Stage-specific sensitivity to p53 restoration during lung cancer progression
Open Access
- 24 November 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 468 (7323), 572-575
- https://doi.org/10.1038/nature09535
Abstract
Inactivation of the p53 tumour-suppressor pathway is a common feature of human cancers, prompting suggestions that restoring p53 function in established tumours might be an effective therapy. However, two papers in this week's Nature highlight a practical limitation of p53-directed cancer therapeutics. They show in a K-Ras-driven lung-cancer model that p53-mediated tumour suppression is engaged only at a late stage of tumour progression, when the K-Ras oncogenic signal reaches a threshold that is sufficient to activate the ARF-p53 pathway. This means that p53 re-expression fails to restrict the early stages of tumorigenesis, although it does induce regression of more aggressive tumours. p53 is an important tumour suppressor gene. Two papers now show in a Kras-driven lung cancer model that p53-mediated tumour suppression is only engaged late during tumour progression, when the Kras oncogenic signal reaches a threshold sufficient to activate the ARF–p53 pathway. Therefore, p53 re-expression in p53-deficient lung tumours does not restrict early stages of tumorigenesis, but induces tumour regression of more aggressive tumours. Tumorigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumour suppressor pathways. Personalized cancer therapy that is based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumour suppressors and activation of oncogenes is essential in advanced cancers. Mutations in the p53 tumour-suppressor pathway are common in human cancer and significant efforts towards pharmaceutical reactivation of defective p53 pathways are underway1,2,3. Here we show that restoration of p53 in established murine lung tumours leads to significant but incomplete tumour cell loss specifically in malignant adenocarcinomas, but not in adenomas. We define amplification of MAPK signalling as a critical determinant of malignant progression and also a stimulator of Arf tumour-suppressor expression. The response to p53 restoration in this context is critically dependent on the expression of Arf. We propose that p53 not only limits malignant progression by suppressing the acquisition of alterations that lead to tumour progression, but also, in the context of p53 restoration, responds to increased oncogenic signalling to mediate tumour regression. Our observations also underscore that the p53 pathway is not engaged by low levels of oncogene activity that are sufficient for early stages of lung tumour development. These data suggest that restoration of pathways important in tumour progression, as opposed to initiation, may lead to incomplete tumour regression due to the stage-heterogeneity of tumour cell populations.Keywords
This publication has 26 references indexed in Scilit:
- Selective activation of p53-mediated tumour suppression in high-grade tumoursNature, 2010
- Tissue-specific p19 Arf regulation dictates the response to oncogenic K-rasProceedings of the National Academy of Sciences of the United States of America, 2010
- Requirement for NF-κB signalling in a mouse model of lung adenocarcinomaNature, 2009
- Restoration of p53 to limit tumor growthCurrent Opinion in Oncology, 2008
- Restoration of p53 function leads to tumour regression in vivoNature, 2007
- Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomasNature, 2007
- Probing tumor phenotypes using stable and regulated synthetic microRNA precursorsNature Genetics, 2005
- The Hallmarks of CancerCell, 2000
- Oncogenic ras Provokes Premature Cell Senescence Associated with Accumulation of p53 and p16INK4aCell, 1997
- Genetic changes in skin tumor progression: Correlation between presence of a mutant ras gene and loss of heterozygosity on mouse chromosome 7Cell, 1990