Solving Peto’s Paradox to better understand cancer
by Viviane Callier
Cancer is as ancient as multicellularity itself. But not all animals get cancer at the same rate. Some, such as elephants and naked mole rats, rarely get it at all, whereas others, such as ferrets and dogs, have cancer at unusually high rates. The question is why.
In 1977, British epidemiologist Richard Peto reasoned that the cells in large-bodied, long-lived animals undergo more cell divisions, and every cell division carries a small but nonnegligible risk of introducing mutations in the daughter cells. Some of those mutations could lead to cancer. So all else being equal, one would expect that large-bodied, long-lived animals would have a greater risk of cancer than small, short-lived ones. But when Peto looked into cancer incidence in some of these animals, that’s not what he found. This seemingly counterintuitive phenomenon was dubbed Peto’s paradox.
To unravel the mystery of Peto’s paradox, researchers are studying the genome sequences of animals across the tree of life, especially those that are particularly large or particularly long-lived. But there’s no one answer. Every species studied so far seems to have solved this paradox in a different way, possibly because of different life histories and evolutionary selective pressures.
Such work could offer leads for treating or preventing human cancers, says Joshua Schiffman, a pediatric oncologist at the Huntsman Cancer Institute at the University of Utah. His research shows that the set of genes and signaling pathways that are deficient or broken in patients with a high genetic risk of cancer are actually the same ones that are protecting the animals. “Now we can say, ‘Nature has really put a spotlight on these pathways in cancer resistance, so these are the proteins and pathways that we want to go after when we start thinking about making new drugs for our patients,’” Schiffman says.
An Elephantine Secret
In 2015, Schiffman’s team and his collaborators, along with another group working independently, led by evolutionary biologist Vincent Lynch at the University of Chicago, began to unravel the elephant’s secret to Peto’s paradox: these giants have 20 copies of the tumor suppressor gene TP53 (or “tumor protein” p53). Once TP53, which is also present in humans and most other animals, detects irreparable DNA damage that could make a cell cancerous, the p53 protein triggers cell death. People born with a mutation in TP53 develop Li-Fraumeni syndrome and have a lifetime risk of developing cancer approaching 100%.
To uncover the elephants’ secrets to cancer resistance, the researchers scoured the elephant genome, discovering those extra TP53 copies. Using RT-PCR, the researchers showed that these extra copies are transcribed into mRNAs. To understand their impact on cellular function, the researchers subjected elephant lymphocytes and fibroblasts to DNA damage using two methods: ionizing radiation and doxorubicin. Compared with the control human cell lines, the elephant lymphocytes and fibroblasts underwent apoptosis at significantly higher rates in response to the treatments, suggesting that those extra TP53 copies in elephants may confer a higher sensitivity to DNA damage — and, hence, the ability to cull potentially cancerous cells earlier.
Some of the elephants’ extra copies of TP53 — called TP53 retrogenes because they were reverse-transcribed and reinserted into the genome over the course of millions of years of evolution — carry mutations that result in a truncated p53 protein. So, based on the gene sequence, the researchers predicted that the extra TP53 copies might not be functional. But the cell-based assays suggest otherwise.
To further decipher the role of each of the TP53 copies, Schiffman’s team isolated one of them and introduced it into a human cancer cell line. At the International Society for Evolutionary Medicine and Public Health meeting in Utah in August, cancer biologist Lisa Abegglen, who works with Schiffman, reported that doing so caused increased cell death in response to DNA damage compared with the same human cancer cell line without the elephant TP53 retrogene. Lynch and his team also showed that elephant cells induce cell death at lower levels of DNA damage than the cells of their closest living relatives, including the African rock hyrax, the East African aardvark, and the southern three-banded armadillo.
Schiffman is teaming up with scientists from the Technion-Israel Institute of Technology and the University of Utah to explore the possibility of attacking tumors by deftly delivering this elephant TP53 retrogene via nanoparticles — although Schiffman emphasizes that it’s very early days. The researchers have created a start-up company called PEEL Therapeutics (peel is the Hebrew word for elephant).
Alternate Routes
This isn’t the elephants’ only secret. A 2018 study from Lynch’s laboratory shows that elephants also have 11 extra copies of a gene called leukemia inhibitory factor (LIF). One of those copies, LIF6, is activated by TP53 in response to DNA damage. Overexpression of LIF6 was sufficient to induce apoptosis in the absence of DNA damage or activation by TP53. When activated, LIF proteins enter the mitochondria, where they trigger leakage of the mitochondrial membrane and, ultimately, cell death. As in the case of extra copies of TP53, this essentially makes the elephant cells more sensitive to DNA damage.
And cell-death triggers may not be the only means of suppressing cancer in these animal outliers. Naked mole rats (Heterocephalus glaber) have some peculiar characteristics outside their cells, in the extracellular matrix, that help them stave off tumorigenesis.
