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Elephants rarely get cancer. This fact has captivated scientists for decades. And, it turns out, elephants are not alone in the animal kingdom in having built-in cancer resistance.
Back in 1977, British epidemiologist Richard Peto noticed something surprising about cancer rates across different species. It occurred to him that large-bodied, long-lived species should get more cancer than small and short-lived ones, simply based on the number of cells in the animal’s body and the odds that random cancer-causing mutations would arise over its lifespan. But that’s not what he observed in the available data—a finding later deemed Peto’s Paradox.
In the past decade, researchers have started to uncover the genetic basis for the unusual cancer resistance of certain animals, including elephants and whales, that defy Peto’s original prediction: They get less cancer than expected based on their large body size or unusually long lifespan. Elephants, for example, have extra copies of a tumor suppressor gene, which makes their cells especially prone to triggering cell death at the first sign that something has gone awry.
Uncovering the naturally evolved cancer resistance mechanisms in different animal lineages has a bigger goal: It could lead to new and better strategies for treating (or preventing) cancer in humans, researchers say. But until recently, there was little information about cancer across the tree of life; might other species hold new secrets to cancer resistance?
Some snake species had unexpectedly high rates of cancer.
“Evolution has had hundreds of millions of years of trial and error, and will beat any scientist today in terms of trying to unlock, understand, and decipher the mechanisms of cancer resistance,” says Joshua Schiffman, a pediatric oncologist and cancer researcher at the University of Utah.
Now, two teams of researchers have assembled the largest-yet datasets of cancer prevalence in a variety of reptiles, amphibians, birds, and mammals. Over many years, the first team of evolutionary biologists, genomicists, and clinicians worked with zoo veterinarians and pathologists to build a dataset representing records of 16,049 animals after their death—from 292 species from dozens of zoos in the United States and London. The second team, which focused on zoos in Europe, assembled a dataset of 9,631 similar reports from 1,030 species.
Because all accredited zoos conduct a necropsy, or a post-mortem examination to determine the cause of death, every time an animal dies at the facility, the researchers could reliably know, of all deaths during the study period, which of those animals had cancer, thus enabling a reliable estimate of cancer prevalence rates. In addition, the zoo animals are not wild, so they are unlikely to die of infectious diseases, starvation, or predators. “So it’s really getting at the basic biology of cancer vulnerability,” explains Amy Boddy, an evolutionary biologist at the University of California, Santa Barbara and co-author of the study of U.S. and London zoo animals, which was published in the journal Cancer Discovery. “What are the cancer rates for different species? What explains the differences?” asks Carlo Maley, an evolutionary genomicist at Arizona State University and co-author of the first study.
The teams of scientists were particularly interested in the extremes—the species that get very little cancer and those that get a lot. In those that have very low rates of cancer, what is the mechanism that has evolved for preventing cancer? And in those that get a lot of cancer, what makes them vulnerable?
First, they wanted to know though: Did Peto’s Paradox hold up? When the Arizona researchers looked at the relationship between body size and cancer incidence, they found that for every tenfold increase in body mass, the risk of cancer increased by 2.1 percent—a finding that contradicts Peto’s Paradox overall.
“Even though we found that body size is a positive predictor of cancer, it’s still somewhat paradoxical, because they’re not getting as much cancer as you would expect,” says Zachary Crompton, the lead author and a postdoctoral fellow at the University of Arizona.
Across all species, the proportion of zoo animals that had cancer at the time of their death was about 5 percent on average. Most of the animals, protected from predation, would die of old age. But what was particularly interesting to the researchers were the outliers: dolphins, the common porpoise, and black-footed penguins had the lowest rates of cancer (all less than 2 percent), while ferrets had extremely high rates (63 percent).
Whereas Peto had his elephants, “Now we’ve looked at many, many more animals and been able to identify more animals that seem to be extraordinarily resistant to cancer,” says Lisa Abegglen, a molecular biologist at the University of Utah and co-author of the study published in Cancer Discovery. “We identified some that I don’t think people necessarily knew about, and that is very exciting, because no one has looked for mechanisms in those animals yet.”
The artiodactyl collared peccary (also known as javelina), the domestic goat, and the rodent Patagonian mara (which looks a little like a rabbit) stood out as having the lowest cancer rates in the European study, which was published as a pre-print study on bioRxiv. As groups, the birds and turtles had the lowest cancer rates (both less than 1 percent). Some snake species had unexpectedly high rates of cancer (for example, the diamondback rattlesnake’s was 29 percent).
