Study Explores Potential Mechanisms for Cancer Resistance in Elephants

Multiple copies of a cancer-suppression gene may play a role in why elephants have a lower-than-expected rate of cancer, findings that have the potential to provide a better understanding of the mechanisms related to cancer suppression, including in humans, according to a study published online by JAMA.1
The mechanisms that prevent accumulation of genetic damage and subsequent uncontrolled proliferation of somatic cells (any cell in the body that is not involved in reproduction) remain poorly understood. Understanding the cellular mechanism of cancer suppression in animals could benefit humans at high risk of cancer. Joshua D. Schiffman, M.D., of the University of Utah School of Medicine, Salt Lake City, and colleagues investigated the cancer rate in different mammals, including elephants, identified potential molecular mechanisms of cancer resistance, and compared response to DNA damage in elephants with that in healthy human controls and patients with Li-Fraumeni syndrome (LFS; a genetic syndrome with a high lifetime risk of cancer).
A comprehensive survey of necropsy data (information on disease and cause of death) was performed across 36 mammalian species to validate cancer resistance in large and long-lived organisms, including elephants (n = 644). The African and Asian elephant genomes were analyzed for potential mechanisms of cancer resistance. Peripheral blood lymphocytes (a type of white blood cell that plays a role in immunity and defending the body against disease) from elephants, healthy human controls, and patients with LFS were tested in vitro in the laboratory for DNA damage response. The study included African and Asian elephants (n = 8), patients with LFS (n = 10), and age-matched human controls (n = 11).
The authors write that a greater number of cells and cell divisions increases the chance of accumulating mutations resulting in malignant transformation. If all mammalian cells are equally susceptible to oncogenic mutations, then cancer risk should increase with body size (number of cells) and species life span (number of cell divisions), although it has been observed that cancer incidence across animals does not appear to increase as theoretically expected for larger body size and life span.
For this study, the researchers found that across mammals, cancer mortality did not increase with body size and/or maximum life span (e.g., for rock hyrax, 1 percent; African wild dog, 8 percent; lion, 2 percent). Despite their large body size and long life span, elephants remain cancer resistant, with an estimated cancer mortality of 4.8 percent, compared with humans, who have 11 percent to 25 percent cancer mortality.
While humans have 1 copy (2 alleles [one of a pair of alternative forms of a gene]) of TP53 (a crucial tumor suppressor gene, mutated in the majority of human cancers), African elephants have at least 20 copies (40 alleles). Patients with LFS inherit only 1 functioning TP53 allele and may have a lifetime risk of cancer approaching 90 percent to 100 percent. TP53 plays a central role in response to DNA damage through apoptosis (a form of cell death) and cell cycle arrest. In response to DNA damage, elephant lymphocytes underwent p53-mediated apoptosis at higher rates than human lymphocytes proportional to TP53 status. The multiple copies of TP53 and the enhanced p53-mediated apoptosis observed in elephants may have evolved to offer such cancer protection.
“Compared with other mammalian species, elephants appeared to have a lower-than-expected rate of cancer, potentially related to multiple copies of TP53. Compared with human cells, elephant cells demonstrated increased apoptotic response following DNA damage. These findings, if replicated, could represent an evolutionary-based approach for understanding mechanisms related to cancer suppression,” the authors write.
“It is not clear what lessons the study of elephants by Abegglen and colleagues 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? 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,” writes Mel Greaves, Ph.D., of the Institute of Cancer Research, London, in an accompanying editorial.2
“However, in other respects, as aging occurs, modern humans appear to be exceptionally vulnerable to cancer, especially in more developed societies. The explanation for this dilemma may involve other factors that greatly increase cancer risk. For instance, most human cancers (approximately 75 percent – 90 percent) are associated with lifestyles that are not found among animals, such as smoking, reproductive, dietary, and sun­soaking 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. Contrariwise, humans have inadvertently become maladapted via mismatches between current lifestyles and inherent genetics that was adaptively forged in a very different ancestral environment.”
1. doi:10.1001/jama.2015.13134;
2. doi:10.1001/jama.2015.13153;