Journal Article

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

van Es, Johan H., van den Born, Maaike, Vooijs, Marc, Clevers, Hans, Cozijnsen, Miranda, Radtke, Freddy, Riccio, Orbicia, Robine, Sylvie, Winton, Doug J., van Gijn, Marielle E., Begthel, Harry

2005

Overview

Alzheimer's drugs for cancer? 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 axis 1 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Adenoma - enzymology / Adenoma - genetics / Adenoma - metabolism / Adenoma - pathology / Alzheimer's disease / Amyloid Precursor Protein Secretases / Animals / Antineoplastic agents / Aspartic Acid Endopeptidases / Biological and medical sciences / Cell differentiation / Cell Differentiation - drug effects / Cell Proliferation - drug effects / Cells / Dibenzazepines - pharmacology / Disease / DNA-Binding Proteins - deficiency / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Endopeptidases - metabolism / Enzymes / Female / General aspects / Genes / Genes, APC / Goblet Cells - cytology / Goblet Cells - drug effects / Goblet Cells - metabolism / Goblet Cells - pathology / Humanities and Social Sciences / Immunoglobulin J Recombination Signal Sequence-Binding Protein / Intestine, Small - cytology / Intestine, Small - drug effects / Intestine, Small - enzymology / Intestine, Small - metabolism / letter / Male / Medical sciences / Membrane Proteins - antagonists & inhibitors / Membrane Proteins - metabolism / Mice / Mice, Inbred C57BL / multidisciplinary / Nuclear Proteins - deficiency / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Pharmacology. Drug treatments / Phenotype / Protease Inhibitors - pharmacology / Receptors, Notch / Science / Science (multidisciplinary) / Signal Transduction - drug effects / Small intestine