Illuminating Cancer Resistance in Elephants

Elephants are perhaps best known for their remarkably good memory and long life span—60 years on average. They also have an unusually generous share of the tumor suppressor gene TP53 and seldom develop cancer, which may contribute to their longevity (JAMA 2015;314:1850–60).

Joshua Schiffman, MD, a pediatric oncologist at the University of Utah's Huntsman Cancer Institute in Salt Lake City and one of the study's senior authors, first learned 3 years ago that co–senior author Carlo Maley, PhD, an evolutionary biologist at Arizona State University in Tempe, had found at least 20 copies of TP53 in both African and Asian elephants. Whole-genome sequencing revealed that one was an ancestral copy comparable to TP53 in other mammals, including the much smaller hyrax, the elephant's closest living relative. The rest were retrogenes, or modified duplicates, that emerged after the evolutionary split between hyrax and elephant. This fascinated Schiffman, because “it suggested a natural protection, evolved over millions of years, against diseases like cancer.”

Schiffman and Maley analyzed 36 mammalian species, from striped grass mice to elephants, and showed that the probability of carcinogenesis did not increase with body size and life span. Combing through 644 deaths in the Elephant Encyclopedia database, the researchers estimated the elephant cancer mortality rate to be 4.81%. In contrast, human cancer mortality rates range from 11% to 25%.

The team then assessed DNA damage repair in elephant cells, healthy human cells, and cells from patients with Li-Fraumeni syndrome (LFS)—who have a compromised copy of TP53 with one functional allele instead of two, making them highly cancer-prone—by bombarding the cells with ionizing radiation and doxorubicin, which induce DNA double-strand breaks.

“We expected that DNA damage repair in elephant cells would be more efficient than human cells, and quite off the charts compared to LFS cells,” Schiffman says, “so we were disappointed to find that double-strand breaks weren't repaired any faster in elephant versus human cells.” Instead, the researchers found that elephant cells had higher rates of apoptosis: twice that of healthy human cells, and five times that of LFS cells. “Thinking about it, this made sense,” Schiffman says. “Eliminating damaged cells could be an effective way to protect from cancer, instead of taking a chance that the DNA damage will be incompletely repaired and escape into future populations.”

An editorial accompanying this study allowed the plausibility of elephants owing “their relatively cancer-free longevity to the acquisition… of extra copies of TP53” (JAMA 2015;314:1806–7). The authors added, though, that “it is perhaps unlikely that the p53 gene deserves all the credit,” noting that other animals—for instance, bowhead whales and naked mole rats—have evolved different ways to resist cancer. They also pointed out that most human cancers are linked to lifestyles “not found among animals.”

“Our cancer risk is artificially higher because of smoking, drinking, and other bad habits,” Schiffman agrees. “However, there are inherent biological differences between human and elephant cells that can't be explained by lifestyle or environmental factors.”

The researchers aren't directly connecting an elephant's low likelihood of cancer to its additional copies of TP53, Schiffman stresses—“we think there's a relationship here, but we have to further explore this mechanism.” They're now closely analyzing individual TP53 retrogenes, each being distinctly different; and exploring the potential involvement of other molecular pathways in elephants' robust apoptotic response to DNA damage.

“In comparative oncology, we've learned a lot about human cancer from cancer-prone animals,” Schiffman observes. “By shifting the focus to understanding why some animals are naturally cancer-resistant, we could learn still more.”

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.