Research Highlights: Barrett’s Esophagus Translational Research Network (BETRNet) Studies Provide Insights into Prevention and Risk for Esophageal Cancer

Findings from two studies aimed at learning more about preventing the type of esophageal cancer with the fastest growing incidence rate have emerged recently from the Barrett’s Esophagus Translational Research Network (BETRNet) as it winds down its collaborative activities.

The studies are just two examples of BETRNet’s achievements since it was launched over a decade ago to accelerate the translation of important research findings into the clinical setting. The multidisciplinary network was formed to centralize and enhance efforts to better understand Barrett’s esophagus and prevent the subsequent development of esophageal adenocarcinoma. BETRNet encouraged collaboration across institutions, leading to early investigators and senior researchers working together, which stimulated more research. The network’s efforts were co-sponsored by two divisions of the National Cancer Institute (NCI), the Division of Cancer Prevention and the Division of Cancer Biology.

Barrett’s esophagus is the only known precursor lesion to esophageal adenocarcinoma, a cancer with the fastest growing incidence rate of any cancer over the past few decades and a low (15%) overall 5-year survival rate. Researchers hope that learning more about the mechanisms behind the development of Barrett’s esophagus and esophageal adenocarcinoma will lead to ways to prevent and slow the development of disease.

Slowing Progression of Esophageal Adenocarcinoma with Cranberry Compounds

In one study, a research team led by investigators at the University of Michigan wanted to see if chemical compounds found in cranberries might slow progression of esophageal adenocarcinoma in rats. They created a translational rat model in which they could assess how cranberry extract affects bile and gastric acids as they spill over into the lower esophagus, causing gastroesophageal reflux disease (GERD), over time. GERD is considered one of the drivers behind Barrett’s esophagus and esophageal adenocarcinoma. The findings were published in the journal bioRxiv.

Prior research has shown that cranberries—rich in chemical compounds called proanthocyanidins—exert powerful anti-inflammatory and antibacterial effects. But until recently, few studies have explored their potential anticancer properties in the microbiome. Interest in cranberries has risen in the past few years from a greater understanding of “absorption, digestion, and the salient role gut microbes play in generating biologically active metabolites,” the researchers wrote.

Rats in the study received either water alone or water with the proposed preventive compound from cranberry (proanthocyanidin) for up to 40 weeks, following reflux-inducing surgery. Compared with the reflux group alone, the rats getting the cranberry-juice mixture had a reduction in cancer progression by 93.6% and 82.4% at 25 and 40 weeks, respectively, after histopathology evaluation and spectral imaging.

The investigators wrote that additional studies are needed to fully characterize the effects of cranberry chemical compounds on specific immune cell populations and barrier functions. But mounting evidence suggests that these cranberry compounds impact the microbial landscape by disrupting the inflammatory-linked bacteria responsible for esophageal injury during the transition from a healthy gut to GERD, Barrett’s esophagus, and esophageal adenocarcinoma. As a result, this cranberry chemical compound seems to be “a safe, promising dietary constituent” for use alone or as an adjuvant to existing therapies to prevent disease progression, the investigators concluded.

Reference: Weh KM, Howard CL, Zhang Y, Tripp BA, Clarke JL, Howell AB, Rubenstein JH, Abrams JA, Westerhoff M, Kresty LA. Prebiotic proanthocyanidins inhibit bile reflux-induced esophageal adenocarcinoma through reshaping the gut microbiome and esophageal metabolome. bioRxiv. 2023 Aug.

Identifying a Germline Mutation’s Role in Barrett’s Esophagus and Esophageal Adenocarcinoma

In another BETRNet study, researchers reported on the discovery of a hereditary germline mutation in a large family with a long history of Barrett’s esophagus and esophageal adenocarcinoma. The investigative team, led by scientists from Duke University’s Department of Medicine in Durham, North Carolina, identified and recruited the eight family members through studies at University Hospitals Cleveland Medical Center and the Hospital of the University of Pennsylvania.

The findings were published in the journal Gastroenterology.

The initial case of Barrett’s esophagus and high-grade dysplasia was seen in a 52-year-old man whose brother died of esophageal adenocarcinoma at age 50, and whose mother had been diagnosed with Barrett’s esophagus at age 60 and breast cancer 8 years later. Others in the family were diagnosed at even younger ages, with one 40-year-old male cousin undergoing removal of his esophagus after diagnosis with Barrett’s esophagus to slow possible cancer progression.

Through molecular analysis and an animal model, the investigators identified a genetic error in the caveolin 3 (CAV3) gene in the submucosal lining of the esophageal glands, a possible site of origin for Barrett’s esophagus. Caveolins are small proteins in the cell membrane that aid in signaling molecules and play a role in cell functions such as movement, development, and growth.

Loss of function of these CAV3-expressing cells in the esophageal glands, the researchers wrote, interferes with normal homeostasis or microbial balance, impairing the body’s ability to respond to organ injury and repair. That, in turn, lays the groundwork for Barrett’s esophagus and esophageal cancers, they wrote.

The study findings suggest these genetic defects are critical players in esophageal homeostasis, the investigators wrote, and reveal new insights into how Barrett’s esophagus and esophageal adenocarcinoma begin.

Reference: Garman KS, Purkayastha BPD, Hogue JA, Fecteau R; BETRNet CONSORTIUM; Guda K, Chak A. Genetic Defect in Submucosal Gland-Associated Caveolin-3: A New Paradigm in Esophageal Adenocarcinoma Risk. Gastroenterology. 2023 Dec;165(6):1561-1564.e3.