Possible mechanism identified to explain cancer rates in elephants

Researchers from the Huntsman Cancer Institute at the University of Utah and Arizona State University believe that they have figured out why elephants have relatively low rates of cancer, an unexpected result given that they contain many more cells than other animals. For instance, despite having 100 times as many cells as humans, they are less likely to develop cancer than humans. Researchers found additional copies of the tumor suppressor gene TP53, which allows for a more robust reaction to damaged cells (1).

Peto’s paradox, named after epidemiologist Richard Peto, states that large animals are at no larger risk of cancer than are small animals (1).  The researchers in this study looked through the Elephant Encyclopedia database to calculate the cancer risk among elephants.  Of 644 elephant deaths, 3.11% were due to cancer, although the researchers made a more conservative estimate of 4.81% due to deaths with unknown causes.  In contrast, humans have a cancer mortality rate between 11 and 25%.  Additionally, humans with Li-Fraumeni syndrome (LFS), in which one copy of the TP53 gene is nonfunctional, have a 90% lifetime risk for cancer (1).

The researchers looked through the genome of elephants to search for a possible mechanism behind these results.  They found that elephants have over 20 copies, or 40 alleles, of the TP53 gene, which encodes a tumor suppressor protein.  In comparison, humans only have one copy of the gene.  Of the 20 copies, 19 were retrogenes. Retrogenes are extra copies of the original TP53 gene that lack introns and were copied into the genome as elephants evolved (1, 2).

The researchers tested whether elephant cells react differently to DNA damage.  P53 is often inactivated in many human cancer cell lines, allowing for apoptosis suppression, increased cell proliferation, genomic instability, and, ultimately, the development of cancer (1).  The researchers exposed elephant and human blood cells to ionizing radiation to induce DNA damage.  Afterwards, the human cells from healthy controls demonstrated an apoptosis rate of 7.17%, cells from humans demonstrated LFS a 2.71% rate, and elephant cells demonstrated a 14.64% rate (1).

These results indicate that elephant cells are sensitive to DNA damage. Damaged cells are quickly destroyed to prevent them from developing into cancerous cells (2).  The researchers also looked to see if the cells’ responses to DNA damage changed with the age of the elephant. They found that the rate of apoptosis among Asian elephants went down with age (52.53% for an 18 year old, 40.03% for a 69 year old) but left this observation for further research (1).

There are some limitations to this study.  The human cancer rates are out of 100,000 people, while such large animal samples are difficult to come by.  Additionally, captive elephants have shorter lifespans than wild elephants, so the databases may not capture some of the elderly elephants that may be at a higher risk of dying from cancer (1).  While other studies suggest different mechanisms for lowered cancer risk in naked mole rats and bowhead whales, this study suggests an evolutionary mechanism which reduces cancer risk among elephants and other large animals (2).

References

1. Joshua D. Schiffman, MD et al. Potential mechanisms for cancer resistance in elephants and comparative cellular response to DNA damage in humans. JAMA, October 2015 DOI: 10.1001/jama.2015.13134
2. University of Utah Health Sciences. (2015, October 8). Why elephants rarely get cancer: Potential mechanism identified that may be key to cancer resistance. ScienceDaily. Retrieved October 17, 2015 from www.sciencedaily.com/releases/2015/10/151008131035.htm