Mystery Behind Barrett's Esophagus: The Origin and Malignant Transformation of Esophageal Adenocarcinoma.

Esophageal cancer (EC) is the eighth most common cancer in the world, with an estimated 604,100 new cases in 2020, accounting for 3.1% of all cancer cases.1 Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the two main histologic subtypes of EC. ESCC predominantly affects developing countries and accounts for more than 88.8% in Chinese EC patients,2,3 while EAC predominantly affects developed countries and accounts for 80.1% in EC patients from United States.4,5 Multiple risk factors, such as Barrett’s esophagus, are associated with EC development. Barrett’s esophagus is a typical metaplastic disease that begins at the gastroesophageal junctions with proximal displacement of the squamocolumnar junctions. Intestinal metaplasia increases the propensity for ECs, especially EACs, and may result from transcriptional switches within gastric cell types or products of intestinal cell types, but the exact origin is unclear. However, half of EAC patients were not observed to have Barrett’s esophagus at the time of diagnosis.6,7 Therefore, we cannot help but ask the following question: does Barrett’s esophagus increase the risk of EAC? This question can be answered by determining the origin of Barrett’s esophagus. Most scientists believe that Barrett’s esophagus originates from many sources, such as various specific cell populations in the gastroesophageal junctions and esophageal submucosal glands. Lineage tracing studies in mouse models is the primary method for exploring Barrett’s esophagus origin. However, the squamous pregastric keratinization and lack of esophageal submucosal glands make this animal model unable to fully mimic human gastroesophageal physiology. Additionally, isolation of esophageal submucosal glands from fresh human tissue is particularly difficult. All of these have become the major obstacles to lineage tracing studies. In a study recently published in Science, titled “Molecular phenotyping reveals the identity of Barrett’s esophagus and its malignant transition,” Nowicki-Osuch et al8 successfully harvested the tissue samples across the gastroesophageal junction and isolated esophageal submucosal glands from patients and healthy individuals to explore the exact source of Barrett’s esophagus. These tissue samples were analyzed by single-cell transcriptomic profiling, in silico lineage tracing of methylation, and somatic mutation/open chromatin array. The functional validation was performed in organoid models. In brief, the authors immuno-stained pan-epithelial tissues, squamous tissues, columnar tissues, and esophageal submucosal glands of fresh human esophagus tissue with cadherin 1 (CDH1), keratin 5 (KRT5), keratin 8 (KRT8), and keratin 7 (KRT7) antibodies, respectively, and then used the three-dimensional confocal microscopy to identify and isolate the ductal cells, oncocytes, mucous cells, and myoepithelial cells. Theyobserved a population of P63þKRT5þKRT7þ cells (transitional basal progenitor) in the intercalated and main duct of esophageal submucosal glands, which is consistent with previous studies and supports that this cell population contributes to Barrett’s esophagus development.9 However, they also observed that, contrary to previous studies, oncocytes (a population of cells characterized by centrally located nuclei and eosinophilic cytoplasm) were prevalent in Barrett’s esophagus-free donors and often formed acini, indicated that they were associated with Barrett’s esophagus development. Subsequent single cellRNA sequencing identified fourmajor cellular components of fresh dissociated esophageal submucosal glands that were quiescent (the vast majority of cells did not express the division marker MKI67) and expressed transcripts previously unrelated to esophageal submucosal gland, including