CancerQuest | Reactivation of tumor suppressor may not be enough to stop cancer.

Tumor suppressor genes ususally function to limit cell growth. Loss of tumor suppressors is a critical step in the development of cancer. One of the most important tumor suppressors is p53 (or TP53). The p53 protein integrates signals affecting a cell (growth factors, DNA damage, oncogene signaling, etc.). The result of p53 activation can be either the suspension of cell division or the death of the cell via apoptosis.

Because p53 activity is lost in over half of all cancers, of any origin, there has been lots of research into what would happen to cancer cells if p53 could be re-activated. The results have been encouraging but not conclusive. In many cases, activation of p53 in cancer cells has been shown to cause their death.

In this research, investigators wanted to know whether or not p53 reactivation could work as a therapy for non-small cell lung cancer (NSCLC). To answer this question, researchers created mice in which they could turn p53 on and off by adding a chemical to the mice's drinking water. They then induced cancer by introducing an oncogenic version of the Ras gene to the lung tissues of the animals that were NOT expressing p53. After waiting for cancer to develop, the researchers turned the p53 gene back on and monitored the tumor cells to see what would happen.

The results were somewhat surprising. The researchers found that reactivation of p53 caused the death of cells in the most advanced (high-grade) tumors but did not kill cells in tumors that were less developed. One possible explanation is that only the most advanced cancer cells send strong enough signals to cause p53 to induce death.

The impact of this study, and a similar one published in the same journal, could be far reaching. If verified, the results indicate that drug-induced reactivation of p53, by itself, would be insufficient to eliminate all of the cancer cells from an individual. The cells that are left behind could then progress and become more aggressive once the drug treatment was terminated.

Bottom Line: Restoration of tumor suppressors is an attractive option for treating cancer. In this research, p53 was reactivated in a mouse model of non-small cell lung cancer (NSCLC). Because only the most advanced tumors were affected by the treatment, p53 activation as a treatment would need to be combined with additional therapies to be completely effective, at least in NSCLC.

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Original Article: Junttila MR, Karnezis AN, Garcia D, Madriles F, Kortlever RM, Rostker F, Swigart LM, Pham DM, Seo Y, Evan GI and Martins CP. Selective activation of p53-mediated tumour suppression in high-grade tumours. (2010) Nature 468(7323) 567-572.