Peto's paradox

Last updated

Peto's paradox is the observation 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] despite whales having more cells than humans. If the probability of carcinogenesis were constant across cells, one would expect whales to have a higher incidence of cancer than humans. Peto's paradox is named after English statistician and epidemiologist Richard Peto, who first observed the connection.

Contents

History

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

Same species

Within members of the same species, cancer risk and body size appear to be positively correlated, even once other risk factors are controlled for. [4]

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. [5] 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. [6] 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. [7]

Across species

Across species, however, the relationship breaks down. In a 2015 study, the San Diego Zoo surveyed results from 36 different mammalian species, ranging in size from the 51-gram striped grass mouse to the nearly 100,000 times larger 4,800-kilogram elephant. The study found no statistically significant relationship between body size and cancer incidence, offering empirical support for Peto's initial observation. [8]

Evolutionary considerations

The evolution of multicellularity has required the suppression of cancer to some extent, [9] and connections have been found between the origins of multicellularity and cancer. [10] [11] 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. [12] 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. [13]

Various species have evolved different mechanisms for suppressing cancer. [14] 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. [15] 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. [16] In October 2015, two independent studies showed that African elephants have 20 copies of tumor suppressor gene TP53 in their genome, Asian elephants have 15 to 20, where humans and other mammals have only one. [17] 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. [18] The TP53 tumor suppressor gene specifies a protein that senses damaged sites in DNA, or a cell experiencing stress. The TP53 protein then either slows the growth of the cell for a brief period during which DNA damage is repaired, or it triggers cell death (apoptosis) if the damage is overwhelming. [18] Enhanced capability to repair DNA damage may explain the observed cancer suppression in elephants. The results suggest an evolutionary relationship between animal size and tumor suppression, as Peto had theorized.[ citation needed ]

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." [19]

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. [20] ) 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. [21] Additionally, larger animals generally have lower basal metabolic rates, following a well-defined inverse logarithmic relationship [ clarification needed ]. 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

Large animals' apparent ability to suppress cancer across vast numbers of cells has spurred an active medical research field. [13]

In one experiment, laboratory mice were genetically altered to express "always-on" (always on meaning it doesn't get deactivated by the MDM2 gene) active TP53 tumor antigens,[ clarification needed ] similar to the ones found in elephants. The mutated mice exhibited increased tumor suppression ability, but also showed signs of premature aging. [22]

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. [23]

See also

Related Research Articles

<span class="mw-page-title-main">Cell cycle</span> Series of events and stages that result in cell division

The cell cycle, or cell-division cycle, is the series of events that take place in a cell that causes it to divide into two daughter cells. These events include the duplication of its DNA and some of its organelles, and subsequently the partitioning of its cytoplasm, chromosomes and other components into two daughter cells in a process called cell division.

p53 Mammalian protein found in Homo sapiens

p53, also known as Tumor protein P53, cellular tumor antigen p53, or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins are crucial in vertebrates, where they prevent cancer formation. As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation. Hence TP53 is classified as a tumor suppressor gene.

<span class="mw-page-title-main">Tumor suppressor gene</span> Gene that inhibits expression of the tumorigenic phenotype

A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or reduction in its function. In combination with other genetic mutations, this could allow the cell to grow abnormally. The loss of function for these genes may be even more significant in the development of human cancers, compared to the activation of oncogenes.

<span class="mw-page-title-main">Multicellular organism</span> Organism that consists of more than one cell

A multicellular organism is an organism that consists of more than one cell, in contrast to unicellular organism. All species of animals, land plants and most fungi are multicellular, as are many algae, whereas a few organisms are partially uni- and partially multicellular, like slime molds and social amoebae such as the genus Dictyostelium.

<span class="mw-page-title-main">DNA repair</span> Cellular mechanism

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encodes its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.

<span class="mw-page-title-main">Li–Fraumeni syndrome</span> Autosomal dominant cancer syndrome

Li–Fraumeni syndrome is a rare, autosomal dominant, hereditary disorder that predisposes carriers to cancer development. It was named after two American physicians, Frederick Pei Li and Joseph F. Fraumeni Jr., who first recognized the syndrome after reviewing the medical records and death certificates of 648 childhood rhabdomyosarcoma patients. This syndrome is also known as the sarcoma, breast, leukaemia and adrenal gland (SBLA) syndrome.

Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnormal cell division. Cell division is a physiological process that occurs in almost all tissues and under a variety of circumstances. Normally, the balance between proliferation and programmed cell death, in the form of apoptosis, is maintained to ensure the integrity of tissues and organs. According to the prevailing accepted theory of carcinogenesis, the somatic mutation theory, mutations in DNA and epimutations that lead to cancer disrupt these orderly processes by interfering with the programming regulating the processes, upsetting the normal balance between proliferation and cell death. This results in uncontrolled cell division and the evolution of those cells by natural selection in the body. Only certain mutations lead to cancer whereas the majority of mutations do not.

<span class="mw-page-title-main">Bert Vogelstein</span> American oncologist (born 1949)

Bert Vogelstein is director of the Ludwig Center, Clayton Professor of Oncology and Pathology and a Howard Hughes Medical Institute investigator at The Johns Hopkins Medical School and Sidney Kimmel Comprehensive Cancer Center. A pioneer in the field of cancer genomics, his studies on colorectal cancers revealed that they result from the sequential accumulation of mutations in oncogenes and tumor suppressor genes. These studies now form the paradigm for modern cancer research and provided the basis for the notion of the somatic evolution of cancer.