But researchers know it is early days in this field. “We’re still at this point where we have very little data compared to the total number of species that are out there in the wild,” cautions Vincent Lynch, an evolutionary biologist at SUNY at Buffalo who co-led the second study. “We’re still in the ground-building phase, which I think in chemistry would be something equivalent to figuring out the periodic table. We need to keep figuring out, is this pattern even real? And if it is, can we order things, the way you would order elements on the periodic table, and say these kinds of elements have these characteristics?”
These foundational observations can point scientists in fruitful research directions, such as which species’ genomes are likely to hold interesting secrets to cancer resistance. In species previously identified as having low cancer rates, evolutionary genomicists have been combing through the animals’ genomes and identifying genes that may contribute to their cancer resistance. But they have only scratched the surface.
For example, elephants appear to have extra copies of a tumor-suppressor gene known as p53 tumor suppressor, which is known to contribute to elephants’ cancer resistance. But elephants likely have other genetic mechanisms at play, too. Lynch and his colleague Jacob Bowman recently identified about 500 genes that are rapidly evolving in elephants and could (in addition to p53) contribute to their unusual cancer resistance; many of those genes play a role in cell death (apoptosis) pathways. Apoptosis is a “clean” form of cell death that organisms use to remove damaged cells, nipping potentially cancerous cells in the bud.
“Nature has discovered lots of ways of preventing cancer.”
Perhaps counterintuitively, Lynch’s team discovered that gene loss can also play an important role in the evolution of useful traits: They discovered a burst of gene losses in the elephants, hyraxes, and sea cows—animals with very low cancer rates. The lost genes are involved in necrosis, an inflammatory form of cell death that is associated with aggressive tumors and metastasis. By losing genes related to necrosis and expanding those related to apoptosis, these lineages are losing the inflammatory form of cell death, associated with aging and metastasis, and relying more heavily on apoptosis, which is non-inflammatory, Lynch suggests.
Ylenia Chiari, an evolutionary biologist at the University of Nottingham who co-led the European study, has expertise in turtles, which are interesting because some lineages, such as the Galapagos giant tortoise, are large and long-lived but have low cancer rates. But searching through the turtle genomes, she and her colleagues did not find any extra copies of p53, suggesting that there are many ways lineages evolved to be big, long-lived, and not get cancer very often. “One solution is not valid for all of them,” Chiari says of the range of animal species. “And that is beautiful.”
There is a veritable Noah’s Ark of animal cell lines—genetically identical cells grown in petri dishes—at the University of Utah, where scientists are looking to test out some of these hypotheses gained from the zoo animal studies. Abegglen and pediatric oncologist Joshua Schiffman maintain more than 2,000 unique cell lines from tissues of more than 150 species of animals, creating a large biobank from which to draw new insights about the ways in which some animals prevent cancer. This collection of cell lines was created from cells collected during the necropsies at the participating zoos.
One of the main ways animals protect themselves from cancer is by detecting DNA damage and quickly triggering cell death to prevent cells with mutated DNA from persisting—and going rogue. Therefore, the ability to detect and respond to DNA damage could be an important aspect of cancer resistance. The researchers hypothesize that the animals with low cancer rates might be very good at nipping mutated cells in the bud, while those with high cancer rates might lack this ability. To test this hypothesis, Abegglen selected 15 different cell lines from different species, some with high cancer rates and some with low cancer rates, and tested their response to DNA damage.
The researchers expected that cancer-resistant species would rapidly trigger apoptosis in response to DNA damage, whereas cancer-prone species would not be so responsive to DNA damage. They studied the cells’ response to ionizing radiation and the chemotherapeutic agent doxorubicin, both of which damage DNA. Unexpectedly, overall, the researchers did not find a relationship between cancer rates and the ability to trigger cell death in response to these challenges. “That suggests there’s not a general mechanism that could explain cancer defense,” Abegglen says.
“There’s no one-size-fits-all for cancer suppression across vertebrates,” Boddy says. “What’s exciting for us is that nature has discovered lots of ways of preventing cancer.”
Many of these cancer resistance mechanisms could lead to new therapies for treating human patients, says Schiffman, who leads a startup called Peel Therapeutics that’s working on using the cancer fighting elephant p53 genes to treat cancer in humans.
These studies of the zoo animals are the foundation for many more surprises to come. “We got lucky by finding elephants and naked mole rats and whales, but that’s because they’re the obvious ones,” Lynch says. “So what are the weird, non-obvious species? They’re the interesting ones to study.” 
Lead image: Volodymyr Burdiak / Shutterstock
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