The tumor suppressor p53 restricts tumor initiation by triggering cell cycle arrest and apoptosis, and it can also limit tumor growth by inducing senescence, which results in the secretion of factors that reinforce growth arrest of the senescent cell. Now, this p53-mediated senescence function is shown to also limit tumorigenesis by directing stromal cells in the tumor microenvironment toward an antitumor phenotype (Cell 153, 449–460).

Amaia Lujambio and her colleagues used a mouse liver cancer model in which injured hepatocytes induce hepatic stellate cells to proliferate and secrete factors. This triggered stromal changes leading to fibrosis and eventually cirrhosis, conditions that often precede liver cancer. During chronic damage, they found that stellate-specific deletion of p53 increased advanced liver injury and the malignancy of neighboring epithelial cells, which expressed p53, suggesting that the effect of this tumor suppressor in liver tumor initiation is not cell autonomous. The authors found that p53 induces senescence of hepatic stellate cells and the secretion of factors, such as interleukin-6 and interferon-γ, that promote a nontumorigenic phenotype in macrophages that limits proliferation of premalignant cells and eliminates senescent cells.

Although other stromal cells besides macrophages may be involved in this non–cell-autonomous tumor suppressive effect, the role of p53-induced senescence in promoting an antitumor microenvironment may allow investigation of new therapeutic avenues for liver cancer.