Journal
CURRENT COLORECTAL CANCER REPORTS
Volume 7, Issue 2, Pages 121-127Publisher
SPRINGER
DOI: 10.1007/s11888-011-0090-5
Keywords
Notch; Delta-like; Jagged; Atoh1; Math1; Hath1; gamma-secretase; Intestine; Colon; Crypts of Lieberkuhn; Stem cell; Cancer; Differentiation
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Funding
- NIH [R01 CA142826, R03 DK084167]
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The Notch receptor signaling pathway regulates expression of the basic helix-loop-helix transcription factor ATOH1 (Math1/Hath1) to determine cell fate in the intestine. In differentiating intestinal stem cells, high levels of Notch activity specify absorptive enterocyte/colonocyte differentiation, whereas high ATOH1 activity specifies secretory (goblet, enteroendocrine, and Paneth) cell differentiation. In colorectal cancer, ATOH1 is a tumor suppressor that is silenced in most tumors, while Notch is oncogenic and often highly active in human tumors. In other gastrointestinal malignancies with features of intestinal metaplasia, such as esophageal and gastric cancers, the Notch-ATOH1 pathway becomes activated. In cancers and preneoplastic tissues that retain the ability to activate ATOH1, therapeutic targeting of this pathway can be achieved by inhibiting Notch activity (with Notch-targeting antibodies or small-molecule inhibitors of gamma-secretase). Thus, targeting the Notch-ATOH1 pathway represents a novel approach to differentiation therapy in gastrointestinal cancers.
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