Esophageal adenocarcinoma (EAC) incidence rates have increased sharply (>500%) throughout the Westernized world since the 1980s, despite the widespread use of endoscopy and anti-reflux medications. Reasons for the rapid increase in EAC are still being unraveled; however, persistent, symptomatic reflux of gastric and duodenal contents, known as gastroesophageal disease (GERD), is considered the strongest risk factor. Our laboratory utilizes the rat esophagogastroduodenal anastomosis (EGDA) surgical model of reflux-induced EAC to evaluate mechanisms by which cranberry proanthocyanidins (C-PAC) delivered in the drinking water inhibit reflux-induced EAC. Findings show that C-PAC inhibits EAC formation by 83% with concomitant restoration of the gut microbial profile and significant reduction of primary and secondary bile acid metabolites in the esophagus of animals with reflux-inducing surgery, but through unknown mechanisms. Herein, we investigated whether transporters, important in bile acid transport, buffering capacity, excretion, and even resistance to anticancer agents, were restored by C-PAC in the context of reflux. Additionally, we utilized a publicly available GEO dataset (GSE37203) to assess transporter expression levels in patients with metaplastic Barrett's esophagus (BE) versus those with high grade dysplasia (HGD) or EAC for translational relevance. Methods included esophageal RNA isolation, transcriptome sequencing using the Illumina HiSeq platform, followed by validation utilizing the PrimePCR Drug Transporter array plate and database mining. Results show significant changes in solute carriers (SLC), ATP-binding cassette (ABC) and aquaporin transporters in the rat reflux-induced model for EAC with C-PAC mitigating alterations. EGDA altered one or more members in 71% of the SLC families with frequent changes observed in SLC25, SLC4, SLC35, SLC2 and SLC6. C-PAC favorably impacted >40% of the EGDA-induced SLC changes. A number of ABC transporters involved in glutathione transport and also implicated in drug resistance were altered by EGDA including Abcc1, Abcc3, Abcc4, Abcc5 and Abcg2 and C-PAC mitigated these changes. Aquaporins, Aqp3 and Aqp4, were significantly modulated in EGDA and restored with C-PAC. Significant differences in ABCC9, ABCC10, AQP6 and AQP9, in addition to several members of the SLC25, SLC4, SLC35, SLC2 and SLC6 families, were observed in patients with HGD/EAC compared to those with BE metaplasia. Therefore, altered expression of transporters following reflux-inducing surgery or GERD is likely a defensive mechanism by which cells attempt to adapt or protect from injurious bile acid exposure. Further research is warranted to investigate agents that restore normal transporter function, which may serve to concomitantly improve epithelial barrier function and mucosal integrity in the context of esophageal cancer progression.
Citation Format: Katherine M. Weh, Bridget A. Tripp, Jennifer L. Clarke, Amy B. Howell, Jules Lin, David G. Beer, Andrew C. Chang, Laura A. Kresty. Cranberry proanthocyanidins mitigate reflux-induced transporter dysregulation in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 279.