Non-cell-autonomous Tumor Suppression by p53

Cell. 2013 Apr 11;153(2):449-60. doi: 10.1016/j.cell.2013.03.020. Epub 2013 Apr 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic*
  • Cellular Microenvironment
  • Cellular Senescence*
  • Fibrosis / pathology
  • Hepatic Stellate Cells / cytology
  • Hepatic Stellate Cells / metabolism*
  • Humans
  • Inflammation / metabolism
  • Kupffer Cells / metabolism
  • Kupffer Cells / pathology
  • Liver / cytology
  • Liver / pathology
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology*
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • NF-kappa B
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • NF-kappa B
  • Tumor Suppressor Protein p53

Associated data

  • GEO/GSE39469