Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.
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 senescence. Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies. 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 carcinoma. 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.
Xue
Wen
W
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Zender
Lars
L
Miething
Cornelius
C
Dickins
Ross A
RA
Hernando
Eva
E
Krizhanovsky
Valery
V
Cordon-Cardo
Carlos
C
Lowe
Scott W
SW
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D016922:Cellular Senescence / Q000502:physiology*; D007113:Immunity, Innate / Q000276:immunology; D008113:Liver Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D034622:RNA Interference; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53