p53 Has Non–Cell-Autonomous Tumor Suppressor Activity

In addition to well-characterized cell-autonomous roles in cell-cycle arrest and apoptosis, p53 also suppresses tumorigenesis by inducing cellular senescence. Although they no longer proliferate, senescent cells can promote remodeling of the extracellular matrix and secrete inflammatory cytokines, but the effects of this senescence-associated secretory phenotype on tumorigenesis are not well understood. Building on previous results showing that p53 triggers senescence in hepatic stellate cells to limit the effects of chronic liver injury, Lujambio and colleagues deleted Tp53 in murine hepatic stellate cells to evaluate the role of p53 in later stages of liver disease and hepatocellular carcinoma. Mice with p53-deficient hepatic stellate cells treated with a liver-damaging agent had significantly increased liver fibrosis and cirrhosis and decreased survival compared with wild-type mice. An increased tumor incidence was also observed in livers with p53-deficient hepatic stellate cells, but surprisingly, these epithelial tumors were largely p53-wild-type, suggesting that loss of p53 in hepatic stellate cells creates a protumorigenic environment. Analysis of hepatic stellate cells from transgenic mice harboring an inducible p53 short hairpin RNA revealed that inactivation of p53 promoted proliferation in hepatic stellate cells, whereas restoration of p53 expression promoted senescence. Notably, p53-proficient and p53-deficient hepatic stellate cells secreted distinct cytokines and showed particular differences in factors that mediate macrophage function. Conditioned media from p53-proficient senescent hepatic stellate cells induced the polarization of M1 macrophages, which eliminated senescent cells, whereas p53-deficient proliferating hepatic stellate cells skewed macrophage polarization to the M2 state, which enhanced the proliferation of premalignant hepatoblast progenitors. Although it remains unknown whether p53 loss in hepatic stellate cells drives natural hepatocellular carcinoma initiation or progression, these findings provide evidence that p53 has non–cell-autonomous roles in establishing an antitumorigenic microenvironment through secretion of factors that regulate macrophage activity.

Lujambio A, Akkari L, Simon J, Grace D, Tschaharganeh DF, Bolden JE, et al. Non-cell-autonomous tumor suppression by p53. Cell 2013 Apr 4 [Epub ahead of print].