TP53: Coordinator of the Processes That Underlie the Hallmarks of Cancer

In 2000, Hanahan and Weinberg proposed that the remarkable diversity of neoplastic diseases and of their underlying molecular mechanisms could be rationalized into six biological processes that, together, constitute the molecular and cellular infrastructure of cancer, thus identifying the “Hallmarks of Cancer” (Hanahan and Weinberg, Cell 100: 57–70, 2000). To the six initial Hallmark processes (sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis), advances in the past decade have added four biological processes, including genome instability, tumor-promoting inflammation, reprogramming of cell bioenergetics, and evading immune destruction. Far from constituting independent biological programs, the Hallmark processes are redundant and deeply interconnected. The p53 protein, encoded by the TP53 tumor suppressor gene, has an exceptionally diverse range of biological functions that endows it with the capability to contribute to each of the ten Hallmark processes. In this overview, I illustrate how p53 may participate in each of these processes and I propose that its unique tumor suppressive properties stem from its capacity to coordinate them into a coherent set of responses. This point of view supports the idea that combining p53-targeted intervention with drugs targeting specific Hallmark capabilities may provide a principle for a form of next-generation adjuvant therapy enhancing and extending the clinical benefits of emerging new anticancer drugs.