Enquiry into the evolution of ageing, or aging, aims to explain why a detrimental process such as ageing would evolve, and why there is so much variability in the lifespans of organisms. The classical theories of evolution suggest that environmental factors, such as predation, accidents, disease, and/or starvation, ensure that most organisms living in natural settings will not live until old age, and so there will be very little pressure to conserve genetic changes that increase longevity. Natural selection will instead strongly favor genes which ensure early maturation and rapid reproduction, and the selection for genetic traits which promote molecular and cellular self-maintenance will decline with age for most organisms.

p14ARF is an alternate reading frame protein product of the CDKN2A locus. p14ARF is induced in response to elevated mitogenic stimulation, such as aberrant growth signaling from MYC and Ras (protein). It accumulates mainly in the nucleolus where it forms stable complexes with NPM or Mdm2. These interactions allow p14ARF to act as a tumor suppressor by inhibiting ribosome biogenesis or initiating p53-dependent cell cycle arrest and apoptosis, respectively. p14ARF is an atypical protein, in terms of its transcription, its amino acid composition, and its degradation: it is transcribed in an alternate reading frame of a different protein, it is highly basic, and it is polyubiquinated at the N-terminus.

<span class="mw-page-title-main">PPM1D</span> Protein-coding gene in the species Homo sapiens

Protein phosphatase 1D is an enzyme that in humans is encoded by the PPM1D gene.

<span class="mw-page-title-main">Cellular senescence</span> Phenomenon characterized by the cessation of cell division

Cellular senescence is a phenomenon characterized by the cessation of cell division. In their experiments during the early 1960s, Leonard Hayflick and Paul Moorhead found that normal human fetal fibroblasts in culture reach a maximum of approximately 50 cell population doublings before becoming senescent. This process is known as "replicative senescence", or the Hayflick limit. Hayflick's discovery of mortal cells paved the path for the discovery and understanding of cellular aging molecular pathways. Cellular senescence can be initiated by a wide variety of stress inducing factors. These stress factors include both environmental and internal damaging events, abnormal cellular growth, oxidative stress, autophagy factors, among many other things.

<span class="mw-page-title-main">Antagonistic pleiotropy hypothesis</span> Proposed evolutionary explanation for senescence

The antagonistic pleiotropy hypothesis was first proposed by George C. Williams in 1957 as an evolutionary explanation for senescence. Pleiotropy is the phenomenon where one gene controls more than one phenotypic trait in an organism. A gene is considered to possess antagonistic pleiotropy if it controls more than one trait, where at least one of these traits is beneficial to the organism's fitness early on in life and at least one is detrimental to the organism's fitness later on due to a decline in the force of natural selection. The theme of G.C. William's idea about antagonistic pleiotropy was that if a gene caused both increased reproduction in early life and aging in later life, then senescence would be adaptive in evolution. For example, one study suggests that since follicular depletion in human females causes both more regular cycles in early life and loss of fertility later in life through menopause, it can be selected for by having its early benefits outweigh its late costs.

Somatic evolution is the accumulation of mutations and epimutations in somatic cells during a lifetime, and the effects of those mutations and epimutations on the fitness of those cells. This evolutionary process has first been shown by the studies of Bert Vogelstein in colon cancer. Somatic evolution is important in the process of aging as well as the development of some diseases, including cancer.

The p53 p63 p73 family is a family of tumor suppressor genes.

<i>Volvox carteri</i> Species of alga

Volvox carteri is a species of colonial green algae in the order Volvocales. The V. carteri life cycle includes a sexual phase and an asexual phase. V. carteri forms small spherical colonies, or coenobia, of 2000–6000 Chlamydomonas-type somatic cells and 12–16 large, potentially immortal reproductive cells called gonidia. While vegetative, male and female colonies are indistinguishable; however, in the sexual phase, females produce 35-45 eggs and males produce up to 50 sperm packets with 64 or 128 sperm each.

<span class="mw-page-title-main">WRAP53</span> Protein-coding gene in the species Homo sapiens

WRAP53 is a gene implicated in cancer development. The name was coined in 2009 to describe the dual role of this gene, encoding both an antisense RNA that regulates the p53 tumor suppressor and a protein involved in DNA repair, telomere elongation and maintenance of nuclear organelles Cajal bodies.

Comparative oncology integrates the study of oncology in non-human animals into more general studies of cancer biology and therapy. The field encompasses naturally seen cancers in veterinary patients and the extremely low rates of cancers seen in large mammals such as elephants and whales.

Laura Attardi is the Catharine and Howard Avery Professor of the school of medicine, and professor of radiation oncology and genetics at Stanford University where she leads the Attardi Laboratory. Attardi studies the tumor suppressor protein p53 and the gene that encodes it, TP53, to better understand mechanisms for preventing cancer.

Human protein 53 intron 1 (Hp53int1) is a protein encoded by the Hp53int1 gene in humans.

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. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.{{cite journal}}: |author7= has generic name (help)
  7. ↑ 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. S2CID   29868508.
  8. ↑ 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
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ Dang, Chi (2012). "Links between metabolism and cancer". Genes & Development. 26 (9): 877–90. doi:10.1101/gad.189365.112. PMC   3347786 . PMID   22549953.
  13. 1 2 Gewin, Virginia (21 January 2013). "Massive animals may hold secrets of cancer suppression". Nature News . doi:10.1038/nature.2013.12258. S2CID   87061133 . Retrieved 12 March 2014.
  14. ↑ Zimmer, Carl (October 8, 2015). "Elephants: Large, Long-Living and Less Prone to Cancer". The New York Times . Retrieved October 13, 2015.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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. S2CID   181698116.
  18. 1 2 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.
  19. ↑ 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.
  20. ↑ Gregory, T. Ryan (3 February 2004). "Mammal erythrocyte sizes". Genome Size. Retrieved 13 October 2015.
  21. ↑ 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.
  22. ↑ 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. S2CID   749047.
  23. ↑ 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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.