p53 restoration in liver carcinomas induces cellular senescence and tumor clearance through an innate immune response

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Although cancer arises from a combination of mutations in oncogenes and tumor suppressor genes, the extent to which tumor suppressor gene loss is required for the maintenance of established tumors is poorly understood. p53 is an important tumor suppressor, whose mutation produces defects in cell cycle checkpoints, senescence, and apoptosis, and promote angiogenesis and genomic instability^1-3. To determine the consequences of p53 reactivation in vivo, we used RNA interference to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma. We show that even brief reactivation of endogenous p53 in p53-deficient tumors can produce complete tumor regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the up-regulation of inflammatory cytokines. This program, while producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumor cells in vivo, thereby contributing to tumor clearance. Our study indicates that p53 loss is required for the maintenance of aggressive carcinomas, and establishes how a cellular senescence program can act together with the innate immune system to potently limit tumor growth.