Cancer- innately incurable or subject to evolutionary resistance?

A , recent, provocative commentary, “What if Cancer Simply Can’t be Cured?” (November 15, 2016), authored by the freelance writer, Melissa Pandike, was recently posted on the web newsletter ozy.com. This article, a news report of a published research manuscript (Tomislav Domazet-Lošo et al., 2014) in the well-renowned journal Nature Communications, reported that one of the most ancient (over 100 million years ago) multicellular organisms, Hydra, develop spontaneous tumors.(1) This finding would strongly suggest that cancer started very early in evolution, representing an ancient cellular process deeply rooted in the “tree of life” itself, provoking questions that efforts to defeat it may be largely futile.

Interestingly, Hydra are considered potentially immortal, with a complete lack of senescence (aging), and perpetual division of stem cells. Thus, one could postulate that the cancer phenotype is selectively advantageous and represents the polar opposite of aging; several theoretical evolution publications have now modeled how such escape from aging (and the arise of immortality) might occur.(2) It also is known that cancer is predominantly a disease of aging, with most malignancies occurring after the age of reproduction (around 40 years of age), and thus not subject to Darwinian selection (Figure 1).(3)

In addition to the Nature Communications article, however, a more recent publication demonstrated that cancer incidence has no association with species' size and longevity, and that elephants have a mere 6.1% incidence of cancer, compared to 25% incidence in humans.(4) This > 4-fold lower occurrence In contrast to hydra, which evolved over 600 million years ago, elephants arose much more recently, around 50-60 million years ago (90% more recently on the evolutionary timescale). This low disease incidence associated with elephants possessing over 20 copies (i.e., 40 alleles) of the "master" tumor suppressor gene TP53 (protein name p53), and that the elephant p53 ortholog predominantly facilitates programmed cell death (“apoptosis”), compared to human p53, which favors cells’ repair of DNA damage.

Consistent with the elephant vs. human comparisons described above, it appears that in vertebrate animals, animal size is even negatively correlated with cancer incidence, and mutation rates (Figure 2). While this dichotomy ("Peto's paradox," first theorized by Richard Peto in 1977)(5) has persistently been held when considering cancer rates across species, it has not yet held true within the same species. For example, in the 25-year Whitehall study of 17,738 London public servants, when corrected for confounding factors such as tobacco use, found that cancer incidence positively correlated with height;(6) another assessment of 74,556 domesticated dogs demonstrated the lowest cancer risk in small dog breeds, and smaller animals within the same breed.(7)

Peto's Paradox

Several hypotheses have been set forth to rationalize Peto’s Paradox. One is that larger-sized cells in sizable animals divide more slowly, thus lessening errors in DNA synthesis (mutation rates, Figure 2). Another is that large-sized animals possess a lower rate of basal metabolism, thus avoiding carcinogens such as free radical generation, glucose production, and the accumulation of carbon backbones for new cancer cell production.(8-10) It is likely that this anticancer  correlation arises from a combination of these mechanisms.

In summary, further study of ageing and cancer, across and among animal species is needed, and increased understanding of the senescence/immortality relationship may lead to superior methods of prevention/therapy of this phenomenon in humans.

Sources:

  1. Domazet-Loso, T., Klimovich, A., Anokhin, B., Anton-Erxleben, F., Hamm, M.J., Lange, C. et al. Naturally occurring tumours in the basal metazoan Hydra. Nat Commun 2014; 5: 4222.
  2. Greaves, M. Evolutionary determinants of cancer. Cancer Discov 2015; 5: 806-820.
  3. DeGregori, J. Evolved tumor suppression: why are we so good at not getting cancer? Cancer Res 2011; 71: 3739-3744.
  4. Abegglen, L.M., Caulin, A.F., Chan, A., Lee, K., Robinson, R., Campbell, M.S. et al. Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans. JAMA 2015; 314: 1850-1860.
  5. Peto, R., Roe, F.J., Lee, P.N., Levy, L., Clack, J. Cancer and ageing in mice and men. Br J Cancer 1975; 32: 411-426.
  6. Smith, G.D., Shipley, M., Leon, D.A. Height and mortality from cancer among men: prospective observational study. BMJ 1998; 317: 1351-1352.
  7. Fleming, J.M., Creevy, K.E., Promislow, D.E. Mortality in north american dogs from 1984 to 2004: an investigation into age-, size-, and breed-related causes of death. J Vet Intern Med 2011; 25: 187-198.
  8. Harman, D. Role of free radicals in mutation, cancer, aging, and the maintenance of life. Radiat Res 1962; 16: 753-763.
  9. Knight, J.A. The biochemistry of aging. Adv Clin Chem 2000; 35: 1-62.
  10. Dang, C.V. Links between metabolism and cancer. Genes Dev 2012; 26: 877-890.

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