Opinion

Mechanisms of cancer resistance in long-lived mammals

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Evolution of anticancer mechanisms shaped by lifespan and body mass.
Fig. 2: Anticancer mechanisms in the naked mole rat.
Fig. 3: Anticancer mechanisms in the blind mole rat.
Fig. 4: Anticancer mechanisms in the largest mammals: elephants and whales.
Fig. 5: Developing anticancer treatments based on naturally evolved cancer resistance.

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).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  6. 6.

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

    Article  PubMed  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  9. 9.

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

    Article  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. 11.

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. 12.

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

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  14. 14.

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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. 15.

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

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  23. 23.

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

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

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

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. 28.

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

    Article  PubMed  CAS  Google Scholar 

  29. 29.

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. 30.

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

    Article  PubMed  CAS  Google Scholar 

  31. 31.

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. 33.

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

    Article  PubMed  CAS  Google Scholar 

  34. 34.

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

    Article  PubMed  CAS  Google Scholar 

  35. 35.

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

    Article  CAS  Google Scholar 

  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).

    Article  Google Scholar 

  37. 37.

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

    Article  PubMed  CAS  Google Scholar 

  38. 38.

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

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. 43.

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

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

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

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  54. 54.

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  56. 56.

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

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. 64.

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. 68.

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

    Article  PubMed  CAS  Google Scholar 

  69. 69.

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. 71.

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

    Article  PubMed  CAS  Google Scholar 

  72. 72.

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

    Article  PubMed  CAS  Google Scholar 

  73. 73.

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. 74.

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. 75.

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. 79.

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

    Article  CAS  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  81. 81.

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. 82.

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

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. 85.

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  PubMed  CAS  Google Scholar 

  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).

    PubMed  Google Scholar 

  88. 88.

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. 91.

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

    Article  PubMed  CAS  Google Scholar 

  92. 92.

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

    Article  PubMed  CAS  Google Scholar 

Download references

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

Authors

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.

Corresponding author

Correspondence to Vera Gorbunova.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Seluanov, A., Gladyshev, V.N., Vijg, J. et al. Mechanisms of cancer resistance in long-lived mammals. Nat Rev Cancer 18, 433–441 (2018). https://doi.org/10.1038/s41568-018-0004-9

Download citation

Further reading

Search

Quick links

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing