Non-cell-autonomous tumor suppression by p53.

Cell 2013 Apr 4;153(2):449-60. Epub 2013 Apr 4.

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.

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.

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http://dx.doi.org/10.1016/j.cell.2013.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3702034PMC
April 2013
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