title: A multiparametric approach to monitor the effects of γ-secretase inhibition along the whole intestinal tract.
abstract: γ-secretase inhibitors (GSIs) have been recently proposed as chemopreventive agents in gastrointestinal neoplasia, because they lead, through inhibition of the Notch signaling pathway, to goblet cell conversion in some intestinal adenomas of the Apc(Min) mice, and halt epithelial cell proliferation. In this study, we examine in depth, in normal mice, the effects of a GSI, dibenzazepine (DBZ), intraperitoneally administered for 8 days at a non toxic dose, on the gene expression pattern of secretory mucin (MUC), goblet cell conversion, organization of the crypt structural-proliferative units, stem cell niche and apoptotic compartments, along the entire length of the small intestine and colon. We demonstrate that DBZ elicits a homogeneous goblet cell conversion all along the mouse intestinal tract, associated with an overexpression of the gene Muc2 without ectopic expression of the gastric genes Muc5ac and Muc6, and with the emergence of lysozyme-positive 'intermediate cells' in the colon. Furthermore, DBZ treatment induces a heterogeneous reorganization of the crypt structural-proliferative units along the intestinal tract and of the stem cell niche in the colon, without disturbing the apoptotic compartment. These findings point to uncoupled effects of a GSI on goblet cell conversion and reorganization of the intestinal crypt structural-proliferative units and stem cell niche, and suggest caution in the use of GSIs as chemopreventive agents for intestinal neoplasia.
authors: EA 4273 Biometadys, Université de Nantes, Faculté de Médecine, Nantes F-44035, France.
authors: Laure
authors: L
authors: Droy-Dupré
authors: Mickaël
authors: M
authors: Vallée
authors: Céline
authors: C
authors: Bossard
authors: Christian L
authors: CL
authors: Laboisse
authors: Anne
authors: A
authors: Jarry
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D051927:CD24 Antigen / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003106:Colon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003984:Dibenzazepines / Q000494:pharmacology*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D041981:Gastrointestinal Tract / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009077:Mucins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D055153:Stem Cell Niche / Q000187:drug effects
chemical_list: D053829:Amyloid Precursor Protein Secretases; D051792:Basic Helix-Loop-Helix Proteins; D051927:CD24 Antigen; D003984:Dibenzazepines; D019394:Ki-67 Antigen; D009077:Mucins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C500943:Atoh1 protein, mouse; C493597:Lgr5 protein, mouse; C527817:dibenzazepine