Massive animals may hold secrets of cancer suppression-Peto’s paradox

Theory suggests trade-off between cancer risk and reproductive potential.

• Virginia
       Gewin

21 January 2013

 

Large animals such as humpback whales may have evolved cancer-fighting mechanisms that smaller
animals lack — but one flip-side could be lower rates of reproduction.

Sue Flood / naturepl.com

 

If every living cell had an equal chance of becoming cancerous, whales and elephants should have a
greater risk of developing cancer than do humans or mice. But across species,
the occurrence of cancer does not show a correlation with body mass. According
to a new model, the paradox could be explained if animals were striking a
balance between reducing cancer risk and other priorities, such as maximising
the number of offspring.

 

The lack of correlation between body mass and cancer risk is known as Peto’s paradox, after epidemiologist Richard Peto of Oxford University in the UK, who noted it in the 1970s.
Evolutionary biologists think that it results from larger animals using
protective mechanisms that many smaller animals do not¹.

In an attempt to identify how greater body mass might foster such mechanisms, evolutionary biologist Benjamin Roche at the Institute of Research for Development in Montpellier, France, and
his colleagues created a theoretical model to simulate which of 100 possible
genetic-mutation strategies would become most prevalent over 4,000 generations.

The model included two gene types: proto-oncogenes, which can cause normal cells to become cancerous, and tumour-suppressor genes, which repair cellular damage that could otherwise lead
to cancer. For carcinogenesis to occur, the team assumed that proto-oncogenes
must be activated and tumour-suppressor genes must be rendered inactive.

“We found that tumour-suppressor genes and proto-oncogenes react differently along a gradient of body masses,” says Roche. “Their evolutionary dynamics are linked.” Proto-oncogene activation
decreased steadily with increasing body mass, the team found.

Cost–benefit ratio

In their model, evolution did not
always favour tumour-suppressor genes. Although these mechanisms could reduce
cancer mortality in any animal, they may come at a cost — reduced fertility, in
the case of the team's model. The result was that for intermediate-sized
animals, the evolutionary cost of having many tumour suppressor genes was
greater than the benefits of cancer protection they offered.

As a consequence, mutations would arise to keep tumour-suppressors in check.
“At this point, it is better for the population, evolutionarily, to tolerate
more deaths from cancer rather than investing in more costly mechanisms to
avoid cancer development,” says Roche.

The results, published in a special issue of Evolutionary Applications focused on cancer biology², could explain why, for example, the incidence of
cancer in humans stands at one in three, whereas it is only 18% in beluga whales³.

Roche and colleagues' is not the
only proposed explanation for Peto’s paradox. “There are a number of different
hypotheses,” says Carlo Maley, director of the Center for Evolution and Cancer
at the University of California, San
  Francisco. “For example, rather than body mass
influencing the number of tumour suppressors and oncogenes, maybe there are
less reactive oxygen species in larger organisms due to their lower metabolic
rate."

Maley and his colleagues are
sequencing the humpback whale genome, which they plan to compare with others,
including the elephant genome, to determine which hypotheses might be valid —
and whether nature has already come up with cancer-prevention mechanisms that
could be translated to the clinic.

Still, some biologists question
whether there is a paradox at all, saying that variations in cancer rates
across species — which range between 20% and 46% — are more similar than
different. “All species get cancer at about the same rate, typically in the
latter part of life span,” says James DeGregori, a molecular biologist at the University of Colorado
in Denver. “We
simply don’t have the data yet to back up the notion that larger animals have
come up with a way to avoid oncogenic mutations.”

Journal name:

Nature

DOI:

doi:10.1038/nature.2013.12258

References

1. 
   Caulin
   A.F., & Maley, C.C., Trends
   Ecol Evol 26, 175–182 (2011).

1.  
   • Article
   • ISI

Show context

1. 
   Roche, B., et
   al., Evo Appl. DOI: 10.1111/eva.12025 (2013).

Show context

1. 
   Martineau, D. et
   al. Environ Health Perspect. 110, 285–292 (2002).

1.  
   • Article
   • PubMed
   • ISI

Show context