Abstract
Proliferation and differentiation of intestinal epithelial cells is assisted by highly specialized and well-regulated signaling cascades. The Wnt pathway, which is one of the fundamental pathways in the intestine, contributes to the organization of proliferative intestinal crypts by positioning and cycling of intestinal stem cells and their derivatives. The Wnt pathway promotes differentiation of intestinal secretory cell types along the crypt-plateau and crypt-villus axis. In contrast to the Wnt pathway, the intestinal Notch cascade participates in cellular differentiation and directs progenitor cells towards an absorptive fate with diminished numbers of Paneth and goblet cells. Opposing activities of Notch and Wnt signaling in the regulation of intestinal stem cells and the enterocytic cell fate have been elucidated recently. In fact, targeting Notch was able to overcome tumorigenesis of intestinal adenomas, prevented carcinogenesis, and counteracted Paneth cell death in the absence of caspase 8. At present, pharmacological Notch inhibition is considered as an interesting tool targeting the intrinsic Wnt pathway activities in intestinal non-neoplastic disease and carcinogenesis.
Highlights
IntroductionThroughout the intestinal tract, a high throughput of surface lining epithelial cells is found
Throughout the intestinal tract, a high throughput of surface lining epithelial cells is found.Type and differentiation of these cells vary along the small and large intestine and contribute to the establishment of the crypt-villus axis (CVA), as well as crypt-plateau axis (CPA)
The current understanding in the Wnt and Notch signaling pathways, their crosstalk, and pharmacological targeting of Wnt via Notch using Dibenzazepine is summarized in the context of intestinal carcinogenesis
Summary
Throughout the intestinal tract, a high throughput of surface lining epithelial cells is found. Four classes of inhibitors are defined according to their specific targets: (i) generic inhibitors, (ii) inhibitors targeting the Wnt-receptor complex, (iii) inhibitors targeting the β-catenin destruction complex, and (iv) inhibitors targeting the nuclear/transcription factor complex. In these categories, several substances and therapeutic agents are available for modulating the Wnt signaling activity. There are few FDA-approved generic drugs that have been shown to non- modulate Wnt pathway activities. In this category, non-steroidal anti-inflammatory drugs (NSAIDs) are important therapeutics probably repressing the canonical. The current understanding in the Wnt and Notch signaling pathways, their crosstalk, and pharmacological targeting of Wnt via Notch using Dibenzazepine is summarized in the context of intestinal carcinogenesis
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