Non-Cell-Autonomous Tumor Suppression by p53
Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, en favorisant la sécrétion de divers facteurs du microenvironnement, la protéine p53 joue son rôle de suppresseur de tumeurs
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. º p53 promotes senescence in hepatic stellate cells, limiting fibrosis, cirrhosis, and liver cancer º Senescent stellate cells secrete factors that promote M1 macrophage polarization º M1 macrophages eliminate senescent cells and support an antitumor microenvironment º p53 acts non-cell autonomously to maintain organ integrity and suppress cancer p53 acts both cell autonomously and nonautonomously in liver stellate cells to limit their tumorigenic activity. p53 expression promotes stellate cell senescence and also induces secretion of factors that influence macrophage polarization, leading to the generation of macrophages that eliminate senescent cells.