Dina Navon | November 26, 2017
Figure 1. An elephant in the wild. (Source: Pixabay User – Skeeze)
Charismatic creatures long renowned for their intelligence and memory, elephants are now making quite a splash in the world of cancer genomics. Their genetic information may hold the key to understanding why larger, longer-lived organisms do not get cancer more frequently than smaller, shorter-lived organisms. Cancer occurs when a cell’s DNA becomes so damaged that it can no longer control its own growth and division, and instead divides uncontrollably , passing on its defective genes and growth patterns, producing a mass of unhealthy cells that sap resources away from the rest of the body.
Figure 2. The initial stages of cancer, in which cancerous cells are beginning to divide uncontrollably, overwhelming nearby healthy cells. (Source: Cancer Research UK)
Cancer biologists previously expected to find that large organisms, which tend to have many more cells than small organisms, would also have more cancerous cells. With all else being equal, more cells mean more opportunities for mutation and therefore a higher chance of getting cancer. Similarly, long lived organisms, which undergo many more cell divisions over the course of a single lifetime, might be expected to have more cancer occurrences, as errors in genome replication during cell division can cause cancerous mutations. However, looking at many species across the tree of life, scientists have found no correlation between cancer rate and cell number or average lifespan. This discrepancy, named “Peto’s paradox”, after the statistical epidemiologist who originally formulated it, has puzzled cancer biologists for three decades [1].
Figure 3. An illustration of Peto’s Paradox. The expected cancer rate, based on lifespan and number of cells, is shown by the orange line (solid vs dashed lines represent different types of statistical models for expected cancer rates). The observed cancer rate is shown in blue. Why don’t elephants have higher rates of cancer? (Source: Tollis et al. 2017)
Researchers have taken to studying large, long-lived organisms like elephants in order to resolve Peto’s Paradox. Since these creatures have apparently evolved an enhanced ability to resist or reduce harmful mutations, human cancer treatments would benefit greatly from understanding the mechanisms by which that resistance has evolved. There are many ways that “cancer resistance” may occur; one of these is through the expansion or fine-tuning of genes and proteins that work to suppress cancerous growth. First discovered as a tumor-associated protein in 1979, p53 has more recently become one of the most famous examples of a “tumor suppressor” gene – a gene which inhibits the formation of tumors. It’s even been given the moniker “guardian of the genome” based on its vital importance in removing damaged DNA from your body. Mutations in p53 can have devastating effects on a cell’s ability to recognize and respond appropriately to damaged DNA.
Recently, two research groups have independently determined a rapid and dramatic expansion in the number of p53 genes that are found in the genomes of elephants and their closest relatives [2,3]. Humans, like most mammals, carry a single copy of the p53 gene in their genomes. Elephants, on the other hand, can have up to 20 copies in their DNA. Sulak and colleagues determined that even extinct relatives of elephants, like the woolly mammoth, had additional copies of p53, if not as many as living elephants. Dr. Lynch, the leader of Sulak’s research team, cautions that not all of those copies are actually being expressed by a cell and turned into proteins. So, elephants’ extra resistance to cancer isn’t simply because they have more copies of p53 and therefore express more of the protein. Both research groups found that elephant cells were much more reactive to DNA-damaging radiation than other types of mammalian cells – that is, the cells were more likely to self-destruct through apoptosis when exposed to radiation, thereby eliminating any harmful mutations from the body before they could replicate.
Figure 4. A graph showing the parallel evolution in the number of copies of p53 found in the genome (blue) and the body size (red) in elephants and their closest relatives. (Source: Sulak et al. 2016)
While it’s clear that p53 is playing a role in elephants’ increased resistance to cancer, it’s also clear that we’re still not sure of the precise mechanism of p53’s involvement. Once we understand precisely how p53 works to enhance elephants’ sensitivity to damaged DNA, we can then begin to think about how to incorporate this knowledge into current medical practice.
References:
1) Tollis, M, Buddy, AM, and Maley CC. 2017. Peto’s Paradox: how has evolution solved the problem of cancer prevention? BMC Biology 15: 60. https://doi.org/10.1186/s12915-017-0401-7
2) Sulak, M, Fong, L, Mika, K, Chigurupati, S, Yon, L, Mongan, NP, … Lynch, V. J. 2016. TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants. eLife 5: e11994. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5061548/3) Abegglen LM, Caulin AF, Chan A, Lee K, Robinson R, Campbell MS, Kiso WK, Schmitt DL, Waddell PJ, Bhaskara S, Jensen ST, Maley CC, Schiffman JD. 2015. Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans. JAMA 314(17):1850–1860. doi:10.1001/jama.2015.13134