notch 信号.ppt

Notch signaling and colorectal cancer 卜晓东 Department of Pathology, SEU Introduction ? The biological role of Notch signaling as a regulator for cell differentiation was first identified in 1937, but its role in cancer was not recognized until 1991 when Notch1 was suspected to be casually related to the development of T-cell acute lymphocytic leukemia (T- ALL)/lymphoma . ? The discovery of the role of ?- secretase in the Notch signaling activation in 1999 had prompted intensive research on the potential application of ?- secretase inhibitors in the treatment of various cancers. ? It is now recognized that Notch signaling plays an important role in determining cell fate and maintaining progenitor cell population as well as the balance between cell proliferation, differentiation and apoptosis . Introduction ? In human and mice, Notch-signaling pathway consists of Notch ligands (Jagged1, Jagged2, DLL1, DLL3 and DLL4), Notch receptors (Notch 1– 4) and several downstream target genes such as p21, Hes-1 and Deltex . ? Notch receptors and their downstream target genes are widely expressed in mammalian tissues including embryonic tissues . Introduction ? Aberrantly activated Notch signaling has been observed during the carcinogenesis of many human cancers, such as pancreatic cancer, breast cancer , prostate cancer , liver cancer, cervical cancer , Ewing a , Kaposi a, lung cancer , ovarian cancer , lymphoma ,renal cancer and colon cancer . ? In addition, overexpression of Notch signaling was found to be associated with poor prognosis or poor response to treatment of some solid tumors such as breast tumor and prostate cancer . ? Thus, Notch signaling has been proposed as an important target for cancer therapy . Notch signaling in normal colonic tissues ? Notch signaling is essential for regulating the differentiation of colonic goblet cells and stem cells/progenitor cells. ? It is well known that colonic crypts are the principal niche for col