Cancer

The blind spot of p53

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It is hoped that reactivating the tumour-suppressor protein p53 will help to combat cancer. However, fresh evidence suggests it is unlikely that all cells in a tumour will respond to such treatment. See Letters p.567 & p.572

The tumour suppressor that is most frequently mutated in human cancers is p53. Reactivation of this protein in tumours, which induces programmed cell death or cell-cycle arrest, is therefore an appealing therapeutic strategy. In this issue, however, Feldser et al.1 and Junttila et al.2 report work in mouse models of cancer showing that restoring p53 activity affects only advanced tumours, leaving untouched early lesions that are likely to one day become cancerous.

Earlier work3,4,5 suggested that restoring p53 function in several independent oncogene-driven mouse tumours elicits a potent anti-tumour response. The outcome was either programmed tumour-cell death by the process of apoptosis, or tumour-cell senescence. In fact, in two of the three animal models3,4,5, even temporary p53 reactivation led to prolonged survival. These data enhanced the appeal of p53 reactivation as a means of treating cancer.

Feldser et al. (page 572) and Junttila et al. (page 567) add a new twist to these observations. Both groups used variants of a mouse model of non-small-cell lung cancer (NSCLC) characterized by sporadic expression of a mutant Kras oncogene; this model closely resembles human NSCLC. Sporadic expression of physiological levels of mutant Kras in mice causes lung tumours that progress through different stages — from hyperplasia to adenoma to carcinoma. The advanced stages of the disease are marked by increased signalling flux through the RAS–MAPK pathway (the pathway in which Kras functions), probably due to additional alterations in this pathway. If sporadic tumour lesions associated with Kras mutations are also p53 deficient, they progress faster and become more malignant. The authors1,2 set out to determine what would happen if p53 function were restored in these tumours.

Junttila and colleagues2 used a variant of the mouse model in which the mutant Kras can be switched on by inhalation of an agent called AdenoCre. The p53 gene in these animals was replaced with a version that is inactive but can regain functionality on administration of the drug tamoxifen. The authors thus initiated tumorigenesis by AdenoCre exposure and then activated p53 functionality with tamoxifen. Feldser et al.1 used a mouse model that randomly activates Kras at low frequency by the process of spontaneous recombination. Their animals could also be treated with tamoxifen to restore p53 functionality. The differences in the mouse models resulted in small differences in some of the measurements between the two studies, but the overall conclusions are fully congruent.

In contrast to the earlier studies3,4,5, both teams found that, after induction of NSCLC by physiological levels of mutant Kras, tumour regression in response to p53 activation was hardly detectable or, at best, very modest. In both systems, in fact, only the more advanced adenocarcinoma lesions responded to induced p53 activity — by either cell-cycle arrest or a combination of cell-cycle arrest and apoptosis — whereas the less advanced lesions remained unaffected (Fig. 1).

Figure 1: Prerequisites for p53 activation.
figure1

It is thought that a minimal level (threshold level) of oncogenic stress and/or DNA damage activates p53. Feldser et al.1 and Junttila et al.2 studied mouse models of non-small-cell lung cancer (NSCLC) characterized by oncogenic mutation of Kras to investigate what happens in the absence of p53. They find that, without p53, tumours could progress even if the oncogenic stress level increased above threshold level and the tumour-suppressor protein p19 Arf was activated. When the authors restored p53 function with tamoxifen, tumour cells with an increased oncogenic flux were either arrested or killed. Less advanced lesions were unaffected, however, probably because their oncogenic flux remained below the threshold level. The authors did not detect DNA-damage response, indicating that, at least in their models, it does not contribute to p53 activation.

At a molecular level, cells in the more malignant lesions showed enhanced signalling flux through the RAS–MAPK pathway, owing to amplification of the mutant Kras, loss of the normal Kras allele (gene copy) or other alterations affecting this pathway. Intriguingly, the high signalling flux was associated with high levels of another tumour-suppressor protein, p19 Arf , which acts upstream of p53. The less advanced lesions did not have increased p19 Arf levels, suggesting that enhanced activity of this protein is required to trigger the tumour-suppressive function of p53. Neither paper reports evidence of DNA damage in either the early or the advanced lesions: in this NSCLC model, therefore, DNA-damage response does not seem to play a significant part in activating p53.

These observations have important implications for understanding not just the 'surveillance' function of p53, but also the usefulness of restoring this tumour suppressor's function as a therapeutic strategy. p53 does not affect early cancerous lesions that have a low oncogenic flux and retain low levels of p19 Arf ; indeed, only after p19 Arf levels increase does p53 spring into action. This could be because organisms do not distinguish between normal pathway activation and moderate oncogenic signals: reacting to the latter would also compromise normal cell proliferation, which is essential for tissue maintenance, as well as tissue restoration after injury.

What do these findings1,2 mean for human cancers and their treatment? There is no reason to be discouraged by them. By the time they are diagnosed, human tumours are usually much more advanced and so will more resemble the tumours described in the earlier papers3,4,5 — those with a high oncogenic flux. Although advanced tumours might still contain cells with a low oncogenic flux from the earlier lesions, such cells probably constitute only a small fraction. Restoring p53 activity should, therefore, have a considerable effect on human tumours.

Nevertheless, Feldser and colleagues and Junttila and co-workers observe that cells with 'early-lesion' features are still present in the animals, even after p53 reactivation. Lesions containing such cells are obviously prone to progress to more advanced stages of cancer. Moreover, the two teams show that, at least in their NSCLC models, the DNA-damage-response pathway does not have a sizeable role in inducing p53's anti-tumour activity — an observation that was also highlighted in a previous investigation of another cancer model6. The idea that the DNA-damage-response pathway does not contribute to p53's tumour surveillance function is counterintuitive and warrants further research.

The studies1,2 do demonstrate that oncogenic flux is the main trigger for effective p53 action. In view of the crucial role of p19 Arf in this response — which might be more prominent than the role of its related human protein p14 ARF — the NSCLC models seem particularly suitable for addressing the question of whether p53 responds to signals other than those from either the oncogene stress pathway, as governed by p19 Arf , or DNA damage.

Previous studies7,8,9 have pointed to p53 and p19 Arf having independent functions in tumour surveillance. A careful comparison of the loss of function of either p19 Arf or both p19 Arf and p53, with subsequent reactivation of p53, in these NSCLC models might help to further clarify the p19 Arf -independent tumour-suppressor roles of p53. This might also provide clues about how to selectively trigger p53 activity in the many human tumours in which the INK4AB/p14ARF tumour-suppressor genes are either deleted or silenced.

References

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    Feldser, D. M. et al. Nature 468, 572–575 (2010).

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    Martins, C. P., Brown-Swigart, L. & Evan, G. I. Cell 127, 1323–1334 (2006).

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    Ventura, A. et al. Nature 445, 661–665 (2007).

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    Xue, W. et al. Nature 445, 656–660 (2007).

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    Christophorou, M. A., Ringshausen, I., Finch, A. J., Brown Swigart, L. & Evan, G. I. Nature 443, 214–217 (2006).

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    Moore, L. et al. Oncogene 22, 7831–7837 (2003).

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Berns, A. The blind spot of p53. Nature 468, 519–520 (2010) doi:10.1038/468519a

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