p53 deregulation in cancer: cell-autonomous and non-autonomous implications

The TP53 gene, encoding the p53 tumor suppressor, is the most frequently mutated gene in human cancer: TP53 mutations occur in about half of all cancer cases. Often, these are missense mutations, associated with accumulation of large amounts of the mutant p53 protein within the cancer cells. In addition to abrogating p53’s tumor suppressor activities, such mutations can also endow the mutant p53 proteins with novel oncogenic gain-of-function (GOF) activities. p53 has a variety of cell autonomous activities, which presumably prevent the cell from becoming cancerous, and which are subverted when the TP53 gene acquires mutations. In addition, p53 can also exert a variety of non-cell autonomous effects. Thus, analysis of TCGA data from a number of different cancer types suggests that p53 mutations, either through loss of wild type p53 activity or/and oncogenic GOF, may quench the anti-tumoral immune response, making the tumors more “immune cold” and probably favoring their escape from immune attack. Additionally, we found that p53 can act as a non-cell autonomous tumor suppressor in normal stromal fibroblasts, restricting the ability of those fibroblasts to support tumor growth. Interestingly, in cancer-associated fibroblasts p53 is rewired, and instead of acting as a tumor suppressor it becomes a non-cell autonomous tumor promoter – without undergoing any mutation. Computational analysis suggests that such non-mutational conversion of wild type p53 into a “pseudomutant” state occurs also in a fraction of human tumors that retain non-mutated p53, and contributes to tumor aggressiveness. Thus, p53 can act through both cell autonomous and non-cell autonomous mechanisms, both in the cancer cells and in the cancer microenvironment.