What Whales and Elephants Can Teach Us About Cancer Prevention

Main Takeaways:

• Genetic mutations that lead to uncontrolled cell proliferation can cause cancerous tumors. Random genetic mutations occur at every cell division. As more cell divisions accumulate, there are increased chances for a cancer-causing mutation. While one would expect that larger organisms would be at an increased risk for cancer because they accumulate greater amounts of cell divisions, this is not the case for elephants and whales.
• Several hypotheses may explain this paradox: shorter telomeres, negative selection against hypertumors, and variation in the TP53 gene. Read below for more detail.

In the United States, the National Cancer Institute estimates that about 1.8 million new cancer diagnoses and approximately 600,000 cancer-related deaths will occur in 2020 [1]. Furthermore, about 39.5% of people can expect to receive a cancer diagnosis at some point in their life [1]. Although cancer has many possible causes, downstream genetic mutations ultimately drive the development of cancer [2].

In multicellular organisms, genetic mutations don’t just affect a single, isolated cell, but can be passed on to many cells in the organism through cell division as the organism grows.  Random genetic mutations occur at every cell division, and some of these can lead to uncontrolled cell proliferation resulting in the growth of tumors that can become cancerous. As an organism grows larger and lives longer, more cell divisions will occur in its body over its lifetime. One might expect that larger organisms would accumulate more mutations due to increased numbers of cell divisions and that there should be more chances for tumor growth. However, mortality due to cancer in large animals with long lifespans is not higher than in humans: this discrepancy is known as Peto’s Paradox [3]. If organisms the size of whales had up to 1,000 times the cancer risk than humans, as we might expect given the increased number of cell divisions and random mutations, it would be very unlikely for them to reproduce before succumbing to cancer.

Several hypotheses have been proposed to account for Peto’s Paradox, using data collected from large animals such as whales and elephants [3,4]. Studying cancer in wild mammals presents unique challenges due the lack of accessibility to populations and inability to control factors such as environmental exposures. However, whales, porpoises, and dolphins are all cetaceans, which is a group of wild animals that has been extensively studied [4]. Except for a few cases linked to environmental pollution, cancer in whales rarely occurs [3,4]. This makes them a great model organism for studying Peto’s Paradox. Since these organisms do not appear to have a high risk of cancer, it is suggested that their cancer prevention mechanisms are likely more effective than those of smaller organisms. Other researchers maintain that the rate of cancer development is the same, but cancer may not be as lethal in larger organisms. Here, I will describe hypotheses explaining Peto’s Paradox involving telomeres, hypertumors, and the tumor suppressor gene p53, in the order of least to most investigated.

Telomeres

Telomeres may play a critical role in cancer suppression in large organisms. Similar to how shoelaces have plastic aglets to prevent fraying, telomeres are repetitive DNA sequences located on both ends of each chromosome to prevent DNA damage [5]. Telomeres protect the important stretches of the genome located in the middle of the chromosomes and have recently become a hot topic in research due to possible implications in aging and cancer [5].

Telomeres deplete with every round of DNA replication. When the telomeres become too short, the cell becomes senescent, entering a dormant state in which it doesn’t divide. Researchers hypothesize that shortened telomeres in large organisms with long lifespans could explain their reduced cancer incidence [3]. Reducing the number of times an individual cell divides would reduce the opportunities for a mutation in an oncogene or tumor suppressor gene to occur. With fewer previous divisions for mutations to accumulate, the cell has a decreased risk of developing cancer. The exploration of telomere modifications as an explanation for Peto’s Paradox has just begun, and further research is needed to investigate the possibility.

Hypertumors

Another new hypothesis proposed to explain Peto’s Paradox is promising, but has only been illustrated in silico, or through a computer simulation. Researchers suggest that in larger animals, malignant tumors have a fitness disadvantage compared to benign tumors [4]. In a population of cancer cells with various phenotypes, natural selection may favor aggressive “hypertumors” that piggyback off the vascular growth of parent tumors. Acting as parasites, these hypertumors deplete the parent tumor’s resources and eventually destroy it. Unlike in small organisms, tumors need to reach a substantial size to have consequences in large organisms. Therefore, hypertumors have plenty of time to develop and damage the original tumor before the original tumor grows to a lethal size. As a result, cancer may still be more common in large organisms, just less lethal [4]. Additional research investigating tumor growth in living whales is needed before any concrete conclusions can be drawn.

