Study Uses Elephants and Other Mammals to Explore Potential Mechanisms of Cancer Resistance

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 by JAMA (2015; doi:10.1001/jama.2015.13134).

Understanding of the mechanisms that prevent accumulation of genetic damage and subsequent uncontrolled proliferation of somatic cells, which are any cell in the body not involved in reproduction, remains poor. Understanding the cellular mechanism of cancer suppression in animals could benefit humans at high risk of cancer.

Joshua D. Schiffman, MD, 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 developing).

A comprehensive survey of necropsy data 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 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 wrote that greater numbers of cells and cell divisions increase 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 (eg, for rock hyrax, 1%; African wild dog, 8%; lion, 2%). Despite their large body size and long life span, elephants remain cancer resistant, with an estimated cancer mortality of 4.8%, compared with humans, who have 11% to 25% cancer mortality.

While humans have 1 copy (2 alleles) of TP53, which is a crucial tumor suppressor gene that is mutated in most human cancers, African elephants have at least 20 copies, or 40 alleles. Patients with LFS inherit only 1 functioning TP53 allele and may have a lifetime risk of cancer approaching 90% to 100%. TP53 plays a central role in response to DNA damage through apoptosis, which is 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 wrote.

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