12 October 2015

Solving the Peto Paradox

Why elephants don't get cancer

Kirill Stasevich, "Science and Life" 

Oncological diseases affect not only people, but also animals. But everything is different – someone more often, someone less often. There are species that are particularly resistant to cancer, and these, oddly enough, include the largest mammals: elephants and whales. Why "oddly enough"? We know that cancer begins with cells in which the mechanism of division control has deteriorated. Obviously, the more cells there are in the body, the more likely it is that something will go wrong in one of them - when dividing, for example, an error may creep into the synthesized DNA chain. However, elephants, despite their size and long lifespan, get cancer even less often than smaller species. This paradox was called the Peto paradox – after Richard Peto, a British epidemiologist from Oxford, who noticed it back in the 1970s. 

Obviously, long-lived large animals have some additional mechanisms that suppress the occurrence of malignant tumors. Among the genes on which the development of cancer depends, there are proto-oncogenes and anti-oncogenes. If the first ones start working the wrong way, the cells "go crazy" and degenerate into cancerous ones; accordingly, the same thing will happen if the anti-oncogenes that monitor whether the cells behave correctly break down. 

Two years ago, researchers from the Development Institute in Montpellier proposed a model that took into account the behavior of proto-oncogenes and anti-oncogenes depending on the size of the animal. The model simulated different mutation distributions over several thousand generations. The conclusion turned out to be this: proto-oncogenes and anti-oncogenes react differently in evolution to an increase in body weight. The greater the body weight, the more difficult it is to activate the genes that can provoke a tumor. 

One of the mutations that makes it more difficult to activate proto-oncogenes may be due to the fact that the number of tumor suppressors in the genome simply increases. Joshua D. Schiffman from the University of Utah, along with colleagues from Arizona State University and the University of Pennsylvania, write about this in their article in the Journal of the American Medical Association (Abegglen et al., Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans, in the public domain). (Why Elephants Rarely Get Cancer). First, the authors of the work analyzed the mortality statistics of elephants, and again they were once again convinced that they are really resistant to cancer more than many other species: only 5% of pachyderms die from tumors, whereas, for example, in hyena-like dogs, cancer destroys 8%, not to mention 25% of people.

Genome analysis showed that African elephants have as many as 40 copies of the p53 gene, Asian elephants have from 30 to 40. This gene is one of the most famous anti–oncogenes. The p53 protein recognizes DNA damage, and if there are enough of them, it turns on the genes responsible for apoptosis – programmed cell suicide. A large amount of genetic damage makes the cell dangerous for the whole body, so it's easiest to get rid of it altogether. Obviously, it is the huge number of copies of p53 that originated in their genome millions of years ago that helps elephants avoid cancer (humans, by the way, have only two copies of p53). 

 Of course, you can do something else – try to repair the damaged DNA, however, when elephant cells were irradiated with ionizing radiation, no activation of DNA repair genes and proteins was observed, but the cells began to actively die. That is, the elephant's way to avoid a malignant tumor is simply to kill the spoiled cell in time. One can only regret that evolution could not supply our genome with an extra dozen copies of p53; perhaps in the future biotechnology will allow such an operation to be performed, and new people with increased protection against cancer will be born. 

 Here it is impossible not to remember about another beast, whose resistance to cancer has long intrigued biologists. We are talking about a naked digger – this unpleasant-looking African rodent lives for an unusually long time, up to 28-31 years, which is 10 times longer than ordinary laboratory rats, and he does not have any malignant tumors. Two years ago, a group from the University of Rochester, led by Andrei Seluanov and Vera Gorbunova, published an article in Nature stating that the diggers owe their resistance to cancer to a large amount of hyaluronic acid filling the intercellular matrix – it prevents cells from sticking together and turning into a tumor. But the blind, the evolutionary cousins of the diggers, also known for their resistance to cancer, went the "elephant" way: the cells of their body are subject to an exceptionally rigid program of apoptosis, which causes them to die if there are too many cells. 

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