Perspective

Opinion

Mechanisms of cancer resistance in long-lived mammals

Published online:

Abstract

Cancer researchers have traditionally used the mouse and the rat as staple model organisms. These animals are very short-lived, reproduce rapidly and are highly prone to cancer. They have been very useful for modelling some human cancer types and testing experimental treatments; however, these cancer-prone species offer little for understanding the mechanisms of cancer resistance. Recent technological advances have expanded bestiary research to non-standard model organisms that possess unique traits of very high value to humans, such as cancer resistance and longevity. In recent years, several discoveries have been made in non-standard mammalian species, providing new insights on the natural mechanisms of cancer resistance. These include mechanisms of cancer resistance in the naked mole rat, blind mole rat and elephant. In each of these species, evolution took a different path, leading to novel mechanisms. Many other long-lived mammalian species display cancer resistance, including whales, grey squirrels, microbats, cows and horses. Understanding the molecular mechanisms of cancer resistance in all these species is important and timely, as, ultimately, these mechanisms could be harnessed for the development of human cancer therapies.

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References

  1. 1.

    Center for Disease Control and Prevention. United States Cancer Statistics: 1999–2014 Cancer Incidence and Mortality Data. CDC https://nccd.cdc.gov/uscs/ (2017).

  2. 2.

    Cleeland, C. S. et al. Reducing the toxicity of cancer therapy: recognizing needs, taking action. Nat. Rev. Clin. Oncol. 9, 471–478 (2012).

  3. 3.

    Lipman, R., Galecki, A., Burke, D. T. & Miller, R. A. Genetic loci that influence cause of death in a heterogeneous mouse stock. J. Gerontol. A Biol. Sci. Med. Sci. 59, 977–983 (2004).

  4. 4.

    Szymanska, H. et al. Neoplastic and nonneoplastic lesions in aging mice of unique and common inbred strains contribution to modeling of human neoplastic diseases. Vet. Pathol. 51, 663–679 (2014).

  5. 5.

    Ikeno, Y. et al. Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein knockout mice. J. Gerontol. A Biol. Sci. Med. Sci. 64, 522–529 (2009).

  6. 6.

    Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2016. CA Cancer J. Clin. 66, 7–30 (2016).

  7. 7.

    Rangarajan, A., Hong, S. J., Gifford, A. & Weinberg, R. A. Species- and cell type-specific requirements for cellular transformation. Cancer Cell 6, 171–183 (2004).

  8. 8.

    Gonzalez, C. A. & Riboli, E. Diet and cancer prevention: Contributions from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Eur. J. Cancer 46, 2555–2562 (2010).

  9. 9.

    Key, T. J. et al. Diet, nutrition and the prevention of cancer. Publ. Health Nutr. 7, 187–200 (2004).

  10. 10.

    Prowse, K. R. & Greider, C. W. Developmental and tissue-specific regulation of mouse telomerase and telomere length. Proc. Natl Acad. Sci. USA 92, 4818–4822 (1995).

  11. 11.

    de Lange, T. How telomeres solve the end-protection problem. Science 326, 948–952 (2009).

  12. 12.

    Shippen-Lentz, D. & Blackburn, E. H. Functional evidence for an RNA template in telomerase. Science 247, 546–552 (1990).

  13. 13.

    Campisi, J., Kim, S. H., Lim, C. S. & Rubio, M. Cellular senescence, cancer and aging: the telomere connection. Exp. Gerontol. 36, 1619–1637 (2001).

  14. 14.

    Kim, N. W. et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011–2015 (1994).

  15. 15.

    Seluanov, A. et al. Telomerase activity coevolves with body mass not lifespan. Aging Cell 6, 45–52 (2007).

  16. 16.

    Seluanov, A. et al. Distinct tumor suppressor mechanisms evolve in rodent species that differ in size and lifespan. Aging Cell 7, 813–823 (2008).

  17. 17.

    Gomes, N. M. et al. Comparative biology of mammalian telomeres: hypotheses on ancestral states and the roles of telomeres in longevity determination. Aging Cell 10, 761–768 (2011).

  18. 18.

    Tian, X. et al. Evolution of telomere maintenance and tumor suppressor mechanisms across mammals. Philos. Trans R. Soc. Lond. B Biol Sci. 373, 20160443 (2018).

  19. 19.

    Buffenstein, R. & Jarvis, J. U. The naked mole rat — a new record for the oldest living rodent. Sci. Aging Knowl. Environ. 2002, pe7 (2002).

  20. 20.

    Buffenstein, R. Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species. J. Comp. Physiol. B 178, 439–445 (2008).

