Why Elephants Don't Get Cancer, at Least Not Often

Alexander M. Castellino, PhD

October 08, 2015

A study of why elephants — one of the largest species — have the lowest rates of cancer has scientists wondering why humans appear to be so ill-adapted to cancer.

The study was published online October 8 in the Journal of the American Medical Association. It suggests that the acquisition of multiple copies of a cancer suppressor gene, TP53, may explain the low rates of cancer seen in elephants.

"To our knowledge, this study offers the first supporting evidence based on empirical data that larger animals with longer life spans may develop less cancer, especially elephants," the authors write in their discussion.

"Despite their enormous size and cell numbers, elephants appear to be no more prone to cancer than other, much smaller mammalian species, and considerably less so than are humans. The potential mechanism may be related to multiple copies of TP53 acquired through evolution," corresponding author Joshua D. Schiffman, MD, Huntsman Cancer Institute (HCI), at the University of Utah, Salt Lake City, told Medscape Medical News.

The new findings offer an explanation for the Peto paradox, which concerns the fact that cancer risk is not proportional to body size in the animal kingdom.

"Peto's paradox was raised 40 years ago. And these data from the Huntsman Cancer Institute provide one explanation how large animals have adapted an evolutionary mechanism to address cancer," Dr Greaves told Medscape Medical News.

Mel Greaves, PhD, and Luca Ermini, PhD, of the Institute of Cancer Research, London, coauthored an editorial that accompanies the article.

Genesis of the Study

For Dr Schiffman, a practicing pediatric oncologist at Primary Children's Hospital, in Salt Lake City, and an investigator of cancer research at HCI, linking his observations in the clinic to understanding how cancer arises is important.

Several years ago, he learned through a colleague — co–senior author Carlo Maley, PhD, Arizona State University, Tempe — that elephants rarely develop cancer despite the fact that they may have 100 times as many cells as humans. "These animals should be developing and dying from cancer, but they do not," he told Medscape Medical News. He was also told that elephants have evolved to have 40 copies of the TP53 tumor suppressor gene.

As a practicing oncologist, Dr Schiffman was aware that the Li-Fraumeni syndrome (LFS) is linked to germline mutations in TP53 and that individuals with LFS have only one functional copy of TP53 with nearly a 100% risk of developing cancer.

The hypothesis connecting multiple copies of TP53 with cancer prevention was developed, and the current publication is a journey of 3 years of collaborations with Utah's Hogle Zoo and the Ringling Bros and Barnum & Bailey Center for Elephant Conservation, in Polk City, Florida.

The genesis of the collaboration was interesting and merits a brief nod. For Dr Schiffman, it began with a trip to the zoo with his three children, which they took shortly after meeting Dr Maley, and learning that elephants rarely develop cancer. He discovered that their zoo elephants receive regular blood draws. He was able to arrange a collaboration with the zoo (and eventually with the Ringling Bros and Barnum & Bailey Circus) to test any extra blood for clues about how elephants avoid cancer.

"Dr Schiffman and his team could have looked agnostically at the whole genome, which would have made this study technically and logistically challenging," Dr Greaves told Medscape Medical News.

The Study and Its Results

To determine cancer rates, Dr Schiffman and colleagues first analyzed necropsy data for 36 mammalian species from a database of the San Diego Zoo. The data for cancer rates in elephants were from the Elephant Encyclopedia database, which captures global elephant deaths and their causes.

What Dr Schiffman and colleagues first observed was that cancer rates did not correspond to body size and life span, as might be expected. For example, the rate of cancer in the rock hyrax was 1%; in the African wild dog, 8%; and in the lion, 2%.

Remarkably, the cancer rate calculated from 644 annotated elephant deaths was 3.11%; accounting for adequate details of lack of death, a conservative cancer rate was estimated at 4.81%. This is in contrast to humans, for whom estimates of cancer mortality range between 11% and 25%.

Using whole genome sequencing technology on blood samples from the African elephant from the Hogle Zoo, the investigators found that the African elephant has 20 copies of TP53 in its haploid genome (40 copies in the two alleles), which contrasts with one copy in the human haploid genome, thereby validating the notion that the African elephant indeed had 20 copies of TP53 in its haploid genome.

Of these, only one was related to the human TP53; the other 19 copies were retrogenes — genes that arise from reverse transcription of the messenger RNA and get randomly and/or tandemly inserted into the genome.

Dr Schiffman and colleagues next determined potential mechanisms for the low rate of cancer by looking at the African elephant (n = 1) cell response to DNA damage and comparing that with the response in humans (n = 11) and in individuals with Li-Fraumeni syndrome (n = 10).

Lymphocytes and fibroblasts both undergo p53-dependent apoptosis. In separate experiments, Dr Schiffman and colleagues looked at the rates of apoptosis in lymphocytes that were exposed to radiation (0.5 - 20 Gy) and doxorubicin (0.0005 - 30 M), both known to confer DNA damage, using the propidium iodide flow cytometry assay, with experiments run in triplicates.

An elevated rate of apoptosis was seen in white blood cells of elephants compared with healthy human control participants and individuals with LFS. For example, the apoptotic rate after exposure to 2 Gy of radiation was 14.64% in elephants vs 7.17% for healthy individuals vs 2.71% for individuals with LFS (P < .001).

