Metaplasia and carcinogenesis in stratified epithelia: the role of chronic inflammation

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• Dr Craig Nowell, EPFL, Switzerland
• Tuesday 03 July 2012, 13:00-14:00
• Sackler Lecture Theatre, CIMR, Level 7.

If you have a question about this talk, please contact Dr Ireena Dutta.

Chronic inflammation is associated with metaplasia and carcinogenesis in a variety of epithelial tissues and an increasing body of evidence suggests that distinct inflammatory profiles are linked to these events. In self-renewing stratified epithelia, such as the epidermis and cornea, inflammation is regulated at least in part by the Notch signaling cascade, which functions to suppress the expression of pro-inflammatory cytokines. The present study has therefore utilized conditional Notch mutant mice to delineate the role of chronic inflammation during metaplasia and carcinogenesis in each of these tissues. In the epidermis, complete ablation of Notch signaling results in a chronic inflammatory condition mediated by the cytokine Thymic Stromal Lymphopoietin (TSLP). Interestingly, the chronic inflammation elicited by TSLP protects mice from cutaneous carcinogenesis, an effect that is mediated by direct signaling on both CD4 and CD8 T cells. Loss of TSLP mediated immunity results in perturbed T cell responses and is followed by the induction of pro-tumourigenic inflammation, which fosters tumour growth by augmenting Wnt/ß-catenin signaling. Loss of Notch signaling in the cornea results in chronic inflammation specifically during wound healing. In this tissue, the chronic inflammatory environment induces a form of squamous cell metaplasia in which the corneal epithelium undergoes a fate switch to epidermis. During this process, Wnt/ß-catenin signaling becomes highly active in corneal epithelial cells, suggesting a functional role for this signaling cascade in cell fate conversion. Accordingly, genetic ablation of ß-catenin prevents squamous cell metaplasia even in the presence of a chronic inflammatory environment, indicating that elevated Wnt/ß-catenin is essential in promoting the metaplastic phenotype. Collectively, these studies demonstrate how chronic inflammation can elicit pathological changes in self-renewing epithelial tissues and provide a platform for further elucidation of the cellular and molecular mechanisms underpinning metaplasia and carcinogenesis.

This talk is part of the MRC Cancer Unit Seminars series.

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• MRC Cancer Unit Seminars
• Sackler Lecture Theatre, CIMR, Level 7

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