Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells

Top Cited Papers
Publisher Website
Google Scholar
Abstract
Notch genes encode a range of membrane receptors that regulate cell-fate decisions by influencing communication between adjacent cells. Two groups now report the involvement of Notch signals in controlling the fate of intestinal epithelial tissue. In addition, blockade of the Notch pathway with the γ-secretase inhibitor DBZ halted growth of adenomas (polyps) in the small intestine and colon. Various γ-secretase inhibitors are being developed for the treatment of Alzheimer's disease; this new work suggests that they might also be used to treat colorectal cancers. The self-renewing epithelium of the small intestine is ordered into stem/progenitor crypt compartments and differentiated villus compartments. Recent evidence indicates that the Wnt cascade is the dominant force in controlling cell fate along the crypt–villus axis1. Here we show a rapid, massive conversion of proliferative crypt cells into post-mitotic goblet cells after conditional removal of the common Notch pathway transcription factor CSL/RBP-J (ref. 2). We obtained a similar phenotype by blocking the Notch cascade with a γ-secretase inhibitor. The inhibitor also induced goblet cell differentiation in adenomas in mice carrying a mutation of the Apc tumour suppressor gene. Thus, maintenance of undifferentiated, proliferative cells in crypts and adenomas requires the concerted activation of the Notch and Wnt cascades. Our data indicate that γ-secretase inhibitors, developed for Alzheimer's disease, might be of therapeutic benefit in colorectal neoplastic disease.