Gene Expression in Barrett’s Esophagus Cell Lines Resemble Esophageal Squamous Cell Carcinoma Instead of Esophageal Adenocarcinoma

Abstract

Esophageal adenocarcinoma (EAC) is strongly associated with Barrett’s esophagus (BE), a pre-malignant condition resulting from gastric reflux. Esophageal squamous cell carcinoma (ESCC), the other major subtype of esophageal cancer, shows strong association with smoking and alcohol intake and no association with gastric reflux. In this study, we constructed and validated gene expression signatures of EAC vs. ESCC tumors using publicly available datasets, and subsequently assessed the enrichment levels of these signatures in commonly used EAC and ESCC cell lines, normal esophageal tissues and normal esophageal cell lines, and primary BE tissues and BE cell lines. We found that unlike ESCC cell lines which were quite similar to primary ESCC tumors, EAC cell lines were considerably different from primary EAC tumors but still more similar to EAC tumors than ESCC tumors, as the genes up in EAC vs. ESCC (EAChi) had considerably lower expression in EAC cell lines than EAC tumors. However, more surprisingly, unlike various normal cell lines (EPC2, Het-1A) which were very similar to various tissues from normal esophagus, BE cell lines (BAR-T, CP-A) were extremely different from primary BE tissues, as BE cell lines had substantially lower levels of EAChi and substantially higher levels of ESCChi gene expression. This ESCC-like profile of the BAR-T remained unaltered even after prolonged exposure to an acidic bile mixture in vitro resulting in malignant transformation of this cell line. However, primary BE tissues had EAC-like gene expression profiles as expected. Only one EAC case from the Cancer Genome Atlas resembled BE cell lines, and while it had the clinical profile and some mutational features of EAC, it had some mutational features, the copy number alteration profile, and the gene expression profile of ESCC instead. These incomprehensible changes in gene expression patterns may result in ambiguous changes in the phenotype and warrants careful evaluation to inform selection of appropriate in vitro tools for future studies on esophageal adenocarcinoma.

Barrett’s Metaplasia Progression towards Esophageal Adenocarcinoma: An Attempt to Select a Panel of Molecular Sensors and to Reflect Clinical Alterations by Experimental Models

“…This is in accordance with Panda et al, who constructed and validated gene expression signatures of EAC vs. ESCC tumors using publicly available datasets. They observed that OE33 clusters are close to primary EAC tumors, while OE19 could be either classified as an EAC or ESCC cell line [ 80 ]. To sum up, differences in gene expression patterns require careful evaluation to enable the selection of appropriate in vitro tools for future BE and EAC studies.…”

“…To sum up, differences in gene expression patterns require careful evaluation to enable the selection of appropriate in vitro tools for future BE and EAC studies. For instance, Tratnjek et al have attempted to standardize an EAC in vitro model for drug testing using an esophageal adenocarcinoma FLO-1 cell line in anticancer drug studies and EAC tumor biology [ 81 ]; however, according to Panda et al, this cell line may not be suitable for studying EAC tumors [ 80 ]. Furthermore, it is worth mentioning that cell cultures apparently lack a mechanical microenvironment and the proper distribution of oxygen, nutrients, and metabolic products; thus, 3D culture models are a novel option used in the research of esophageal diseases as a perspective in future research [ 82 ].…”

Long noncoding RNA LIPH-4 promotes esophageal squamous cell carcinoma progression by regulating the miR-216b/IGF2BP2 axis

“…Esophageal cancer is the seventh most commonly diagnosed cancer (604,100 new cases) and the sixth commonest cause of cancer-related mortality (544,076 deaths) around the world in 2020 [1]. Two main EC types are known, including esophageal adenocarcinoma and esophageal squamous cell carcinoma (ESCC), which have quite distinct epidemiology and etiology [2]. ESCC, which usually originates from the lining of the esophageal squamous epithelium and occurs predominantly in the upper and mid-esophagus, is the predominant form of EC worldwide.…”