A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen.
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.
Coppé
Jean-Philippe
JP
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.
Patil
Christopher K
CK
Rodier
Francis
F
Krtolica
Ana
A
Beauséjour
Christian M
CM
Parrinello
Simona
S
Hodgson
J Graeme
JG
Chin
Koei
K
Desprez
Pierre-Yves
PY
Campisi
Judith
J
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology*; D002868:Chromosomal Proteins, Non-Histone; D004249:DNA Damage; D004268:DNA-Binding Proteins; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology*; D042822:Genomic Instability; D006801:Humans; D018976:Insulin-Like Growth Factor Binding Protein 6 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000378:metabolism / Q000502:physiology*; D010641:Phenotype; D020543:Proteome / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D014183:Transplantation, Heterologous; D047368:Tumor Burden; D000071857:Tumor Suppressor p53-Binding Protein 1
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D018976:Insulin-Like Growth Factor Binding Protein 6; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D020543:Proteome; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1; D020782:Matrix Metalloproteinases; D010100:Oxygen