Peto's paradox

Peto's paradox is the observation, named after English statistician and epidemiologist Richard Peto, that at the species level, the incidence of cancer does not appear to correlate with the number of cells in an organism.[1] For example, the incidence of cancer in humans is much higher than the incidence of cancer in whales.[2] This is despite the fact that a whale has many more cells than a human. If the probability of carcinogenesis were constant across cells, one would expect whales to have a higher incidence of cancer than humans.

Original formulation

Peto, a statistical epidemiologist at the University of Oxford, first formulated the paradox in 1977.[3] Writing an overview of the multistage model of cancer, Peto noted that, on a cell-for-cell basis, humans were much less susceptible to cancer than mice:

A man has 1000 times as many cells as a mouse... and we usually live at least 30 times as long as mice. Exposure of two similar organisms to risk of carcinoma, one for 30 times as long as the other, would give perhaps 30⁴ or 30⁶ (i.e., a million or a billion) times the risk of carcinoma induction per epithelial cell. However, it seems that, in the wild, the probabilities of carcinoma induction in mice and in men are not vastly different. Are our stem cells really, then, a billion or a trillion times more "cancerproof" than murine stem cells? This is biologically pretty implausible; if human DNA is no more resistant to mutagenesis in vitro than mouse DNA, why don't we all die of multiple carcinomas at an early age?

— "Epidemiology and Multistage Models", 1977[4]

Peto went on to suggest that evolutionary considerations were likely responsible for varying per-cell carcinogenesis rates across species.

Evidence

Within members of the same species, cancer risk and body size appear to be positively correlated, even once other risk factors are controlled for.[5] A 25-year longitudinal study of 17,738 male British civil servants, published in 1998, showed a positive correlation between height and cancer incidence with a high degree of statistical confidence, even after risk factors like smoking were controlled for.[6] A similar 2011 study of more than one million British women found strong statistical evidence of a relationship between cancer and height, even after controlling for a number of socioeconomic and behavioral risk factors.[7] A 2011 analysis of the causes of death of 74,556 domesticated North American dogs found that cancer incidence was lowest in the smaller breeds, confirming the results of earlier studies.[8]

Across species, however, the relationship breaks down. A 2015 study, using data from necropsies performed by the San Diego Zoo, surveyed results from 36 different mammalian species, ranging in size from the 51-gram striped grass mouse to the 4,800-kilogram elephant, nearly 100,000 times larger. The study found no relationship between body size and cancer incidence, offering empirical support for Peto's initial observation.[9]

Evolutionary considerations

The evolution of multicellularity has required the suppression of cancer to some extent,[10] and connections have been found between the origins of multicellularity and cancer.[11][12] In order to build larger and longer-lived bodies, organisms required greater cancer suppression. Evidence suggests that large organisms such as elephants have more adaptations that allow them to evade cancer.[13] The reason that intermediate-sized organisms have relatively few of these genes may be because the advantage of preventing cancer these genes conferred was, for moderately-sized organisms, outweighed by their disadvantages—particularly reduced fertility.[14]

Various species have evolved different mechanisms for suppressing cancer.[15] A paper in Cell Reports in January 2015 claimed to have found genes in the bowhead whale (Balaena mysticetus) that may be associated with longevity.[16] Around the same time, a second team of researchers identified a polysaccharide in the naked mole-rat that appeared to block the development of tumors.[17] In October 2015, two independent studies showed that elephants have 20 copies of tumor suppressor gene TP53 in their genome, where humans and other mammals have only one.[18] Additional research showed 14 copies of the gene present in the DNA of preserved mammoths, but only one copy of the gene in the DNA of manatees and hyraxes, the elephant's closest living relatives.[19] The results suggest an evolutionary relationship between animal size and tumor suppression, as Peto had theorized.

Metabolic and cell size considerations

A 2014 paper in Evolutionary Applications by Maciak and Michalak emphasized what they termed "a largely underappreciated relation of cell size to both metabolism and cell-division rates across species" as key factors underlying the paradox, and concluded that "larger organisms have bigger and slowly dividing cells with lower energy turnover, all significantly reducing the risk of cancer initiation."[20]

Maciak and Michalak argue that cell size is not uniform across mammalian species, making body size an imperfect proxy for the number of cells in an organism. (For example, the volume of an individual red blood cell of an elephant is roughly four times that of one from a common shrew).[21] Furthermore, larger cells divide more slowly than smaller ones, a difference which compounds exponentially over the life-span of the organism. Fewer cell divisions means fewer opportunities for cancer mutations, and mathematical models of cancer incidence are highly sensitive to cell-division rates.[22] Additionally, larger animals generally have lower basal metabolic rates, following a well-defined inverse logarithmic relationship. Consequently, their cells will incur less damage over time per unit of body mass. Combined, these factors may explain much of the apparent paradox.