TP53

Variation in TP53 has been identified as another possible explanation for Peto’s Paradox [3,6]. As a tumor suppressor gene, TP53 helps control cell growth, and mutations in the TP53 gene have been found in up to 50% of human cancers. The p53 protein expressed by this gene has primary roles in cell cycle arrest, DNA repair, and apoptosis. Mutations in the TP53 can lead to reduced expression of p53 and the uncontrolled cell growth that is a hallmark of cancer [7].

Imagine the cell cycle as the process of loading laundry into your washing machine. You’ve put the clothes and detergent in and started the wash cycle when soapy water suddenly starts seeping out of the crevices. Your instinct in this situation is probably to stop and turn off the washing machine to investigate the problem. Likewise, cell cycle arrest occurs when the cell notices that something is wrong, and all duplication processes stop to identify the problem. If you notice a fraying, broken wire poking out from behind the wall, you will probably choose to call an electrician instead of risking a do-it-yourself fix. In the cell cycle, p53 recognizes DNA damage and activates DNA damage response pathways to initiate DNA repair. Sometimes, your machine might be too broken to fix, and you must resort to removing it from your house and heading out to buy a new one. In a cell, the analogous process is apoptosis, where a severely damaged cell is marked for destruction and effectively killed before it can do further damage or proliferate.

To investigate the relationship of p53 and Peto’s Paradox, genome-wide studies were conducted, synthesizing data from 61 animals with a range of sizes [6]. These animals included large species   such as the Asian elephant and woolly mammoth. Researchers found that as species evolved to be bigger, they acquired more copies of TP53, the gene that encodes the p53 protein. While humans only have one copy of the TP53 gene, the elephant genome contains 20 copies of TP53, resulting in greater production of p53 protein. This increase may be responsible for protecting these large organisms from developing cancer [6,8]. The role of p53 has evolutionary implications because when p53 evolved as a way to regulate the cell cycle, it fortified the system in place to ensure DNA was replicated correctly and cells with mistakes were killed before the issue could spread.

Although many explanations have been proposed to account for Peto’s Paradox, more research is necessary to elucidate the precise molecular basis of the paradox. Mouse models currently dominate studies in cancer research, but they are small organisms with short life spans. Although these characteristics are useful when researchers want to conduct a study over an organism’s lifetime, they also mean that the mouse model is not the ideal model for studying cancer suppression. Expanding the study of cancer to a more diverse variety of organisms would allow for a more complete understanding of the underlying mechanisms.

Understanding Peto’s Paradox is not only important for conservation scientists and wildlife zoologists; it also has implications in human medicine. Peto’s Paradox provides an interesting opportunity for potential research that may provide insight into cancer treatment. Determining the mechanism behind cancer resistance in large animals could reveal powerful techniques to develop novel treatments for human cancers by targeting telomere length, p53 expression, or hypertumors.

References

[1] Cancer Statistics. National Cancer Institute. https://www.cancer.gov/about-cancer/understanding/statistics. Accessed December 20, 2020.

[2] Griffiths AJF, Miller JH, Suzuki DT, et al. An Introduction to Genetic Analysis. 7th edition. New York: W. H. Freeman; 2000. Mutation and cancer. Available from: https://www.ncbi.nlm.nih.gov/books/NBK21809/

[3] Caulin AF, Maley CC. Peto’s Paradox: evolution’s prescription for cancer prevention. Trends in Ecology & Evolution. 2011;26(4):175-182. doi:10.1016/j.tree.2011.01.002

[4] Nagy JD, Victor EM, Cropper JH. Why don’t all whales have cancer? A novel hypothesis resolving Peto’s paradox. Integrative and Comparative Biology. 2007;47(2):317-328. doi:10.1093/icb/icm062

[5] Are Telomeres the Key to Aging and Cancer. Learn.Genetics Genetic Science Learning Center. https://learn.genetics.utah.edu/content/basics/telomeres/. Accessed November 15, 2020.

[6] Sulak M, Fong L, Mika K, et al. TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants. eLife. 2016;5. doi:10.7554/elife.11994

[7] Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010;2(1):a001008. doi:10.1101/cshperspect.a001008

[8] Abegglen LM, Caulin AF, Chan A, et al. Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans. JAMA. 2015;314(17):1850-1860. doi:10.1001/jama.2015.13134