Esophageal cancer, illustration
Esophageal cancer, 3D illustration showing malignant tumor in the human esophagus

Abnormal cells that develop into esophageal cancer start life in the stomach, according to scientists at the University of Cambridge. The researchers found that a particular subtype of esophageal cancer—esophageal adenocarcinoma—is always preceded by Barrett’s esophagus, even if these cells are no longer visible at the time of cancer diagnosis. This confirms that screening for Barrett’s is important for esophageal cancer control.

The scientists were led by professor Rebecca Fitzgerald at the Medical Research Council Cancer Unit, University of Cambridge, UK. Said Fitzgerald: “Even if the pre-cancerous Barrett’s is not visible at the time of cancer diagnosis, our data suggests the cancer cells will have been through this stage. This has been debated for some time.”

The study was published this week in Science.

Cancer of the esophagus is the sixth most deadly cancer, and esophageal adenocarcinoma is on the rise in western countries. Scientists and doctors have known for some time that the development of this cancer is linked with Barrett’s esophagus, which shows up in endoscopy as a pink ‘patch’ in the surface of esophagus.

This condition affects around one out of every 100 to 200 people in the United Kingdom—and between 3 and 13 people out of 100 with Barrett’s will go on to develop esophageal adenocarcinoma. However, the question of where these abnormal cells come from has been a question until now.

Lizhe Zhuang, joint first author of the study, said: “It’s intriguing that, although Barrett’s esophagus predominately occurs in the lower part of esophagus close to stomach, it has so-called ‘goblet cells’ resembling a much more distant organ, the small intestine. Over the past twenty years there have been at least six different hypotheses about the origin of Barrett’s esophagus.”

The research team analyzed tissue samples from patients with Barrett’s esophagus and from organ donors who had never had the condition.

Lead authors Karol Nowicki-Osuch and Zhuang established a detailed ‘atlas’ of human cells and tissues from all possible origins of Barrett’s esophagus, including esophageal submucosal glands, an elusive tissue structure that acts in a similar way to saliva glands and has never before been isolated from fresh human tissue.

The researchers then compared the maps of cells from healthy tissues, Barrett’s esophagus and esophageal adenocarcinoma using a number of state-of-the-art molecular technologies, including single cell RNA sequencing. They also looked at methylation profiles, and genetic linage to trace back where a particular cell type originated.

The results showed a striking similarity between stomach cells and Barrett’s esophagus, suggesting that the cells at the very top of the stomach can be reprogrammed to adopt a new tissue identity, becoming more like intestine cells, and replace the esophageal cells. Furthermore, in this new study the team showed that two genes, MYC and HNF4A, are the keys that switch the tissue identity from stomach to intestinal cells.

Nowicki-Osuch said: “The techniques we used have shown us the internal processes that happen in the stomach cells when they become Barrett’s. The big question now is: what triggers these genes? It’s likely to be a complex combination of factors that include bile acid reflux (often felt as heartburn) and other risk factors, such as obesity, age, male sex and Caucasian ethnicity.”

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