Medical research

The apparent ability of bigger animals to suppress cancer across very large numbers of cells has spurred an active field of medical research.[14] In one experiment, laboratory mice were genetically altered to express "always-on" active TP53 tumor antigens, similar to the ones found in elephants. The mutated mice exhibited increased tumor suppression ability, but also showed signs of premature aging.[23]

Another study placed p53 under normal regulatory control and did not find signs of premature aging. It is assumed that under its native promoter p53 does not cause premature aging, unlike constitutively expressed p53.[24]

See also

• Comparative oncology
• Tumor suppressor gene
• Metabolic theory of ecology

References

1. Peto, R.; Roe, F. J. C.; Lee, P. N.; Levy, L.; Clack, J. (October 1975). "Cancer and ageing in mice and men". British Journal of Cancer. 32 (4): 411–426. doi:10.1038/bjc.1975.242. PMC 2024769. PMID 1212409.
2. Nagy, John D.; Victor, Erin M.; Cropper, Jenese H. (2007). "Why don't all whales have cancer? A novel hypothesis resolving Peto's paradox". Integrative and Comparative Biology. 47 (2): 317–328. doi:10.1093/icb/icm062. PMID 21672841.
3. Nunney, Richard (January 2013). "The real war on cancer: the evolutionary dynamics of cancer suppression". Evolutionary Applications. 6 (1): 11–19. doi:10.1111/eva.12018. PMC 3567467. PMID 23396311.
4. Peto, R. (1977). "Epidemiology, multistage models, and short-term mutagenicity tests" (PDF). The Origins of Human Cancer. Cold Spring Harbor Conferences on Cell Proliferation. 4. Cold Spring Harbor Laboratory. pp. 1403–1428. Archived from the original (PDF) on September 12, 2015. Retrieved October 13, 2015.
5. Caulin, Aleah; Maley, Carlo (April 2011). "Peto's Paradox: Evolution's Prescription for Cancer Prevention". Trends in Ecology and Evolution. 26 (4): 175–182. doi:10.1016/j.tree.2011.01.002. PMC 3060950. PMID 21296451.
6. Smith, George; Shipley, Martin (14 November 1998). "Height and mortality from cancer among men: prospective observational study". BMJ. 317 (7169): 1351–1352. doi:10.1136/bmj.317.7169.1351. PMC 28717. PMID 9812932.
7. Jane Green; Benjamin J Cairns; Delphine Casabonne; F Lucy Wright; Gillian Reeves; Valerie Beral; Million Women Study collaborators (August 2011). "Height and cancer incidence in the Million Women Study: prospective cohort, and meta-analysis of prospective studies of height and total cancer risk". Lancet Oncology. 12 (8): 785–794. doi:10.1016/S1470-2045(11)70154-1. PMC 3148429. PMID 21782509.
8. Fleming, J.M.; Creevy, K.E. (25 February 2011). "Mortality in North American Dogs from 1984 to 2004: An Investigation into Age-, Size-, and Breed-Related Causes of Death". Journal of Veterinary Internal Medicine. 25 (2): 187–198. doi:10.1111/j.1939-1676.2011.0695.x. PMID 21352376.
9. Schiffman, Joshua (8 October 2015), "Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans", JAMA, 314 (17): 1850–60, doi:10.1001/jama.2015.13134, PMC 4858328, PMID 26447779
10. Caulin, A. F.; Maley, C. C. (2011). "Peto's Paradox: Evolution's prescription for cancer prevention". Trends in Ecology & Evolution. 26 (4): 175–182. doi:10.1016/j.tree.2011.01.002. PMC 3060950. PMID 21296451.
11. Kobayashi, H; Man, S (15 April 1993). "Acquired multicellular-mediated resistance to alkylating agents in cancer". Proceedings of the National Academy of Sciences of the United States of America. 90 (8): 3294–8. Bibcode:1993PNAS...90.3294K. doi:10.1073/pnas.90.8.3294. PMC 46286. PMID 8475071.
