Two recent studies correct a long-standing misconception about the origins of Barrett’s esophagus and, in doing so, may point to new avenues of treatment or prevention to lower the risk of esophageal cancer. The first study, published by Singh et al in the journal Gastroenterology, demonstrated that Barrett’s esophagus does not, in fact, involve esophageal cells turning into intestinal cells, but stomach cells adopting some of the characteristics of intestinal cells. The second study, published by Singh et al in Genes and Development, traces the series of molecular events by which this process occurs.
“Barrett’s esophagus is caused by long-term gastrointestinal reflux disease, in which stomach acid repeatedly flows back into the esophagus,” explained Ramesh Shivdasani, MD, PhD, of Dana-Farber and Brigham and Women’s Hospital, the senior author of both papers. “Exposure to the acidic contents of the stomach produces changes in the cells where the stomach and esophagus meet. Very similar changes are seen in a condition called gastric intestinal metaplasia, which occurs lower in the stomach.”
Ramesh Shivdasani, MD, PhD
The changes are easily seen under a microscope. The inner lining of the digestive tract is made up of cells known as epithelial cells. In the esophagus, they take the form of squamous, or stratified, cells. In the intestine, they’re known as columnar cells. Stratified cells have a protective function, preventing harmful substances from coming into contact with underlying cells; columnar cells absorb nutrients from food. In people with Barrett’s esophagus, cells at the intersection of the esophagus and stomach, which should appear stratified, look exactly like columnar, intestinal cells.
Examining Chromatin Organization
In the Gastroenterology paper, the research team investigated these seemingly intestinal cells at the molecular level. They focused on the cells’ chromatin—their DNA and its protein wrapping. Within chromatin, where DNA is tightly coiled, genes are silent; where there’s more slack, genes are active. The pattern of coiled and uncoiled DNA within a cell indicates the cell’s core identity, its fundamental role within the body. Each type of cell has a distinctive chromatin signature.
Dr. Shivdasani and his colleagues examined chromatin organization in biopsied samples of human Barrett’s esophagus tissue.
“When we analyzed entire samples, each of which contained thousands or tens of thousands of cells, we found a very clear signature of stomach cells and intestinal cells,” he said. “But there was no semblance of an esophageal signature.”
The finding also left considerable ambiguity: did the tissue consist of a mix of stomach and intestinal cells, or of cells with a partly stomach and partly intestinal nature?
The answer came when advances in technology enabled researchers to probe chromatin organization within single cells. The team’s analysis showed that a Barrett’s esophagus cell “is essentially a schizophrenic or hybrid cell, with both stomach and intestinal features,” Dr. Shivdasani said. “This tells us what’s at the heart of Barrett’s esophagus and gastric intestinal metaplasia.”
These findings demonstrated that Barrett’s esophagus doesn’t violate the dictum against one cell type turning fully into another cell type, but it left open the question of how stomach cells take on some intestinal cell qualities.
HNF4A and CDX2
The Genes and Development paper takes an important step in solving that conundrum. That step involves a transcription factor called HNF4A, which is normally present in stomach cells at low levels. Dana-Farber’s Harshabad Singh, MD, found that high levels of HNF4A activate a second factor, called CDX2, which is never produced in normal stomach cells but is needed to activate intestinal genes.
Harshabad Singh, MD
Dr. Singh, the first author of both studies, went on to show that CDX2 switches on about a quarter of all intestine-related genes. Although the research was done largely in mouse tissues, it’s likely to be applicable to human tissue as well, Dr. Shivdasani added.
The findings have enabled the researchers to construct a hypothesis about what happens at the cellular and molecular level as Barrett’s esophagus develops.
“Barrett’s esophagus, and the cancer it gives rise to in a small minority of cases, always occurs at the very bottom of the esophagus, where the normal stratified epithelium meets the columnar epithelium of the stomach,” Dr. Shivdasani explained. “Our theory is that some injuries to the esophageal lining—such as those caused by chronic stomach acid reflux—are too severe for the esophageal epithelium to heal by itself. The damaged area needs some kind of barrier, so stomach epithelial cells travel there to seal the gap. When they arrive, they remain stomach cells, but the local environment triggers transcription factors that induce intestinal properties.”
The research may eventually yield treatments to prevent or alleviate Barrett’s esophagus, he continued. “To treat a disease of this nature, it’s necessary to understand exactly what type of cell is involved. Knowing the true identity of Barrett’s esophagus cells and their molecular triggers are important first steps.”
Disclosure: The research was supported by the National Institutes of Health, the Dana-Farber/Novartis Drug Discovery Program, and the Sarah Rhodes Fund for Cancer Research. For full disclosures of the study authors, visit gastrojournal.org or genesdev.cshlp.org.
