors: Dawson
authors: L
authors: L
authors: Li
authors: A
authors: A
authors: Chak
authors: J
authors: J
authors: Willis