12. Domazet-Lošo, Tomislav; Tautz, Diethard (21 May 2010). "Phylostratigraphic tracking of cancer genes suggests a link to the emergence of multicellularity in metazoa". BMC Biology. 8 (66): 66. doi:10.1186/1741-7007-8-66. PMC 2880965. PMID 20492640.
13. Dang, Chi (2012). "Links between metabolism and cancer". Genes & Development. 26 (9): 877–90. doi:10.1101/gad.189365.112. PMC 3347786. PMID 22549953.
14. Gewin, Virginia (21 January 2013). "Massive animals may hold secrets of cancer suppression". Nature News. doi:10.1038/nature.2013.12258. Retrieved 12 March 2014.
15. Zimmer, Carl (October 8, 2015). "Elephants: Large, Long-Living and Less Prone to Cancer". The New York Times. Retrieved October 13, 2015.
16. Keane, Michael; Semeiks, Jeremy; Webb, Andrew E.; Li, Yang I.; Quesada, Víctor; Craig, Thomas; Madsen, Lone Bruhn; van Dam, Sipko; Brawand, David; Marques, Patrícia I.; Michalak, Pawel; Kang, Lin; Bhak, Jong; Yim, Hyung-Soon; Grishin, Nick V.; Nielsen, Nynne Hjort; Heide-Jørgensen, Mads Peter; Oziolor, Elias M.; Matson, Cole W.; Church, George M.; Stuart, Gary W.; Patton, John C.; George, J. Craig; Suydam, Robert; Larsen, Knud; López-Otín, Carlos; O’Connell, Mary J.; Bickham, John W.; Thomsen, Bo; de Magalhães, João Pedro (6 January 2015). "Insights into the Evolution of Longevity from the Bowhead Whale Genome". Cell Reports. 10 (1): 112–122. doi:10.1016/j.celrep.2014.12.008. PMC 4536333. PMID 25565328.
17. Xian, T.; Azpurua, J. (27 January 2015). "INK4 locus of the tumor-resistant rodent, the naked mole rat, expresses a functional p15/p16 hybrid isoform". Proceedings of the National Academy of Sciences. 112 (4): 1053–8. Bibcode:2015PNAS..112.1053T. doi:10.1073/pnas.1418203112. PMC 4313802. PMID 25550505.
18. Callaway, E. (8 October 2015). "How elephants avoid cancer: Pachyderms have extra copies of a key tumour-fighting gene". Nature. 526. doi:10.1038/nature.2015.18534.
19. Sulak, Michael; Fong, Lindsey; Mika, Katelyn; Chigurupati, Sravanthi; Yon, Lisa; Mongan, Nigel P.; Emes, Richard D.; Lynch, Vincent J. (September 19, 2016). "TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants". eLife. 5: e11994. bioRxiv 10.1101/028522. doi:10.7554/eLife.11994. PMC 5061548. PMID 27642012.
20. MacIak, S.; Michalak, P. (2015). "Cell size and cancer: A new solution to Peto's paradox?". Evolutionary Applications. 8 (1): 2–8. doi:10.1111/eva.12228. PMC 4310577. PMID 25667599.
21. Gregory, T. Ryan (3 February 2004). "Mammal erythrocyte sizes". Genome Size. Retrieved 13 October 2015.
22. Calabrese, Peter; Shibata, Darryl (5 January 2010). "A simple algebraic cancer equation: calculating how cancers may arise with normal mutation rates". BMC Cancer. 10 (3): 3. doi:10.1186/1471-2407-10-3. PMC 2829925. PMID 20051132.
23. Tyner, Stuart D.; Venkatachalam, Sundaresan; Choi, Jene; Jones, Stephen; Ghebranious, Nader; Igelmann, Herbert; Lu, Xiongbin; Soron, Gabrielle; Cooper, Benjamin; Brayton, Cory; Hee Park, Sang; Thompson, Timothy; Karsenty, Gerard; Bradley, Allan; Donehower, Lawrence A. (January 2002). "p53 mutant mice that display early ageing-associated phenotypes". Nature. 415 (6867): 45–53. Bibcode:2002Natur.415...45T. doi:10.1038/415045a. PMID 11780111.
24. García-Cao, Isabel; García-Cao, Marta; Martín-Caballero, Juan; Criado, Luis M.; Klatt, Peter; Flores, Juana M.; Weill, Jean-Claude; Blasco, María A.; Serrano, Manuel (15 November 2002). "'Super p53' mice exhibit enhanced DNA damage response, are tumor resistant and age normally". The EMBO Journal. 21 (22): 6225–6235. doi:10.1093/emboj/cdf595. PMC 137187. PMID 12426394.

Bibliography

• Natterson-Horowitz, Barbara; Bowers, Kathryn (2012). Zoobiquity: What Animals Can Teach Us about Health and the Science of Healing. Alfred A. Knopf. ISBN 978-0-307-95838-9.