Restoring P53 Activity Slows the Spread of Advanced Tumors

In a mouse lung-cancer model, restoration of normal p53 tumor suppressor activity was found to prevent spread of adenocarcinomas but not to effect growth of immature adenomas.

If the cellular genome is damaged by chemicals, viruses, or ionizing radiation, the effects can be severe. For instance, if key regulatory elements are damaged, the normal controls on cell growth may be blocked, and the cell will rapidly multiply and grow into a tumor. The p53 tumor suppressor is a critical defender against this type of damage. P53 is normally found at low levels, but when DNA damage is sensed, p53 levels rise and initiate protective measures. P53 binds to many regulatory sites in the genome and begins production of proteins that halt cell division until the damage is repaired. Alternatively, if the damage is too severe, p53 initiates the process of apoptosis, permanently removing the damage.

Cancer cells typically contain two types of mutations: mutations that cause uncontrolled growth and multiplication of cells, and other mutations that block the normal defenses that protect against unnatural growth. p53 is in this second category and mutations in the p53 gene contribute to about half of the cases of human cancer. Most of these are missense mutations, changing the information in the DNA at one position and, by inserting an incorrect amino acid at one point in the protein chain, causing the cell to produce p53 with an error. In these mutants normal p53 function is blocked, and the protein is unable to stop multiplication of the damaged cell. If the cell has other mutations that cause uncontrolled growth, it will develop into a tumor.

Investigator at the Massachusetts Institute of Technology (Cambridge, USA) worked with a line of mice that lacked p53 activity in lung tissue. They reported in the November 25, 2012, issue of the journal Nature that treatment with a drug to restore p53 activity had no effect on young tumors (adenomas at four weeks), but blocked the growth and metastasis of mature tumors (adenocarcinomas at 10 weeks).

The significance of this finding is that while normal p53 activity may be restored in the mature tumors, there will continue to be a supply of abnormal p53 in the immature population. Thus, drug treatment would have to be maintained as long as any adenoma cells were present.

The investigators summed this up by stating, "Our observations also underscore that the p53 pathway is not engaged by low levels of oncogene activity that are sufficient for early stages of lung tumor development. These data suggest that restoration of pathways important in tumor progression, as opposed to initiation, may lead to incomplete tumor regression due to the stage-heterogeneity of tumor cell populations.”

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Massachusetts Institute of Technology