Conversion of metaplastic Barrett’s epithelium into post-mitotic goblet cells by γ-secretase inhibition

Abstract

SUMMARYBarrett's esophagus (BE) affects approximately 2% of the Western population and progresses to esophageal adenocarcinoma (EAC) in 0.5% of these patients each year. In BE, the stratified epithelium is replaced by an intestinal-type epithelium owing to chronic gastroduodenal reflux. Since selfrenewal of intestinal crypts is driven by Notch signaling, we investigated whether this pathway was active in the proliferative crypts of BE. Immunohistochemistry confirmed the presence of an intact and activated Notch signaling pathway in metaplastic BE epithelium, but not in the normal human esophagus. Similar observations were made in two well-known human Barrett's-derived EAC cell lines, OE33 and SKGT-5. We then sought to investigate the effects of Notch inhibition by systemic treatment with a -secretase inhibitor in a well-validated rodent model for BE. As we have shown previously in normal intestinal epithelium, Notch inhibition converted the proliferative Barrett's epithelial cells into terminally differentiated goblet cells, whereas the squamous epithelium remained intact. These data imply that local application of -secretase inhibitors may present a simple therapeutic strategy for this increasingly common pre-malignant condition.

Hedgehog signaling regulates FOXA2 in esophageal embryogenesis and Barrett’s metaplasia

“…To our knowledge, direct nongoblet-to-goblet transition has not been demonstrated in esophageal epithelium in vitro. In vivo, treatment with γ-secretase inhibitors and resultant loss of Notch signaling in a surgical rat model of reflux esophagitis and Barrett's metaplasia leads to esophageal goblet cell hyperplasia within the reflux-induced metaplasia (58). During mouse esophageal development, hypomorphic SOX2 or complete loss of expression of either p63 or Noggin causes the appearance of goblet-like cells within the epithelium (53,59,60).…”

Bile acids induce Delta-like 1 expression via Cdx2-dependent pathway in the development of Barrett's esophagus

“…In the esophagus, Notch signaling has also been reported to be important for esophageal epithelial homeostasis, 9 as well as for the development of BE 10,11 and Barrett's adenocarcinoma. 12 In addition, we recently reported that activation of ATOH1 via Hes1 suppression in esophageal epithelial cells due to induction of Cdx2 expression in response to bile acids has important functions in induction of metaplastic changes during BE development.…”

Modeling colorectal cancer as a 3-dimensional disease in a dish: the case for drug screening using organoids, zebrafish, and fruit flies

“…Indeed two recent studies independently identified small molecules that suppress activating mutations in the Wnt pathway by stabilizing Axin, an endogenous repressor of the Wnt pathway [39,40]. Likewise a class of inhibitors of the Notch pathway called gamma-secretase inhibitors have been shown to effectively block stem cell maintenance and to force the differentiation of progenitor cells in murine models of intestinal adenoma [38] and a related cancer, metaplastic Barrett's esophagus [41].…”