Abstract
BackgroundToll-like receptors (TLRs) recognize known molecules from microbes and have an established role in tumorigenesis. Using a rat model of esophageal adenocarcinoma, and human clinical samples, we investigated genes central to TLR-mediated signal transduction and characterized the esophageal microbiome across the spectrum of esophageal adenocarcinoma carcinogenesis.MethodsWe surgically induced bile/acid reflux in rats and their esophagi were harvested at 40 weeks post-surgery. Tissue samples from the model were selected for gene expression profiling. Additionally, for rat and human samples microbiome analysis was performed using PCR-ESI-MS-TOF technology with validation by fluorescence in situ hybridization.ResultsGene expression results in the rat model indicated a significant upregulation of TLRs 1-3, 6, 7 and 9 in EAC compared to normal epithelium. PCR-ESI-MS-TOF analysis revealed a prevalence of Escherichia coli in Barrett’s esophagus (60 %) and esophageal adenocarcinoma (100 %), which was validated by fluorescence in situ hybridization. In the human clinical samples, Streptococcus pneumonia was detected in high abundance in gastroesophageal reflux disease and Barrett’s esophagus (50–70 %) in comparison to tumor adjacent normal epithelium, dysplasia, and esophageal adenocarcinoma (20–30 %). E. coli was detected in the Barrett’s esophagus and esophageal adenocarcinoma groups but was absent in the tumor adjacent normal epithelium, dysplasia, and the gastroesophageal reflux disease groups.ConclusionsWe demonstrated an association between the TLR signaling pathway and E. coli hinting towards possible early molecular changes being mediated by microbes in the rat model of esophageal adenocarcinoma carcinogenesis. Studies on human clinical samples also corroborate results to some extent; however, a study with larger sample size is needed to further explore this association.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2093-8) contains supplementary material, which is available to authorized users.
Highlights
Toll-like receptors (TLRs) recognize known molecules from microbes and have an established role in tumorigenesis
Of the 26 rats that survived to 40 weeks, 19 were chosen for macro dissection based on the presence of tumor adjacent normal epithelium (TANE) (4), Barrett’s esophagus (BE) (5), dysplasia (5) and esophageal adenocarcinoma (EAC) (5)
Activation of TLRs along with dysregulation of target genes in this pathway were confirmed by quantitative RT-polymerase chain reaction (PCR) and the differential presence of E. coli and S. cerevisiae across the EAC spectrum was confirmed by PCR-electrospray ionization (ESI)-mass spectrometry (MS)-time of flight (TOF) and validated by Fluorescent in situ hybridization (FISH)
Summary
Toll-like receptors (TLRs) recognize known molecules from microbes and have an established role in tumorigenesis. Barrett’s esophagus (BE) is the established precursor to EAC that progresses through a metaplasia-dysplasiacarcinoma sequence. BE is characterized by replacement of normal stratified squamous epithelium by more intestinal-like, simple columnar epithelium containing goblet cells. It is postulated that conversion to a more intestinal-like epithelium is an attempt to provide protection from acid and bile induced tissue damage in the esophagus. Intestinal epithelial cells (IECs) provide this protection in the gut by allowing colonization of the intestinal tract by commensal bacteria which aid in digestion. This markedly influences the development and function of the mucosal immune system [3]
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