The biological paradox offers new insights into the mystery of cancer


22 December 2021

Researchers analyze interspecies database to find out why very large animals have remarkably low cancer rates

The body’s cells can be thought of as tiny archery targets, each vulnerable to the deadly arrow of cancer. The more cells an animal has and the longer it lives, the more likely it is to accumulate harmful cell mutations that can eventually lead to cancer. Or at least, that’s what intuition suggests.

Nonetheless, many very large animals carrying huge cell populations, including elephants and whales, not only survive to old age, but have remarkably low cancer rates. This biological enigma is called the Peto Paradox. In short, the paradox says that the size and longevity of species should be proportional to the incidence of cancer, but real-world data across species suggests that this association does not hold.

In a new study published in the journal Nature, Carlo Maley, a searcherIn addition to conducting research at ASU’s Biodesign Center for Biocomputing, Security and Society, Maley is also a researcher at the Biodesign Center for Immunotherapy, Vaccines and Virotherapy, as well as the Biodesign Center for Mechanisms of Evolution. He is Associate Professor in the School of Life Sciences at ASU and Director of the Arizona Cancer Evolution Center. with Arizona State University’s Biodesign Center for Biocomputing, Security and Society, with international colleagues, explores recent implications of the Peto Paradox and highlights what science is learning about cancer through the tree of life .

Researchers are analyzing the largest interspecies database of its kind – a pool of adult mammals from zoo records that includes 110,148 individuals spanning 191 species.

The aim is to assess species-specific cancer death rates in a wide range of mammals, to reexamine claims of Peto’s paradox in a rigorously quantitative manner, and to explore relevant cancer suppression mechanisms for combating against disease in humans and animals.

The study provides the most in-depth assessment of the Peto Paradox to date. The results provide conclusive evidence that the risk of cancer mortality is largely independent of both body mass and adult life expectancy across species.

The solution to the paradox lies in the fact that the evolution towards greater size and longevity of species has been accompanied by the co-evolution of powerful mechanisms of resistance to cancer.

Incessant battle

The fight against cancer has recorded some recent victories. Annual statistics for 2020 reveal the largest single-year drop in cancer mortality on record, according to the American Cancer Society. Yet despite significant advances in the diagnosis and treatment of cancer, the disease remains one of the leading killers, with an estimated toll of over 600,000 last year in the United States alone.

The scourge is not limited to humans. Indeed, the new study reports a significant cancer burden in all species, especially in some mammals treated by humans, where the number of cancer deaths in the adult population can reach an astonishing rate of 20. at 40%.

While cancer is a reality across the gamut of multicellular species on Earth, the disease is hardly democratic in the selection of its victims. Some species have significantly higher or lower cancer rates, for reasons researchers are still working to elucidate.

The new study explores some of the surprises, including the unusually high vulnerability to cancer of certain carnivorous mammals. The disparity has been found to be closely associated with diet, with the highest cancer rates seen in mammals that consume other mammals, although other factors play an important role as well.

More cells, more problems?

Multicellular organisms, from the simplest to the very complex, face challenges when their cells divide. Cellular mutations can occur when DNA copying mechanisms fail to faithfully duplicate the 6 billion base pairs of the genetic code. Environmental factors such as radiation can also damage the integrity of DNA, leading to mutations.

Most of these mutations have no noticeable effect on the health of an organism. Some, however, set off a devastating chain reaction, resulting in cancer, an often fatal affliction.

The problem can be exacerbated as organisms grow and acquire more cells in their bodies. Another key factor is the accumulation of mutations over time, with age being a key risk factor for cancer. The trend is easily seen in a variety of species, including dogs and humans.

But while this common sense rule applies within a given species, researchers see something quite different when examining a wide range of diverse species, where large, long-lived species are often seen to thrive with low rates of cancer.

This apparent contradiction was first expressed by epidemiologist Richard Peto. He studied cancer rates in humans and mice, finding the incidence of cancer in the two species roughly equivalent. Considering that humans have around 1,000 times more cells than mice and live 30 times longer, this presents a puzzle. Even more surprising is the observation that large, long-lived wild animals do not appear to show a significantly higher propensity for cancer.

It appears that nature has confronted the problem of cancer in large and long-lived species and has come up with a number of solutions, which differ depending on the species involved. These cancer suppression mechanisms may offer clues to suppress cancer in other animals, including humans.

Explore a paradox

Although the fundamental ideas of the Peto Paradox have long been recognized, scientific confirmation has been difficult. So far, there was insufficient data available in terms of sample size, age distribution, species relatedness, and cause of death to draw firm conclusions to support the Peto paradox.

The current study takes advantage of a large dataset known as the Zoological Information Management System (ZIMS), which compiles detailed information on age, sex, dead / alive status, and post-disease data. mortem for non-domesticated adult mammals. This rich repository of cross-species information was crucial for an in-depth analysis of the Peto Paradox.

A high risk of cancer has been observed in the zoological survey in carnivores. This may be due to the use of progestins and other forms of hormonal contraception, as well as the postponement of pregnancy in zoo animals. Both factors have been linked to the development of cancers in humans, as well as in non-domestic cats.

Still, researchers have determined that contraceptive practices cannot fully explain the increased risk of cancer in carnivores. If they could, a clear sexual bias in the data would be evident, with female carnivores showing higher cancer rates. On the contrary, a key determinant appears to be diet.

Food as fate?

Carnivores generally eat a diet high in fat and low in fiber, which is a known risk factor for cancer. Because carnivores are at the top of the food chain, they can ingest pollutants or other carcinogenic compounds at more concentrated levels than animals that appear lower in the food chain.

Additionally, eating meat can expose carnivores to various pathogens that have been linked to cancer-forming processes. Viruses in particular can present a considerable cancer risk, with 10-20% of all cancers thought to be of viral origin.

Further analysis of data from the zoo showed that among carnivores, those who ate other vertebrates as part of their diet had the highest cancer rates, compared to carnivores who rarely or never ate other mammals. . The data suggests a high cost in terms of cancer risk for a carnivorous diet, especially rich in mammalian prey.

Other factors that could affect cancer rates in these animals include poor microbiome diversity, the degree of exercise in captivity, or other physiological factors. Unlike carnivores, ruminants have the lowest cancer risk among mammals.

Talk to animals

The results of the study confirm the central assumptions of the Peto paradox. The data show no significant association between the risk of cancer mortality and body mass between species, suggesting that natural selection of cancer resistance mechanisms in large animals is what significantly reduces their risk of carcinogenesis.

These various mechanisms have already become the subject of intensive research for their potential to prevent this deadly disease, both in wild animals and in humans, although much remains unknown. The study provides the basis for further exploration in this area and highlights the power of zoological data for future cancer research.

Top photo by Rachel Claire from Pexels.


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