Hyperinsulinemia Promotes Esophageal Cancer Development in a Surgically-Induced Duodeno-Esophageal Reflux Murine Model

Diletta Arcidiacono, Arben Dedja, Cinzia Giacometti, Matteo Fassan, Daniele Nucci, Simona Francia, Federico Fabris, Alice Zaramella, Emily J Gallagher, Mauro Cassaro, Massimo Rugge, Derek LeRoith, Alfredo Alberti, Stefano Realdon

Research output: Contribution to journalArticlepeer-review

Abstract

Hyperinsulinemia could have a role in the growing incidence of esophageal adenocarcinoma (EAC) and its pre-cancerous lesion, Barrett's Esophagus, a possible consequence of Gastro-Esophageal Reflux Disease. Obesity is known to mediate esophageal carcinogenesis through different mechanisms including insulin-resistance leading to hyperinsulinemia, which may mediate cancer progression via the insulin/insulin-like growth factor axis. We used the hyperinsulinemic non-obese FVB/N (Friend leukemia virus B strain) MKR (muscle (M)-IGF1R-lysine (K)-arginine (R) mouse model to evaluate the exclusive role of hyperinsulinemia in the pathogenesis of EAC related to duodeno-esophageal reflux. FVB/N wild-type (WT) and MKR mice underwent jejunum-esophageal anastomosis side-to end with the exclusion of the stomach. Thirty weeks after surgery, the esophagus was processed for histological, immunological and insulin/Insulin-like growth factor 1 (IGF1) signal transduction analyses. Most of the WT mice (63.1%) developed dysplasia, whereas most of the MKR mice (74.3%) developed squamous cell and adenosquamous carcinomas, both expressing Human Epidermal growth factor receptor 2 (HER2). Hyperinsulinemia significantly increased esophageal cancer incidence in the presence of duodenal-reflux. Insulin receptor (IR) and IGF1 receptor (IGF1R) were overexpressed in the hyperinsulinemic condition. IGF1R, through ERK1/2 mitogenic pattern activation, seems to be involved in cancer onset. Hyperinsulinemia-induced IGF1R and HER2 up-regulation could also increase the possibility of forming of IGF1R/HER2 heterodimers to support cell growth/proliferation/progression in esophageal carcinogenesis.

Original languageEnglish
Article number10.3390/ij
JournalInternational Journal of Molecular Sciences
Volume19
Issue number4
DOIs
Publication statusPublished - Apr 14 2018

Keywords

  • Animals
  • Disease Models, Animal
  • Duodenogastric Reflux/complications
  • Esophageal Neoplasms/etiology
  • Esophagus/metabolism
  • Female
  • Hyperinsulinism/complications
  • Insulin/analysis
  • Male
  • Mice
  • Receptor, ErbB-2/analysis
  • Signal Transduction

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