Coppe, JP;
Patil, CK;
Rodier, F;
Krtolica, A;
Beausejour, CM;
Parrinello, S;
Hodgson, JG;
... Campisi, J; + view all
(2010)
A Human-Like Senescence-Associated Secretory Phenotype Is Conserved in Mouse Cells Dependent on Physiological Oxygen.
PLOS ONE
, 5
(2)
, Article e9188. 10.1371/journal.pone.0009188.
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Abstract
Cellular senescence irreversibly arrests cell proliferation in response to oncogenic stimuli. Human cells develop a senescence-associated secretory phenotype (SASP), which increases the secretion of cytokines and other factors that alter the behavior of neighboring cells. We show here that "senescent'' mouse fibroblasts, which arrested growth after repeated passage under standard culture conditions (20% oxygen), do not express a human-like SASP, and differ from similarly cultured human cells in other respects. However, when cultured in physiological (3%) oxygen and induced to senesce by radiation, mouse cells more closely resemble human cells, including expression of a robust SASP. We describe two new aspects of the human and mouse SASPs. First, cells from both species upregulated the expression and secretion of several matrix metalloproteinases, which comprise a conserved genomic cluster. Second, for both species, the ability to promote the growth of premalignant epithelial cells was due primarily to the conserved SASP factor CXCL-1/KC/GRO-alpha. Further, mouse fibroblasts made senescent in 3%, but not 20%, oxygen promoted epithelial tumorigenesis in mouse xenographs. Our findings underscore critical mouse-human differences in oxygen sensitivity, identify conditions to use mouse cells to model human cellular senescence, and reveal novel conserved features of the SASP.
| Type: | Article |
|---|---|
| Title: | A Human-Like Senescence-Associated Secretory Phenotype Is Conserved in Mouse Cells Dependent on Physiological Oxygen |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pone.0009188 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pone.0009188 |
| Language: | English |
| Additional information: | © 2010 Coppe et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Supported by grants from the National Institutes of Health (research grants AG09909, AG017242 and CA126540 to JC; training grant AG000266; center grant AG0025708), Larry L. Hillblom Foundation (to CKP), California Breast Cancer Research Program (8KB-0100 to AK) and the US Department of Energy under contract DE-AC03-76SF00098 (JC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| Keywords: | CELLULAR SENESCENCE, DNA-DAMAGE, REPLICATIVE SENESCENCE, HUMAN-FIBROBLASTS, GENE-EXPRESSION, IN-VIVO, TRIGGERS SENESCENCE, CANCER PROGRESSION, EPITHELIAL-CELLS, GROWTH-FACTOR |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio |
| URI: | https://discovery.ucl.ac.uk/id/eprint/168031 |
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