May 2003 Vol 3 No 5 REVIEW

Nature Reviews Cancer 3, 339-349 (2003)

CANCER AND AGEING: RIVAL DEMONS? Judith Campisi about the author

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CORRESPONDENCE

Cellular senescence as a tumour promoter Kamb, A 1 October 2003

Cancer turnover at old age Pompei, F., Lee, E. E. and Wilson, R. 30 January 2004

Reply: Cancer turnover at old age Campisi, J. 30 January 2004

Cellular senescence as a tumour promoter

Kamb, A

1 October 2003

We are accustomed to think of programmed senescence and apoptosis as protections against cancer. A fine, recent review by Judith Campisi invites speculation that such protections also entail a cost in cancer susceptibility1. She discusses work supporting the view that certain tumour suppressors protect from cancer but accelerate ageing. However, there is another related factor involved in such 'antagonistic pleiotropy'. Papers by Frank and Nowak2 and others3, 4 have shown that strategies for tissue production and maintenance that minimize total cell division, and lineage branch length in particular, engender a lower risk of tumorigenic mutations. The reverse is also true. Decades ago, cancer researchers began to characterize the so-called tumour promoters — agents that stimulate cell proliferation and increase the probability of cancer.

It is well known that aged animals have a reduced capacity for regeneration. Their stem cells are fewer in number and/or have diminished replicative properties5. Notwithstanding this fact, certain tissues — such as the gut — continue to create replacement cells at a constant rate throughout life. These seemingly contradictory observations can be reconciled by the hypothesis that as animals age, fewer of the original adult stem cells assume more of the burden for tissue production.

If we combine the theoretical work of Frank and Nowak with experimental observations in ageing tissues, we reach the paradoxical conclusion that programmed cellular senescence must be partly tumorigenic. In the ageing animal, replacement of equivalent numbers of cells after functional loss of stem cells requires that the remaining stem cells divide more. So, as attrition continues throughout life, surviving stem cells shoulder more and more of the load, increasing the branch length of their descendants. Indeed, the survivors might be those stem cells that, as Frank and Nowak propose, have sustained mutations early during development, which enhance their longevity. Studies of somatic evolution in the colon, blood and other tissues have yielded results consistent with genetic drift and an age-related decline in stem-cell populations, as well as a supralinear increase in somatic mutation number with age6.

Programmed senescence might explain all or part of the exponential rise in cancer incidence/mortality and age7. Depending on the original number of adult stem cells, their rate of loss, and the regenerative demands of the tissue, branch lengths might increase in different

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populations at different rates. For instance, some cell populations — such as lymphoid tissue — might experience a gradual decline in stem-cell function and a comparatively flat age-versus-incidence relationship. By contrast, prostate epithelium might have a sudden and relatively late crisis in stem-cell numbers, perhaps accounting for the steep dependence on age of prostate cancer. The basis for such tissue differences is not known, but might involve telomere shortening as well as activity of "gatekeeper" tumour suppressors. The observation that telomerase-deficient mice are prone to tumours has been attributed to genetic instability as a result of chromosome-end fusions8. But this heightened cancer susceptibility might also be a consequence of the increased branch length in those stem-cell clones that outlive their sisters.

Whether or not telomere shortening is involved, programmed senescence fosters an opportunity for the stem cells that endure to expand into the void, increasing generation number and the probability of tumorigenic mutation. These considerations have implications for the use of adult stem cells in therapy. To borrow from J. B. S. Haldane, high cancer mortality in old age might bethe price we pay for the privilege of low cancer incidence in youth.

Alexander Kamb Global Head of Oncology, Novartis Institutes for Biomedical Research,Cambridge, Massachusettes 02139, USA. References

Cancer turnover at old age

Pompei, F., Lee, E. E. and Wilson, R.

30 January 2004

It is often assumed that cancer incidence continues to increase with age. This was assumed recently by Judith Campisi1, whose figure 1 shows cancer reaching 100% well before the end of a lifetime. Campisi then accepts that the number of senescent cells, which cannot proliferate, increases with age. Campisi has to invent a somewhat tortured explanation of the apparent paradox that senescent cells increase cancer incidence. The recent correspondence on the Campisi paper by Kamb2 seems to accept that such an explanation is required.

However, our analysis of extensive data (a quarter of the United States population) compiled by the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) programme3 shows that cancer incidence peaks at about age 80 (at approximately 2.7% per year for males and 1.5% for females), and then seems to decrease towards 0% (ONLINE FIG. 1). If this is true,there is no paradox and no need for a tortured explanation.

1.

Campisi, J. Cancer and ageing: rival demons? Nature Rev. Cancer 3, 339–49 (2003). | Article

2.

Frank, S. A. & Nowak M. A. Cell biology: developmental predisposition to cancer. Nature 422, 494 (2003). | PubMed | Article

3.

Frank, S. A., Iwasa, Y. & Nowak, M. A. Patterns of cell division and the risk of cancer. Genetics 163, 1527–1532 (2003). | PubMed

4.

Vickers, M. et al. Modelling haemopoietic stem cell division by analysis of mutant red cells. Br.J. Haematol. 110, 54–62 (2000). | PubMed | Article

5.

Van Zant, G. Genetic control of stem cells: implications for aging. Int. J. Hematol. 77, 29–36 (2003). | PubMed

6.

Kirkwood, T. B. & Proctor, C. J. Somatic mutations and ageing in silico. Mech. Ageing Dev. 124, 85–92 (2003). | PubMed | Article

7.

