[HTML][HTML] Non-cell-autonomous tumor suppression by p53

A Lujambio, L Akkari, J Simon, D Grace… - Cell, 2013 - cell.com
A Lujambio, L Akkari, J Simon, D Grace, DF Tschaharganeh, JE Bolden, Z Zhao, V Thapar
Cell, 2013cell.com
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 …
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.
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