Abstract 846: Excess energy impacts global gene expression, proteomic profiles and histopathologic progression in a rodent model for esophageal adenocarcinoma
Authors: Kresty Laura A. , Exum Amy , Zeyzus-Johns Bree 
Published: June 2012

Rates of esophageal adenocarcinoma (EAC) have dramatically increased (500%) over the last three decades in the US resulting in EAC being identified as the fastest increasing of all cancer types. Persistent, symptomatic, reflux of gastric and duodenal contents, known as gastroesophageal disease (GERD) have long been known to correlate with Barrett's esophagus (BE) and EAC development. Recently elevated body mass index (BMI) and obesity have emerged as strong, consistent, and dose-dependent risk factors likely contributing to the rising incidence of EAC. Insights into the mechanisms underlying the obesity/GERD/EAC linkage are poorly understood; yet, urgently needed to inform preventive strategies for this extremely deadly malignancy. Two pilot studies were conducted in Sprague Dawley rodents to assess the effects of a high fat diet (40% Kcals from fat) on global gene expression changes, altered proteomic profiles and esophageal histopathologic progression given acid-reflux. Reflux was surgically induced utilizing the esophagogastroduodenal anastomosis (EGDA) rat model of EAC. Serum leptin and adiponectin levels were assessed by ELISA. Rats consuming the 40% fat diet gained significantly greater weight compared to those fed the AIN93M base diet (9% Kcals from fat). Serum leptin levels were significantly elevated in the high fat group (25.4 ng/mL vs 12.3 ng/mL). Serum adiponectin levels were significantly reduced in rats consuming the high fat diet and in rats that had undergone the EGDA surgical procedure. The esophagi of EGDA+ rats consuming the high fat diet displayed extensive histopathological changes extending 8 cm from the gastroesophageal junction. Top pathways up-regulated in the esophageal epithelium by the 40% fat diet included cytokine-cytokine receptor interaction, MAPK signaling and focal adhesion; while those down regulated included calcium signaling, focal adhesion and apoptosis. The top over-represented gene ontology category down-regulated by high fat was muscle contraction, development and regulation; whereas, the top category up-regulated by high fat was cellular process. Proteomic analysis revealed that the largest number of proteins were deregulated in the EGDA+/40% fat group followed by the EGDA-/high fat group and the EGDA+ base diet group. A partial list of proteins significantly altered in the esophagus by feeding 40% fat to the EGDA+ rats included transgelin, annexin A2, APOBEC-2, beta-enolase and troponin T3. Differential protein expression was noted for the esophageal epithelium compared to the underlying submucosa supporting that separate analysis is most informative. Cell cycle linked changes were induced in the EGDA+/high fat group. The rodent EGDA model for EAC appears promising for conducting studies focused on unraveling the molecular mechanisms involved in the obesity/GERD /EAC relationship.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 846. doi:10.1158/1538-7445.AM2011-846