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

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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

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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

Cite this

Arcidiacono, D., Dedja, A., Giacometti, C., Fassan, M., Nucci, D., Francia, S., Fabris, F., Zaramella, A., Gallagher, E. J., Cassaro, M., Rugge, M., LeRoith, D., Alberti, A., & Realdon, S. (2018). Hyperinsulinemia Promotes Esophageal Cancer Development in a Surgically-Induced Duodeno-Esophageal Reflux Murine Model. International Journal of Molecular Sciences, 19(4), [10.3390/ij]. https://doi.org/10.3390/ijms19041198