Loss of p53 in Enterocytes Generates an Inflammatory Microenvironment Enabling Invasion and Lymph Node Metastasis of Carcinogen-Induced Colorectal Tumors
Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel, pendant la phase de progression tumorale, la perte du gène p53 dans des entérocytes induit la formation d'un micro-environnement inflammatoire et une transition épithélio-mésenchymateuse dans des tumeurs du côlon-rectum
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-
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B-dependent inflammatory microenvironment and the induction of epithelial-mesenchymal 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. º Loss of p53 in murine enterocytes triggers invasive cancer after carcinogen exposure º Tumor progression depends on an NF-
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B-controlled inflammatory microenvironment º NF-
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B activation is triggered by intestinal microflora º AOM-treated Tp53”IEC mice comprise a useful model for preclinical studies