  21. 21.

    Liang, S., Mele, J., Wu, Y., Buffenstein, R. & Hornsby, P. J. Resistance to experimental tumorigenesis in cells of a long-lived mammal, the naked mole-rat (Heterocephalus glaber). Aging Cell 9, 626–635 (2010).

  22. 22.

    Delaney, M. A., Nagy, L., Kinsel, M. J. & Treuting, P. M. Spontaneous histologic lesions of the adult naked mole rat (Heterocephalus glaber): a retrospective survey of lesions in a zoo population. Vet. Pathol. 50, 607–621 (2013).

  23. 23.

    Delaney, M. A. et al. Initial Case Reports of Cancer in Naked Mole-rats (Heterocephalus glaber). Vet. Pathol. 53, 691–696 (2016).

  24. 24.

    Seluanov, A. et al. Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat. Proc. Natl Acad. Sci. USA 106, 19352–19357 (2009).

  25. 25.

    Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

  26. 26.

    Tian, X. et al. INK4 locus of the tumor-resistant rodent, the naked mole rat, expresses a functional p15/p16 hybrid isoform. Proc. Natl Acad. Sci. USA 112, 1053–1058 (2015).

  27. 27.

    Kim, E. B. et al. Genome sequencing reveals insights into physiology and longevity of the naked mole rat. Nature 479, 223–227 (2011).

  28. 28.

    Sharpless, N. E. INK4a/ARF: a multifunctional tumor suppressor locus. Mutat. Res. 576, 22–38 (2005).

  29. 29.

    Tian, X. et al. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature 499, 346–349 (2013).

  30. 30.

    Toole, B. P. Hyaluronan: from extracellular glue to pericellular cue. Nat. Rev. Cancer 4, 528–539 (2004).

  31. 31.

    Miyawaki, S. et al. Tumour resistance in induced pluripotent stem cells derived from naked mole-rats. Nat. Commun. 7, 11471 (2016).

  32. 32.

    Folmes, C. D. et al. Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metab. 14, 264–271 (2011).

  33. 33.

    Suva, M. L., Riggi, N. & Bernstein, B. E. Epigenetic reprogramming in cancer. Science 339, 1567–1570 (2013).

  34. 34.

    Ben-David, U. & Benvenisty, N. The tumorigenicity of human embryonic and induced pluripotent stem cells. Nat. Rev. Cancer 11, 268–277 (2011).

  35. 35.

    Tan, L. et al. Naked mole rat cells have stable epigenome that resists iPSC reprogramming. Stem Cell Rep. 9, 1721–1734 (2017).

  36. 36.

    Lee, S. et al. Naked mole rat induced pluripotent stem cells and their contribution to interspecific chimera Stem Cell Rep. 9, 1706–1720 (2017).

  37. 37.

    Park, T. J. et al. Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat. Science 356, 307–311 (2017).

  38. 38.

    Liu, H. et al. Fructose induces transketolase flux to promote pancreatic cancer growth. Cancer Res. 70, 6368–6376 (2010).

  39. 39.

    Azpurua, J. et al. Naked mole-rat has increased translational fidelity compared with the mouse, as well as a unique 28 S ribosomal RNA cleavage. Proc. Natl Acad. Sci. USA 110, 17350–17355 (2013).

  40. 40.

    Lewis, K. N. et al. Regulation of Nrf2 signaling and longevity in naturally long-lived rodents. Proc. Natl Acad. Sci. USA 112, 3722–3727 (2015).

  41. 41.

    Zhao, S. et al. High autophagy in the naked mole rat may play a significant role in maintaining good health. Cell Physiol. Biochem. 33, 321–332 (2014).

  42. 42.

    Rodriguez, K. A. et al. A cytosolic protein factor from the naked mole-rat activates proteasomes of other species and protects these from inhibition. Biochim. Biophys. Acta 1842, 2060–2072 (2014).

  43. 43.

    Meredith, R. W. et al. Impacts of the Cretaceous Terrestrial Revolution and KPg extinction on mammal diversification. Science 334, 521–524 (2011).

  44. 44.

    Edrey, Y. H. et al. Sustained high levels of neuregulin-1 in the longest-lived rodents; a key determinant of rodent longevity. Aging Cell 11, 213–222 (2012).

  45. 45.

    Gorbunova, V. et al. Cancer resistance in the blind mole rat is mediated by concerted necrotic cell death mechanism. Proc. Natl Acad. Sci. USA 109, 19392–19396 (2012).

  46. 46.