Renan, M. J. How many mutations are required for tumorigenesis? Implications from human cancer data. Mol. Carcinog. 7, 139–146 (1993). | PubMed

8.

Rudolph, K. L. et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96, 701–712 (1999). | PubMed

Online Figure 1 | Age-specific incidence of all Surveillance, Epidemiology and End Results cancers.

Includes the beta function I(t) = ( t)k-1(1- t) fit to the data, for

males ( = 0.00076, = 0.0092, k = 5.7) and females ( =

0.0062, = 0.0092, k = 5.1). Error bars are 1 standard error

of the mean.

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Historically, there has been some controversy over the quality of the cancer data for the oldest people in the population, but modern cancer registries seem to be accurate, and other investigations in addition to our own work have reported this change in incidence4-6. ONLINE FIG. 1 is an analysis of more recent SEER data, which includes cancer incidence rates to older ages than have previously been available. The incidence change seems to be present for all individual cancers recorded by SEER, both male and female. Moreover, we have recently reported a similar change in incidence in a sufficiently large cohort (for data to be statistically significant) of mice that have been allowed to live their full natural lifetimes7.

We have found that the data can be fit by a beta function I(t) = ( t)k-1(1- t), in which , and k are constants and t is age. We derived this equation by adding the factor (1- t) to the

well known Armitage–Doll8 multistage cancer model, and then searched for a possible biological meaning for this new factor. Cellular senescence increasing linearly with age is a plausible interpretation, as senescent cells lose proliferative ability and, so, cannot cause cancer9. This introduction of senescence so that increasing age reduces the pool of proliferating cells is similar to that of Campisi in her figure 4. But the data do not indicate that we have to introduce an ad hoc explanation to explain continuing cancer increases in spite of the reduction in proliferation.

We are studying whether the data still demand the extra factor when we use a mathematically exact multistage cancer model and allow for variations in individual susceptibility.

Francesco Pompei, Ellen E. Lee & Richard Wilson Department of Physics, Harvard University, Cambridge, Massachusetts 02138, USA. References

Reply: Cancer turnover at old age

Campisi, J.

30 January 2004

Pompei and colleagues make an interesting point, although a somewhat different one than that made in my recent article1. Figure 1 shows idealized curves, not actual data, and makes the point that, at least among mammals, cancer incidence remains low for a substantial fraction of the life span, after which it rises with approximately exponential kinetics. Pompei and colleagues point out recent analyses that indicate cancer incidence, like cancer mortality, in fact declines at very old ages (>80 years). This is a very interesting phenomenon, possibly related to the mechanisms that have been proposed for the decline in cancer mortality at very old age2, 3, or because of selection for genotypes with unusually robust tumour suppression. Whatever the case, the fact remains that age is the largest single risk factor for developing cancer. My article attempted to provide one explanation for the close link between ageing and cancer, taking into account evolutionary theory and what is known about the biology of cancer and ageing. Hence

1.

Campisi, J. Cancer and ageing: rival demons? Nature Rev. Cancer 3, 339–349 (2003). | Article

2.

Kamb, A. Cellular senescence as a tumour promoter [online]. Nature Rev. Cancer (cited 05 Jan 2004), <http://www.nature.com/cgi-taf/DynaPage.taf?file=/nrc/journal/v3/n5/corres/nrc1073_fs.html> (2003).

3.

SEER Public-Use 1995-1999 when Using SEER*Stat: Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 11 Regs, Nov 2001 Sub (1973-2000), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2002, based on the November 2001 submission.

4.

Pompei, F. & Wilson R. Age distribution of cancer: the incidence turnover at old age. Hum. Ecol. Risk Assess. 7, 1619–1650 (2001).

5.

de Rijke, J. M. et al. Cancer in the very elderly Dutch population. Cancer 89, 1121–1133 (2000). | PubMed | Article

6.

Saltzstein, S. L., Behling, C. A. & Baergen, R. N. Features of cancer in nonagenarians and centenarians. J. Am. Geriatr. Soc. 46, 994–998 (1998). | PubMed

7.

Pompei, F., Polkanov, M. & Wilson, R. Age distribution of cancer in mice: the incidence turnover at old age. Toxicol. Ind. Health 17, 7–16 (2001). | PubMed | Article

8.

Armitage, P. & Doll, R. The age distribution of cancer and a multistage theory of carcinogenesis. Br. J. Cancer 8, 1–12 (1954). | PubMed

9.

Pompei, F. Cancer Turnover at Old Age. Ph.D. Thesis, Harvard Univ. (2002).

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the hypothesis that synergy between mutation accumulation and tissue degradation, driven in part by senescent cells, might explain the age-related rise in cancer incidence. If this is a tortured hypothesis, so be it! The question is, is it biology? This question can be answered satisfactorily only by further experimentation, which I hope my article will stimulate.

Judith Campisi Life Sciences Division, Lawrence Berkeley National Laboratory and Buck Institute for Age Research. References

1.

Campisi, J. Cancer and ageing: rival demons? Nature Rev. Cancer 3, 339–349 (2003). | Article

2.

Pili, R. et al. Altered angiogenesis underlying age-dependent changes in tumor growth. J. Natl Cancer Inst. 86, 1303–1314 (1994). | PubMed

3.

Bonafe, M., Valensin, S., Gianni, W., Marigliano, V. & Franceschi, C. The unexpected contribution of immunosenescence to the leveling off of cancer incidence and mortality in the oldest old. Crit. Rev. Oncol. Hematol. 39, 227–233 (2001). | PubMed

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