Inhibition of tumor angiogenesis by p53: a new role for the guardian of the genome

The p53 tumor suppressor protein has long been recognized as the central factor protecting humans from cancer. It has been famously dubbed the guardian of the genorne due to its ability to respond to genotoxic stress, such as DNA damage and other stress signals, and to protect the genome by inducing a variety of biological responses including DNA repair, cell cycle arrest, and apoptosis. However, the tumor suppressive effects of p53 go far beyond its roles in mediating these three processes. There is growing evidence that p53 also exerts its effects on multiple aspects of tumor formation, including suppression of metastasis and, as summarized in this review, inhibition of new blood vessel development (angiogenesis). The p53 protein has been shown to limit angiogenesis by at least three mechanisms: (1) interfering with central regulators of hypoxia that mediate angiogenesis, (2) inhibiting production of proangiogenic factors, and (3) directly increasing the production of endogenous angiogenesis inhibitors. The combination of these effects allows p53 to efficiently shut down the angiogenic potential of cancer cells. Inactivation of p53, which occurs in approximately half of all tumors, reverses these effects; as a consequence, tumors carrying p53 mutations appear more vascularized and are often more aggressive and correlate with poor prognosis for treatment. Thus, the loss of functional p53 during tumorigenesis likely represents an essential step in the switch to an angiogenic phenotype that is displayed by aggressive tumors.