Researchers discover how acid reflux leads to esophageal cancer

First discovery of signaling pathway

Providence, RI - A particular enzyme is significantly higher in cancer cells that have been exposed to acid, leading to the overproduction of hydrogen peroxide, and offering a possible explanation for how acid reflux may lead to cancer of the esophagus, according to a recent study in the Journal of Biological Chemistry.

The study found that the enzyme NOX5-S is affected by exposure to acid and that it produces stress on cells, activating genes that lead to DNA damage. For the first time, researchers have outlined the signaling pathway from cells damaged by acid, to the progression of esophageal cancer. They believe the same process may happen in the body when cells are exposed to acid reflux.

"The role of acid is controversial. But we show that by exposing cells to acid for short periods of time, that affects a particular enzyme, triggering a chain of events that possibly leads to cancer of the esophagus. Now that we have a better understanding of the signaling pathway, we can possibly identify who is at risk of developing cancer by determining the levels of this enzyme," says senior author Weibiao Cao, a researcher at Rhode Island Hospital and an assistant professor of medicine and surgery at Brown Medical School.

The study looked at human cancer cells and biopsies from patients with Barrett's esophagus (BE), a condition where cells in the esophagus have been altered by gastroesophageal reflux disease (GERD), or acid reflux. Acid reflux is believed to be a major risk factor for cancer in people with Barrett's esophagus.

However, the mechanisms of the progression to cancer have not been fully understood. In this study, researchers found that the enzyme NOX5-S is significantly higher in Barrett's esophageal tissues, which creates a pre-cancerous condition, as well as in esophageal cancer. Acid exposure leads to an increase in calcium in Barrett's esophageal cancer cells, thus activating a cAMP response element binding protein (CREB). This causes the activation of NOX5-S and overproduction of reactive oxygen species (ROS), thereby increasing cell growth and decreasing cell death optimal conditions for cancer to develop.

It was previously known that levels of ROS are increased in Barrett's Esophagus and in esophageal cancer and that ROS may play an important role in the development of cancer. However, the sources of ROS had not been defined. Researchers showed that the production of ROS begins with NOX5. When this enzyme was removed, acid-induced production of hydrogen peroxide was reduced, confirming that NOX5 is responsible. Also, when calcium was removed, the prevalence of NOX5 decreased, along with the production of hydrogen peroxide.

"Now that we know the sequence, we may be able to slow down or even block the progression of cancer by blocking these different steps," Cao says. "This may have therapeutic value if we can block this particular enzyme, NOX5, in Barrett's esophageal cancer cells."

Incidences of esophageal cancer related to BE have increased over the past three decades at a rate exceeding that of any other cancer in the past 10 years. Patients have a poor prognosis, with a median survival of less than 18 months after diagnosis. The five-year survival rate is less than 20 percent after surgery on operable tumors. The major risk factor is gastroesophageal reflux disease (GERD) complicated by Barrett's esophagus.

Approximately 10 percent of GERD patients develop Barrett's esophagus. A middle-aged person with BE for 20 years or more has a 10 to 20 percent lifetime risk of developing esophageal cancer, which is similar to the risk of lung cancer among heavy smokers or of liver cancer among chronic hepatitis-B virus carriers.

In order to prevent the progression, it may be necessary to increase treatment with proton pump inhibitors in patients with Barrett's Esophagus, the authors write.

"Elucidating the pathways leading from acid exposure to increased ROS production, increased proliferation and decreased apoptosis may provide a number of potentially useful therapeutic targets," the authors write.

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Other authors on the paper are: Xiaoying Fu, Jose Behar and Jack Wands, all of Rhode Island Hospital and Brown Medical School; David G. Beer of the University of Michigan Medical School; and David Lambeth of Emory University School of Medicine.

This study was supported in part by the National Institutes of Health COBRE grant and by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.

Founded in 1863, Rhode Island Hospital (www.rhodeislandhospital.org) is a private, not-for-profit hospital and is the largest teaching hospital of Brown Medical School. A major trauma center for southeastern New England, the hospital is dedicated to being on the cutting edge of medicine and research. Rhode Island Hospital ranks 13th among independent hospitals who receive funding from the National Institutes of Health, with research awards of more than $27 million annually. Many of its physicians are recognized as leaders in their respective fields of oncology, cardiology, orthopedics and minimally invasive surgery. The hospital's pediatrics wing, Hasbro Children's Hospital, has pioneered numerous procedures and is at the forefront of fetal surgery, orthopedics and pediatric neurosurgery.


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