Abstract
SUMMARYγ-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 ApcMin 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.
Highlights
The self renewing intestinal epithelium is ordered into structural proliferating and differentiated units that are tightly regulated by signaling pathways, including the -secretase-Notch pathway (Van der Flier and Clevers, 2009). -secretase is a multi-protein complex that proteolyzes the transmembrane region of the Notch-receptor intracellular domain (NICD), and of other proteins such as the amyloid precursor protein (APP) and CD44 in various cell types
Expression of Muc and Math1 mRNA along the mouse gastrointestinal tract We first determined the expression profile of secretory MUC genes along the gastrointestinal tract (GIT) of wt C57BL6 mice
The expression of MUC genes is well established in the human GIT (Allen et al, 1998; Van Seuningen et al, 2001), there has been, to our knowledge, no thorough investigation of the expression pattern of these genes in the mouse GIT, except one study at the protein level (Linden et al, 2008)
Summary
The self renewing intestinal epithelium is ordered into structural proliferating and differentiated units that are tightly regulated by signaling pathways, including the -secretase-Notch pathway (Van der Flier and Clevers, 2009). -secretase is a multi-protein complex that proteolyzes the transmembrane region of the Notch-receptor intracellular domain (NICD), and of other proteins such as the amyloid precursor protein (APP) and CD44 in various cell types (for a review, see Artavanis-Tsakonas et al, 1999; Iwatsubo, 2004). Because aberrant Notch signaling has been implicated in tumorigenesis, GSIs have been proposed as chemopreventive and/or chemotherapeutic agents in colon cancer (Meng et al, 2009), Barrett’s esophagus (Menke et al, 2010) and several non gastrointestinal cancers (Real et al, 2009; Wei et al, 2010; Al-Husaini et al, 2011). This therapeutic potential of GSIs is based on Notch signaling being essential to maintain the undifferentiated, proliferative state of intestinal crypt progenitors (Fre et al, 2005). By inhibiting Notch signaling, GSIs lead to an increase in the BHLH transcription factor Math
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