Goblet Cell Ratio in Combination with Differentiation and Stem Cell Markers in Barrett Esophagus Allow Distinction of Patients with and without Esophageal Adenocarcinoma

Abstract

The rising incidence of esophageal adenocarcinoma (EAC) is mirrored by the increasing prevalence of Barrett’s Esophagus (BE), a precursor lesion resulting in a large number of individuals “at risk” for this lethal malignancy. Among BE patients only ~0.3% annually will develop EAC. Since large numbers of patients are followed in endoscopic surveillance, there is a need for risk prediction among a growing population of BE patients. We identified 4 potential biomarkers from an inflammation (IL-1β)-dependent mouse model of Barrett’s esophagus and tested them in 189 BE patients with and without HGD/early cancer (T1). The primary goal was to distinguish BE patients with no evidence of dysplasia from those with dysplasia. Increasing stem cell marker LGR5 and niche cell marker DCLK1 and decreasing differentiation marker (secretory mucus cells, TFF2+ cells) correlated with elevated tumor score in the mouse. Having outlined the origin of those markers in the BE mouse model we showed the applicability for human BE: We compared 96 patients with non-dysplastic BE tissue to 97 patients with BE and HGD or early cancer. Low levels of TFF2 (AUC 87.2%) provided the best discrimination between non-dysplastic BE and BE with cancer, followed by high levels of DCLK1 (AUC 83.4%), low GC ratio (AUC 79.4%) and high LGR5 (AUC 71.4%). The GC ratio, rather than the presence of GCs per se, was found to be an important discriminator. These findings may be useful in developing future risk prediction models for BE patients and ultimately to improve EAC surveillance.

The metaplastic mosaic of Barrett’s oesophagus

“…However, this result unequivocally shows that intestinal metaplasia is not the sole precursor to cancer in the metaplastic distal oesophagus. In fact, recent studies have suggested that progression to cancer may occur less often in patients with higher goblet cell counts [ 32 , 33 ]. This suggests that goblet cell differentiation may in fact protect against neoplastic transformation.…”

Esophageal Cancer: Genomic and Molecular Characterization, Stem Cell Compartment and Clonal Evolution

“…In this mouse model, exposure of the esophagus to bile acids accelerates the development of Barrett-like metaplasia and dysplasia, through a mechanism involving a strong activation of the NOTCH signaling pathway [ 91 ]. The analysis of this mouse model allowed also to explore the cell progenitor involved in the development of Barrett metaplasia, providing evidence in favor of a possible involvement of gastric cardia progenitor cells [ 92 ]. The analysis of this mouse model of Barrett’s esophagus provided evidence that increasing stem cell marker LGR5 and niche cell marker DCLK1 and decreasing differentiation marker (secretory mucus cells, TFF2 + cells) correlated with a high tumor score [ 92 ].…”

“…The analysis of this mouse model allowed also to explore the cell progenitor involved in the development of Barrett metaplasia, providing evidence in favor of a possible involvement of gastric cardia progenitor cells [ 92 ]. The analysis of this mouse model of Barrett’s esophagus provided evidence that increasing stem cell marker LGR5 and niche cell marker DCLK1 and decreasing differentiation marker (secretory mucus cells, TFF2 + cells) correlated with a high tumor score [ 92 ]. In a subsequent study, it was tested the applicability of these markers for human Barrett’s esophagus, particularly for distinguishing patients with Barrett’s esophagus with no evidence of dysplasia from those with dysplasia [ 92 ].…”

“…The analysis of this mouse model of Barrett’s esophagus provided evidence that increasing stem cell marker LGR5 and niche cell marker DCLK1 and decreasing differentiation marker (secretory mucus cells, TFF2 + cells) correlated with a high tumor score [ 92 ]. In a subsequent study, it was tested the applicability of these markers for human Barrett’s esophagus, particularly for distinguishing patients with Barrett’s esophagus with no evidence of dysplasia from those with dysplasia [ 92 ]. Low levels of TFF2 supported the best discrimination between nondysplastic Barrett’s esophagus and Barrett’s esophagus with cancer, followed by high levels of DCLK1, low goblet ratio and high LGR5 expression [ 92 ].…”

“…In a subsequent study, it was tested the applicability of these markers for human Barrett’s esophagus, particularly for distinguishing patients with Barrett’s esophagus with no evidence of dysplasia from those with dysplasia [ 92 ]. Low levels of TFF2 supported the best discrimination between nondysplastic Barrett’s esophagus and Barrett’s esophagus with cancer, followed by high levels of DCLK1, low goblet ratio and high LGR5 expression [ 92 ]. These findings support a risk prediction model of cancer progression of Barrett’s esophagus.…”