    Shams, I., Avivi, A. & Nevo, E. Hypoxic stress tolerance of the blind subterranean mole rat: expression of erythropoietin and hypoxia-inducible factor 1 alpha. Proc. Natl Acad. Sci. USA 101, 9698–9703 (2004).

  47. 47.

    Ashur-Fabian, O. et al. Evolution of p53 in hypoxia-stressed Spalax mimics human tumor mutation. Proc. Natl Acad. Sci. USA 101, 12236–12241 (2004).

  48. 48.

    Manov, I. et al. Pronounced cancer resistance in a subterranean rodent, the blind mole-rat, Spalax: in vivo and in vitro evidence. BMC Biol. 11, 91 (2013).

  49. 49.

    Fang, X. et al. Genome-wide adaptive complexes to underground stresses in blind mole rats Spalax. Nat. Commun. 5, 3966 (2014).

  50. 50.

    Nasser, N. J. et al. Alternatively spliced Spalax heparanase inhibits extracellular matrix degradation, tumor growth, and metastasis. Proc. Natl Acad. Sci. USA 106, 2253–2258 (2009).

  51. 51.

    Siegal-Willott, J., Heard, D., Sliess, N., Naydan, D. & Roberts, J. Microchip-associated leiomyosarcoma in an Egyptian fruit bat (Rousettus aegyptiacus). J. Zoo Wildl. Med. 38, 352–356 (2007).

  52. 52.

    McLelland, D. J., Dutton, C. J. & Barker, I. K. Sarcomatoid carcinoma in the lung of an Egyptian fruit bat (Rousettus aegyptiacus). J. Vet. Diagn. Invest. 21, 160–163 (2009).

  53. 53.

    Bradford, C., Jennings, R. & Ramos-Vara, J. Gastrointestinal leiomyosarcoma in an Egyptian fruit bat (Rousettus aegyptiacus). J. Vet. Diagn. Invest. 22, 462–465 (2010).

  54. 54.

    Crameri, G. et al. Establishment, immortalisation and characterisation of pteropid bat cell lines. PloS ONE 4, e8266 (2009).

  55. 55.

    Wang, L. F., Walker, P. J. & Poon, L. L. Mass extinctions, biodiversity and mitochondrial function: are bats ‘special’ as reservoirs for emerging viruses? Curr. Opin. Virol. 1, 649–657 (2011).

  56. 56.

    Brook, C. E. & Dobson, A. P. Bats as ‘special’ reservoirs for emerging zoonotic pathogens. Trends Microbiol. 23, 172–180 (2015).

  57. 57.

    Huang, Z., Jebb, D. & Teeling, E. C. Blood miRNomes and transcriptomes reveal novel longevity mechanisms in the long-lived bat, Myotis myotis. BMC Genom. 17, 906 (2016).

  58. 58.

    Seim, I. et al. Genome analysis reveals insights into physiology and longevity of the Brandt’s bat Myotis brandtii. Nat. Commun. 4, 2212 (2013).

  59. 59.

    Zhang, G. et al. Comparative analysis of bat genomes provides insight into the evolution of flight and immunity. Science 339, 456–460 (2013).

  60. 60.

    David, A. et al. Evidence for a continuum of genetic, phenotypic, and biochemical abnormalities in children with growth hormone insensitivity. Endocr. Rev. 32, 472–497 (2011).

  61. 61.

    Guevara-Aguirre, J. et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci. Transl Med. 3, 70ra13 (2011).

  62. 62.

    Peto, R. in Origins of Human Cancer (eds Hiatt, H. H., Watson, J. D. & Winsten, J. A.) (Cold Spring Harbor Publications, 1977).

  63. 63.

    Nordling, C. O. A new theory on cancer-inducing mechanism. Br. J. Cancer 7, 68–72 (1953).

  64. 64.

    Nunney, L. Lineage selection and the evolution of multistage carcinogenesis. Proc. Biol. Sci. 266, 493–498 (1999).

  65. 65.

    Tollis, M., Boddy, A. M. & Maley, C. C. Peto’s Paradox: how has evolution solved the problem of cancer prevention? BMC Biol. 15, 60 (2017).

  66. 66.

    Sulak, M. et al. TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants. eLife 5, e11994 (2016).

  67. 67.

    Abegglen, L. M. et al. Potential mechanisms for cancer resistance in elephants and comparative cellular response to DNA damage in humans. JAMA 314, 1850–1860 (2015).

  68. 68.

    Tyner, S. D. et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 415, 45–53 (2002).

  69. 69.

    Maier, B. et al. Modulation of mammalian life span by the short isoform of p53. Genes Dev. 18, 306–319 (2004).

