Journal
CANCER CELL
Volume 23, Issue 1, Pages 93-106Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2012.11.014
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Funding
- Deutsche Forschungsgemeinschaft [SFB 824, OR 1916/3-1]
- Deutsche Krebshilfe [108872]
- Fritz-Thyssen Stiftung [10.10.2]
- European Research Council (ERC) [281967]
- European Research Council (ERC) [281967] Funding Source: European Research Council (ERC)
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Loss of p53 is considered to allow progression of colorectal tumors from the adenoma to the carcinoma stage. Using mice with an intestinal epithelial cell (IEC)-specific p53 deletion, we demonstrate that loss of p53 alone is insufficient to initiate intestinal tumorigenesis but markedly enhances carcinogen-induced tumor incidence and leads to invasive cancer and lymph node metastasis. Whereas p53 controls DNA damage and IEC survival during the initiation stage, loss of p53 during tumor progression is associated with increased intestinal permeability, causing formation of an NF-kappa B-dependent inflammatory microenvironment and the induction of epithelial-rnesenchymal transition. Thus, we propose a p53-controlled tumor-suppressive function that is independent of its well-established role in cell-cycle regulation, apoptosis, and senescence.
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