The ground-dwelling, mouse-sized naked mole rat lives up to 30 years — more than seven times the lifespan of a mouse. The animals have an extraordinary hive-like behavior, unlike any other mammal. They also hardly ever get cancer.
Studies show that the cells of the naked mole rats have evolved really sensitive contact inhibition. “The cells don’t like to be crowded,” says Lynch. Maintaining space among cells is a nice way to reduce your cancer risk, he explains. When naked mole rat cells get too crowded, cell signaling networks tell the cells to stop dividing. This hypersensitivity to contact inhibition is due to unusually high-mass hyaluronan, a carbohydrate polymer that is found throughout the extracellular matrix. When researchers degraded hyaluronan in the extracellular matrix by overexpressing an enzyme that chews it up, the naked mole rat cells readily formed tumors.
So might, then, the hyaluronan offer a target for preventing or treating cancer in humans? If so, the remedy won’t simply be injecting high-mass hyaluronan into human tumors — the cellular signaling networks are too different. But human tumors frequently show an accumulation of hyaluronan, stymieing cancer drugs. So one therapeutic approach involves nanoparticle-based treatments targeting the hyaluronan itself, degrading it so that the drugs can reach their intended targets.
Other animals boast different evolutionary advantages — and, hence, different potential cancer-treating strategies. Weighing more than 60 kg and typically living for about 10 years, the capybara is a large rodent native to South America. The capybara genome, recently published on bioRxiv, reveals several interesting changes, compared with their smaller rodent ancestors, that could elucidate capybara cancer resistance: The animals’ insulin signaling pathway allowed them to grow larger than their ancestors. But as with humans, increased stature comes with an increased risk of cancer. To compensate, capybaras appear to have an expanded family of immune-related genes that made their immune system hypervigilant against cancer cells.
Those two changes probably coevolved in response to each other, says Santiago Herrera-Alvarez, an evolutionary biologist and coauthor of the bioRxiv preprint. Increased insulin signaling promotes growth, but that same signaling pathway is often hijacked by cancer cells to trigger their growth and proliferation. A compensatory mechanism had to evolve to reduce the risk of cancer, he explains. “So what we were trying to understand is, how are those mechanisms that are involved in growth regulation and cancer suppression coevolving?” Herrera-Alvarez says.
Additional clues may come from some species of bats, which can live 45 years. Their longevity stems not only from extra copies of TP53 in some cases but also from resilient telomeres that remain long despite advanced age. Short telomeres cause the cells to senesce and die rapidly whereas long telomeres allow the cells (and thus the animals) to grow old — the extra copies of TP53 cull DNA-damaged cells, preventing tumors from forming. Early studies of the bowhead whale, which boasts an incredible lifespan of more than 200 years, suggest that they manage their incredible longevity without extra TP53 genes. “There has to be some kind of way that they’re doing it,” says Lynch. “It just means that it’s not the most obvious way.”
Diverse Strategies, Common themes
To better understand Peto’s Paradox and the evolutionary roots of cancer, some researchers are tackling a related mystery: Why high cancer rates appear to be more common in mammals. Evolutionary biologist Amy Boddy at the University of California, Santa Barbara is exploring the hypothesis that the discrepancy boils down to how mammals reproduce. In mammalian pregnancies, the placenta is fetal tissue that invades the maternal uterus, triggering a proliferation of blood vessels and suppressing the maternal immune system so that the mother can tolerate the fetus’s genetically different cells. Like an invasive placenta, a metastatic tumor consists of genetically different tissue that invades the host’s body and suppresses the immune system. After mammals evolved this placenta, perhaps tumors co-opted those genetic mechanisms to do the same thing.
There are many benefits to having an invasive placenta, including more nutrients for the offspring, Boddy says. “But the tradeoff is that later on, this invasive cellular phenotype can get turned back on and do some damage to the body,” she notes. This phenomenon, known as antagonistic pleiotropy, occurs when a gene regulates more than one function and those functions come in direct conflict.
But thus far, Boddy’s data show no relationship between the degree of placental invasiveness and cancer incidence — only that mammals as a whole tend to have a higher cancer incidence than other groups. Because placental mammals evolved almost 100 million years ago, compensatory mechanisms may have coevolved with invasive placentation, she suggests.
Peto’s paradox has yet to be completely solved, but investigating the phenomenon has certainly become a fertile research area. Investigating the strategies that different animals have evolved, says Schiffman, may eventually offer a variety of therapeutic avenues, each suited to a different subset of cancer patients. “I think the fact that each animal took different routes through nature, through evolution,” he says, “really is very exciting.”
Published under the PNAS license.
Originally published at www.pnas.org on February 5, 2019.