  70. 70.

    Garcia-Cao, I. et al. “Super p53” mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J. 21, 6225–6235 (2002).

  71. 71.

    Matheu, A. et al. Delayed ageing through damage protection by the Arf/p53 pathway. Nature 448, 375–379 (2007).

  72. 72.

    Yim, H. S. et al. Minke whale genome and aquatic adaptation in cetaceans. Nat. Genet. 46, 88–92 (2014).

  73. 73.

    Foote, A. D. et al. Convergent evolution of the genomes of marine mammals. Nat. Genet. 47, 272–275 (2015).

  74. 74.

    Foote, A. D. et al. Genome-culture coevolution promotes rapid divergence of killer whale ecotypes. Nat. Commun. 7, 11693 (2016).

  75. 75.

    Keane, M. et al. Insights into the evolution of longevity from the bowhead whale genome. Cell Rep. 10, 112–122 (2015).

  76. 76.

    George, J. C. et al. Age and growth estimates of bowhead whales (Balaena mysticetus) via aspartic acid racemization. Can. J. Zool. 77, 571–580 (1999).

  77. 77.

    Tacutu, R. et al. Human Ageing Genomic Resources: integrated databases and tools for the biology and genetics of ageing. Nucleic Acids Res. 41, D1027–D1033 (2013).

  78. 78.

    Seim, I. et al. The transcriptome of the bowhead whale Balaena mysticetus reveals adaptations of the longest-lived mammal. Aging 6, 879–899 (2014).

  79. 79.

    Failla, G. The aging process and carcinogenesis. Ann. New York Acad. Sci. 71, 1124–1135 (1958).

  80. 80.

    Baer, C. F., Miyamoto, M. M. & Denver, D. R. Mutation rate variation in multicellular eukaryotes: causes and consequences. Nat. Rev. Genet. 8, 619–631 (2007).

  81. 81.

    Lynch, M. Evolution of the mutation rate. Trends Genet. 26, 345–352 (2010).

  82. 82.

    Britten, R. J. Rates of DNA sequence evolution differ between taxonomic groups. Science 231, 1393–1398 (1986).

  83. 83.

    Thomas, G. W. & Hahn, M. W. The human mutation rate is increasing, even as it slows. Mol. Biol. Evol. 31, 253–257 (2014).

  84. 84.

    MacRae, S. L. et al. Comparative analysis of genome maintenance genes in naked mole rat, mouse, and human. Aging Cell 14, 288–291 (2015).

  85. 85.

    Milholland, B. et al. Differences between germline and somatic mutation rates in humans and mice. Nat. Commun. 8, 15183 (2017).

  86. 86.

    Tollis, M., Schiffman, J. D. & Boddy, A. M. Evolution of cancer suppression as revealed by mammalian comparative genomics. Curr. Opin. Genet. Dev. 42, 40–47 (2017).

  87. 87.

    Croco, E. et al. DNA damage detection by 53BP1: relationship to species longevity. J. Gerontol. A Biol. Sci. Med. Sci. 72, 763–770 (2017).

  88. 88.

    MacRae, S. L. et al. DNA repair in species with extreme lifespan differences. Aging 7, 1171–1184 (2015).

  89. 89.

    Ma, S. et al. Cell culture-based profiling across mammals reveals DNA repair and metabolism as determinants of species longevity. eLife 5, e19130 (2016).

  90. 90.

    de Magalhaes, J. P. & Kean, M. Endless paces of degeneration — applying comparative genomics to study evolution’s moulding of longevity. EMBO Rep. 14, 661–662 (2013).

  91. 91.

    Dial, K. P. Wing-assisted incline running and the evolution of flight. Science 299, 402–404 (2003).

  92. 92.

    Munson, L. & Moresco, A. Comparative Pathobiology of mammary gland cancers in wild and domestic animals. Breast Dis. 28, 7–21 (2007).

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Acknowledgements

The authors thank E. Teeling for recommending the literature on cancer in wild bats. The work in the authors’ laboratories is supported by grants from the US National Institutes of Health and the Life Extension Foundation.

Author information

Affiliations

  1. University of Rochester, Department of Biology, Rochester, NY, USA

    • Andrei Seluanov
    •  & Vera Gorbunova
  2. Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    • Vadim N. Gladyshev
  3. Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA

    • Jan Vijg

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Contributions

A.S. and V.G. wrote the article and prepared the figures. V.N.G. wrote the section on cancer resistance in bats, and J.V. wrote the section on mutation rates. All authors contributed equally to the review and editing of the article before submission.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Vera Gorbunova.