CORE CONCEPTS
CORE CONCEPTS
Solving Peto’s Paradox to better understand cancer
Viviane Callier, Science Writer
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 rea-
soned 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 muta-
tions 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
Despite their size and lifespan, elephants are able to stave off cancer by having 20 copies of the tumor suppressor gene
TP53 and 11 extra copies of LIF. Image credit: Shutterstock.com/ronnybas frimages.
Published under the PNAS license.
www.pnas.org/cgi/doi/10.1073/pnas.1821517116
seemingly counterintuitive phenomenon was dubbed
Peto’s paradox (1).
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. Ev-
ery 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 prevent-
ing 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
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To ward off cancer, the naked mole rat has evolved very sensitive contact
inhibition—when its cells get too crowded, cell signaling networks tell the cells
to stop dividing. Image credit: Shutterstock.com/belizar.
are actually the same ones that are protecting the
animals (2). “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) (2, 3).
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 de-
veloping cancer approaching 100%.
To uncover the elephants’ secrets to cancer re-
sistance, the researchers scoured the elephant ge-
nome, discovering those extra TP53 copies. Using RT-
PCR, the researchers showed that these extra copies
are transcribed into mRNAs. To understand their im-
pact on cellular function, the researchers subjected
elephant lymphocytes and fibroblasts to DNA dam-
age using two methods: ionizing radiation and doxo-
rubicin. 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 poten-
tially 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
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mutations that result in a truncated p53 protein. So,
based on the gene sequence, the researchers pre-
dicted that the extra TP53 copies might not be func-
tional. 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 In-
ternational Society for Evolutionary Medicine and
Public Health meeting in Utah in August, cancer bi-
ologist 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 ele-
phant 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 Uni-
versity of Utah to explore the possibility of attacking
tumors by deftly delivering this elephant TP53 retro-
gene via nanoparticles—although Schiffman empha-
sizes 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 (4). Overexpression
of LIF6 was sufficient to induce apoptosis in the ab-
sence 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 life-
span 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. Main-
taining 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 carbohy-
drate polymer that is found throughout the extracellular
matrix (5, 6). When researchers degraded hyalur-
onan in the extracellular matrix by overexpressing
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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 hyalur-
onan into human tumors—the cellular signaling net-
works are too different. But human tumors frequently
show an accumulation of hyaluronan, stymieing can-
cer drugs. So one therapeutic approach involves
nanoparticle-based treatments targeting the hyalur-
onan itself, degrading it so that the drugs can reach
their intended targets (7).
Other animals boast different evolutionary advan-
tages—and, hence, different potential cancer-treating
strategies. Weighing more than 60 kg and typically
living for about 10 years, the capybara is a large ro-
dent native to South America. The capybara genome,
recently published on bioRxiv (8), reveals several in-
teresting changes, compared with their smaller rodent
ancestors, that could elucidate capybara cancer re-
sistance: 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 (9). 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 re-
sponse 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 ad-
vanced age (10). 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 in-
credible longevity without extra TP53 genes (11).
“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 evolu-
tionary roots of cancer, some researchers are tackling
a related mystery: Why high cancer rates appear to be
more common in mammals (12). Evolutionary bi-
ologist Amy Boddy at the University of California,
Santa Barbara is exploring the hypothesis that the
discrepancy boils down to how mammals reproduce
(13). 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 tol-
erate the fetus’s genetically different cells. Like an in-
vasive placenta, a metastatic tumor consists of genetically
different tissue that invades the host’s body and sup-
presses the immune system. After mammals evolved this
placenta, perhaps tumors co-opted those genetic mech-
anisms 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 in-
vasive cellular phenotype can get turned back on and
do some damage to the body,” she notes. This phe-
nomenon, 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.”

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