A report on the study — which was led by a team from Columbia University Medical Center (CUMC) in New York City, NY, and published in the journal Nature — describes how they used mice and human tissue to pinpoint the "cell of origin" for Barrett's esophagus.
In Barrett's esophagus, some of the tissue that lines the esophagus, or the tube that carries food from the mouth to the stomach, changes into tissue that is more like that which lines the intestines. This can be felt as heartburn and difficulty swallowing food.
Most cases arise from gastroesophageal reflux disease (GERD), a chronic condition in which acid from the stomach regurgitates into the lower part of the food pipe.
Better screening and treatment needed
The incidence of esophageal adenocarcinoma has increased rapidly in the United States over recent decades. But unfortunately, this has not been matched by improved screening and treatment.
As with other cancers, early detection is the key to prolonging survival in esophageal cancer. At present, under 20 percent of patients survive for longer than 5 years after diagnosis.
Scientists probing the origins of Barrett's esophagus have put forward models based on at least five different cell types.
"However," explains study leader Jianwen Que, an associate professor of medicine at CUMC, "none of these experimental models mimics all of the characteristics of the condition."
He and his colleagues believed, therefore, that the "cell of origin" for Barrett's esophagus was still waiting to be discovered.
The gastroesophageal junction
The researchers started their investigation by breeding mice genetically engineered to develop Barrett's esophagus, and then examining the area where the food pipe joins the stomach. This area, called the gastroesophageal junction, is where abnormal tissue that is typical of Barrett's oesophagus occurs.
Here, at the gastroesophageal junction, the tissue that lines the digestive tract, or the epithelium, changes gradually — as it nears the stomach — from that of the food pipe to that of the intestines. At this "transitional epithelium," the cell types transition from "stratified squamous epithelium cells" to "simple columnar cells."
Prof. Que explains that, while the examination revealed that all the "known cells in this tissue remained the same," the team found "a previously unidentified zone populated by unique basal progenitor cells."
Progenitor cells are stem cells that have just started to differentiate. Much like stem cells, they still have the potential to become different types of cell, but they have already started down the path that will lead to a particular tissue type.
'Cell of origin' for Barrett's esophagus
In the next phase of the study, the team used a method called "lineage tracing" to find out whether the unique progenitor cells that they discovered can develop into Barrett's esophagus.
They used several mouse models to show how genetic changes or exposure to bile acid reflux can cause the cells to grow and give rise to Barrett's esophagus.
The researchers also replicated these findings in "organoids" grown from unique basal progenitor cells sampled from the gastroesophageal junctions of mice and humans. Organoids are masses of cells that are grown in the laboratory and which have many of the tissue properties of organs.
In an accompanying article, experts comment that the findings set the stage "to investigate whether the transitional epithelium is the sole origin" of Barrett's esophagus, and "what role this tissue has in the progression to oesophageal cancer."
""Now that we know the cell of origin for Barrett's esophagus, the next step is to develop therapies that target these cells or the signaling pathways that are activated by acid reflux."
Prof. Jianwen Que