title: Non-cell-autonomous tumor suppression by p53.
abstract: The p53 tumor suppressor can restrict malignant transformation by triggering cell-autonomous programs of cell-cycle arrest or apoptosis. p53 also promotes cellular senescence, a tumor-suppressive program that involves stable cell-cycle arrest and secretion of factors that modify the tissue microenvironment. In the presence of chronic liver damage, we show that ablation of a p53-dependent senescence program in hepatic stellate cells increases liver fibrosis and cirrhosis associated with reduced survival and enhances the transformation of adjacent epithelial cells into hepatocellular carcinoma. p53-expressing senescent stellate cells release factors that skew macrophage polarization toward a tumor-inhibiting M1-state capable of attacking senescent cells in culture, whereas proliferating p53-deficient stellate cells secrete factors that stimulate polarization of macrophages into a tumor-promoting M2-state and enhance the proliferation of premalignant cells. Hence, p53 can act non-cell autonomously to suppress tumorigenesis by promoting an antitumor microenvironment, in part, through secreted factors that modulate macrophage function.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Amaia
authors.initials: A
authors.lastname: Lujambio
authors.forename: Leila
authors.initials: L
authors.lastname: Akkari
authors.forename: Janelle
authors.initials: J
authors.lastname: Simon
authors.forename: Danielle
authors.initials: D
authors.lastname: Grace
authors.forename: Darjus F
authors.initials: DF
authors.lastname: Tschaharganeh
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Bolden
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
authors.forename: Vishal
authors.initials: V
authors.lastname: Thapar
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Joyce
authors.forename: Valery
authors.initials: V
authors.lastname: Krizhanovsky
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D060833:Cellular Microenvironment; D016922:Cellular Senescence; D005355:Fibrosis / Q000473:pathology; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000166:cytology / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53
references.citation: Cell. 2005 Dec 16;123(6):1001-11
references.pmid: 16360031
references.citation: Nat Genet. 2004 Dec;36(12):1306-11
references.pmid: 15565109
references.citation: Cell. 2010 Apr 2;141(1):39-51
references.pmid: 20371344
references.citation: Nature. 2011 Nov 09;479(7374):547-51
references.pmid: 22080947
references.citation: Cell. 2008 Aug 22;134(4):657-67
references.pmid: 18724938
references.citation: Genes Dev. 2011 Oct 15;25(20):2125-36
references.pmid: 21979375
references.citation: J Clin Invest. 2005 Jan;115(1):56-65
references.pmid: 15630444
references.citation: Nature. 2000 Apr 20;404(6780):892-7
references.pmid: 10786798
references.citation: Cancer Res. 2005 Mar 1;65(5):1627-30
references.pmid: 15753354
references.citation: Science. 2007 Jul 6;317(5834):121-4
references.pmid: 17615358
references.citation: Genes Dev. 2011 Oct 15;25(20):2137-46
references.pmid: 21979374
references.citation: Oncogene. 2008 Oct 9;27(46):5975-87
references.pmid: 18711403
references.citation: Am J Pathol. 2005 Mar;166(3):695-708
references.pmid: 15743782
references.citation: Hepatology. 2012 Aug;56(2):769-75
references.pmid: 22378017
references.citation: Nat Cell Biol. 2004 Feb;6(2):121-8
references.pmid: 14730312
references.citation: Oncogene. 2011 Jun 16;30(24):2707-17
references.pmid: 21278794
references.citation: Nature. 2009 Oct 22;461(7267):1084-91
references.pmid: 19847259
references.citation: Cancer Res. 2010 Jul 15;70(14):5728-39
references.pmid: 20570887
references.citation: Nat Rev Mol Cell Biol. 2007 Sep;8(9):729-40
references.pmid: 17667954
references.citation: PLoS Biol. 2008 Dec 2;6(12):2853-68
references.pmid: 19053174
references.citation: Cell. 2009 May 1;137(3):413-31
references.pmid: 19410540
references.citation: PLoS One. 2011;6(6):e21381
references.pmid: 21731723
references.citation: Cancer Cell. 2010 Mar 16;17(3):262-72
references.pmid: 20227040
references.citation: J Neurosci. 2006 Sep 13;26(37):9593-602
references.pmid: 16971543
references.citation: J Clin Invest. 2005 Feb;115(2):209-18
references.pmid: 15690074
references.citation: Cell. 2008 Jun 13;133(6):1019-31
references.pmid: 18555778
references.citation: Cell. 2008 Jun 13;133(6):1006-18
references.pmid: 18555777
references.citation: Nat Rev Cancer. 2010 Jan;10(1):51-7
references.pmid: 20029423
references.citation: Hepatology. 2012 Sep;56(3):1150-9
references.pmid: 22473749
references.citation: Cell. 2011 Apr 1;145(1):145-58
references.pmid: 21458673
references.citation: Proc Natl Acad Sci U S A. 2012 Nov 13;109(46):E3186-95
references.pmid: 23100531
references.citation: Genes Dev. 2000 Apr 15;14(8):994-1004
references.pmid: 10783170
references.citation: Nat Genet. 2002 Nov;32(3):355-7
references.pmid: 12379854
references.citation: Cell. 2012 Jun 8;149(6):1269-83
references.pmid: 22682249
references.citation: Nat Immunol. 2010 Oct;11(10):889-96
references.pmid: 20856220
references.citation: Nature. 2007 Feb 8;445(7128):656-60
references.pmid: 17251933
references.citation: Cell. 2008 Nov 28;135(5):852-64
references.pmid: 19012953
references.citation: Science. 1994 Sep 9;265(5178):1582-4
references.pmid: 7521539
references.citation: Oncogene. 2009 Aug 27;28(34):3081-92
references.pmid: 19543321
references.citation: Am J Pathol. 2000 Sep;157(3):945-55
references.pmid: 10980133