The investigators also noted a corresponding increase in p21, a molecule downstream of p53 and associated with cell-cycle regulation. Compared with cells not treated with radiation, a 20.1- times increase was seen in white blood cells of elephants compared with a 3.5-times increase in healthy human white blood cells.

These results were mirrored in white blood cells from Asian elephants of different ages.

Significance to Elephants

"Compared with human cells, elephant cells demonstrated increased apoptotic response following DNA damage," the authors write in their discussion.

"The increased apoptotic response may help prevent elephants from developing cancer, given that TP53 plays a major role in cancer suppression and response to DNA damage," Dr Schiffman told Medscape Medical News.

With apoptotic rates increasing proportionally with TP53 genes, "the data suggest a lower threshold for DNA damage before triggering p53-dependent apoptosis in elephants than in humans, a possible evolutionary strategy to avoid cancer by efficiently removing mutant cells," Dr Schiffman and colleagues write in their discussion.

"Based on the study results, the TP53 retrogenes may functionally increase elephant cell response to DNA damage by triggering p53-dependent apoptosis rather than increasing DNA repair," the authors further write.

However, Dr Greaves and Dr Ermini offer another view. They suggest that the TP53-dependent protection against cancer is an added bonus. "Accrual of extra functional copies of TP53 could have served some other fitness benefit other than cancer protection," they write.

"The p53 gene functions as a cellular stress sensor, and its evolutionary origin predates multicellularity and cancer. Some less-ancient evolutionary, functional changes in TP53 most likely reflect adaptations to life in hypoxic environments," they add.

They also point to other evolutionary mechanisms that protect larger species. "The bowfin whale is large and can live for more than 200 years. A first draft of its genome was published recently, and the preliminary data hint at unique, variant DNA repair genes," they write.

Beyond possessing variants in p15/16, perhaps subterranean naked mole rats live longer and are more cancer resistant compared with inbred laboratory mice because of high-molecular-mass hyaluronan, which influences cell adhesion, they suggest.

Significance to Humans

The evolutionary angle of this study is a given. "These findings, if replicated, could represent an evolutionary-based approach for understanding mechanisms related to cancer suppression," Dr Schiffman and colleagues write.

Beyond that, what, if any, is the significance of this study to the understanding of human cancers?

For Dr Schiffman, it is a new way of looking at cancer. "Instead of asking who gets cancer and why, our study suggests a novel way of understanding cancer by asking who does not get cancer and why," he told Medscape Medical News.

Dr Greaves indicated some caveats of the study. "It is simplistic to equate size with cancer risk," he told Medscape Medical News. "Compared with humans, elephants are sluggish, have a low metabolic rate and a low turnover number," he said.

"Only certain cells are prone to cancer. Mutations in stem cells and their progeny are particularly susceptible to cancer," Dr Greaves told Medscape Medical News. The editorial noted that elephants have a low cell turnover in epithelia, the main tissue for cancer risk in humans.

"It is not clear what lessons the study of elephants...has for informing cancer risk in humans. Perhaps the main message from this innovative investigation is to bring into focus the question of why humans appear to be so ill-adapted to cancer, given the average size and life span," Dr Greaves and Dr Ermini write.

"The human genome is replete with footprints of positive selection in the not too distant historical past. Humans may have acquired, in one particular respect, an extra cancer suppressor gene variant early on in evolutionary history approximately 1.8 million years ago," they add. They cite the acquisition of black, heavily-pigmented skin as an adaptation among hairless, pale-skinned human ancestors in equatorial Africa.

"But what is it we do that elephants do not do?" Dr Greaves contemplated with Medscape Medical News.

"Evolution is quite good at solving problems. But as a species, we have evolved socially at a rapid pace. Our social habits and lifestyle elevate cancer risk that outpaces evolutionary adaptation," he said.

Dr Greaves circled back to Peto. "As an epidemiologist, Peto calculated that 75% of cancer is preventable. If we didn't do what elephants didn't do, we might also be cancer resistant," he said.

"Most human cancers...are associated with lifestyles that are not found among animals, such as smoking, reproductive, dietary, and sun-soaking habits. These behaviors are relatively recently acquired by humans, over a few hundred years, and the risks they impart far exceed prior and otherwise effective cancer suppressor mechanisms that were inherited from primate ancestors," the editorialists write.

"When is the last time you saw an elephant smoke?" Dr Greaves asked Medscape Medical News.

Nevertheless, Dr Schiffman and his colleagues are excited about further exploring their findings. "The human cells we used to compare to the elephants cells were from nonsmokers, and we believe the difference in apoptotic responses reflect inherent biology of the elephant, which may contribute to their cancer resistance," Dr Schiffman told Medscape Medical News.

Now Dr Schiffman and his research collaborators plan to further explore the role of these extra TP53 genes and their potential to perhaps one day affect human health.

The study received federal funding and additional support from Soccer for Hope, the Ringling Bros and Barnum & Bailey Circus (Feld Entertainment), and the Primary Children's Hospital Pediatric Cancer Research Program. The authors and editorialiasts have reported no relevant financial relationships.

JAMA. Published online October 8, 2015. Full text, Editorial

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