Cell
Volume 153, Issue 2, 11 April 2013, Pages 449-460
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Article
Non-Cell-Autonomous Tumor Suppression by p53

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Summary

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.

Highlights

► p53 promotes senescence in hepatic stellate cells, limiting fibrosis, cirrhosis, and liver cancer ► Senescent stellate cells secrete factors that promote M1 macrophage polarization ► M1 macrophages eliminate senescent cells and support an antitumor microenvironment ► p53 acts non-cell autonomously to maintain organ integrity and suppress cancer

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