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SUMMARY:Metaplasia and carcinogenesis in stratified epithelia: the role of
  chronic inflammation - Dr Craig Nowell\, EPFL\, Switzerland
DTSTART:20120703T120000Z
DTEND:20120703T130000Z
UID:TALK38838@talks.cam.ac.uk
CONTACT:Dr Ireena Dutta
DESCRIPTION:Chronic inflammation is associated with metaplasia and carcino
 genesis in a variety of epithelial tissues and an increasing body of evide
 nce suggests that distinct inflammatory profiles are linked to these event
 s. In self-renewing stratified epithelia\, such as the epidermis and corne
 a\, inflammation is regulated at least in part by the Notch signaling casc
 ade\, which functions to suppress the expression of pro-inflammatory cytok
 ines. The present study has therefore utilized conditional Notch mutant mi
 ce to delineate the role of chronic inflammation during metaplasia and car
 cinogenesis in each of these tissues.\nIn the epidermis\, complete ablatio
 n of Notch signaling results in a chronic inflammatory condition mediated 
 by the cytokine Thymic Stromal Lymphopoietin (TSLP). Interestingly\, the c
 hronic inflammation elicited by TSLP protects mice from cutaneous carcinog
 enesis\, an effect that is mediated by direct signaling on both CD4+ and C
 D8+ T cells. Loss of TSLP mediated immunity results in perturbed T cell re
 sponses and is followed by the induction of pro-tumourigenic inflammation\
 , which fosters tumour growth by augmenting Wnt/ß-catenin signaling.\nLos
 s of Notch signaling in the cornea results in chronic inflammation specifi
 cally during wound healing. In this tissue\, the chronic inflammatory envi
 ronment induces a form of squamous cell metaplasia in which the corneal ep
 ithelium undergoes a fate switch to epidermis. During this process\, Wnt/
 ß-catenin signaling becomes highly active in corneal epithelial cells\, s
 uggesting a functional role for this signaling cascade in cell fate conver
 sion. Accordingly\, genetic ablation of ß-catenin prevents squamous cell 
 metaplasia even in the presence of a chronic inflammatory environment\, in
 dicating that elevated Wnt/ß-catenin is essential in promoting the metapl
 astic phenotype.\nCollectively\, these studies demonstrate how chronic inf
 lammation can elicit pathological changes in self-renewing epithelial tiss
 ues and provide a platform for further elucidation of the cellular and mol
 ecular mechanisms underpinning metaplasia and carcinogenesis.\n
LOCATION:Sackler Lecture Theatre\, CIMR\,  Level 7
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