Review
Peto's Paradox: evolution's prescription for cancer prevention

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The evolution of multicellularity required the suppression of cancer. If every cell has some chance of becoming cancerous, large, long-lived organisms should have an increased risk of developing cancer compared with small, short-lived organisms. The lack of correlation between body size and cancer risk is known as Peto's paradox. Animals with 1000 times more cells than humans do not exhibit an increased cancer risk, suggesting that natural mechanisms can suppress cancer 1000 times more effectively than is done in human cells. Because cancer has proven difficult to cure, attention has turned to cancer prevention. In this review, similar to pharmaceutical companies mining natural products, we seek to understand how evolution has suppressed cancer to develop ultimately improved cancer prevention in humans.

Section snippets

The evolutionary theory of cancer

Cancer (see Glossary) is a consequence of multicellularity and a striking example of multilevel selection. The theory of cancer initiation and progression is deeply rooted in evolutionary and ecological concepts [1]. Cancer develops through somatic evolution, with genetic and epigenetic instability generating fitness variation among the cells in a body (Box 1). Selection at the level of organisms has led to the evolution of tumor suppressor mechanisms, such as cell cycle check points and

Peto's paradox

The challenge of suppressing somatic evolution dramatically increases with larger bodies and longer lifespans. Because cancer develops through the accumulation of mutations, each proliferating cell is at risk of malignant transformation, assuming all proliferating cells have similar probabilities of mutation. Therefore, if an organism has more cells (i.e. more chances of initiating a tumor), the probability of developing cancer should increase. Similarly, if an organism has an extended

The need and potential for cancer prevention

Cancer has proven difficult to cure. Since former US President Richard Nixon declared the ‘War on Cancer’ almost 40 years ago, little progress has been made on reducing the lifetime risk of cancer and increasing survival rates for patients with late-stage diagnoses 10, 11. Most cancer research focuses on treatment rather than prevention, and this often leads to the recurrence of tumors that are resistant to therapy. With 109–1012 cells in a tumor and perhaps 105 mutations 12, 13, 14, 15, it

Peto's paradox appears to be real

Cancer incidence records for wild and captive animals are not well documented for most species, making it difficult to compare incidence records of humans and other animals directly. However, it is still clear that cancer incidence does not scale with body size across species (Box 2). If blue whales developed 1000 times more cancer than did humans, they would probably die before they were able to reproduce and the species would quickly go extinct [17]. The mere existence of whales suggests that

Hypotheses to resolve Peto's paradox

Limited research efforts have been focused on resolving Peto's paradox. However, there are many hypotheses that might explain how organisms could overcome the burden of cancer despite an increased number of cells and extended lifespan. Some have been previously proposed 2, 25, 26, 27, 28, 29 and others, to the best of our knowledge, are new in this review. Large bodies evolved independently along multiple lineages; therefore, one would not expect that all large, long-lived animals have evolved

Lower somatic mutation rates

If large animals have lower somatic mutation rates per cell generation, then more cell divisions would need to occur for a cell to acquire the necessary mutations to become malignant compared with smaller animals. Mutation rate is a function of the error rate and the rate at which these errors are repaired. This could be achieved through several mechanisms, including better DNA damage detection and repair mechanisms. However, experimental data seem to suggest that mice and humans have

Fewer reactive oxygen species due to lower basal metabolic rate

A lower somatic mutation rate could also be a result of metabolism. Reactive oxygen species (ROS) are byproducts of metabolism and can cause DNA damage thought to contribute to aging and cancer 52, 53, 54. The rate at which ROS are produced in a cell is a function of the basal metabolic rate (BMR) [55]. BMR per unit mass (mass-specific BMR) is proportional to (body mass)–1/4 [56] and has been shown to correlate with the amount of oxidative damage [57]. Knocking out oxidative repair genes, and

Suggestions for the future

If the current understanding of cancer is correct, there must be something fundamentally different in large, long-lived organisms that enhances their suppression of carcinogenesis. These mechanisms have allowed for the evolution of large bodies and extended lifespans without increasing the burden of cancer. Most of the hypotheses that have been proposed have not been directly tested, and most related questions remain open (Box 3).

Large bodies have evolved independently multiple times in the

Conclusion

There has been no observed correlation between body size, longevity and lifetime cancer risk [2]. Every additional cell and extra year of life should increase the probability of carcinogenesis. The fact that large, long-lived organisms are not over burdened by cancer suggests that they are more resistant to malignant transformation. Research focusing on what mechanisms have evolved to yield this cancer resistance will not only help explain Peto's paradox, but should also open new doors in the

Acknowledgments

This work was supported, in part, by the US Department of Energy Computational Science Graduate Fellowship, DE-FG02-97ER25308, the Martha W. Rodgers Charitable Trust, a McLean Contributionship, the Landon AACR Innovator Award for Cancer Prevention, Research Scholar Grant #117209-RSG-09-163-01-CNE from the American Cancer Society and NIH grants R03 CA137811, P01 CA91955, P30 CA010815, R01 CA119224 and R01 CA140657.

Glossary

Angiogenesis
the process of growing new blood vessels. The size of a tumor is limited by the diffusion distance of oxygen and glucose before angiogenesis.
Angiogenic cell
a cell producing factors to induce angiogenesis.
Apoptosis
programmed cell death.
Cancer
a disease defined by the uncontrolled growth of abnormal cells that have the ability to invade other tissues or spread to a new part of the body.
Crypt
a well-like structure of epithelial cells. Stem cells remain at the base and, as cells

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