Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas

Abstract

The p53 tumour suppressor is either mutated or inactivated by other alterations in most human cancers. Two papers in this issue show that even brief reactivation of the endogenous p53 genes in established tumours can cause cancer regression in some animal models. In some tumours, p53 reactivation causes cellular senescence associated with an innate immune response that contributes to tumour clearance. These experiments used gene manipulation to alter p53 levels, but they lend further support to the idea that p53-boosting drugs could be a useful form of cancer treatment. One of two papers showing that reactivation of the endogenous p53 tumour suppressor genes in established tumours causes cancer regression. In some tumours, p53 reactivation causes cellular senescence associated with an innate immune response that contributes to tumour clearance. Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence1,2. Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies3. To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma4,5. We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour 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 upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth.