Why don't elephants and whales get cancer?

Author: Denovo

It is well known that cancer is caused by abnormal cell proliferation due to gene mutations. It is a disease unique to multicellular animals. If the probability of gene mutation in each cell of each organism is the same, then the incidence of cancer in elephants and whales, which are larger in size and have more cells, would be much greater than that in humans. However, elephants and whales do not seem to be so prone to cancer. British epidemiologist and statistician Richard Petto first discovered this paradox in 1977 - the incidence of cancer seems to have nothing to do with the number of cells in an organism. This paradox is called the "Petto's paradox."

As organisms grow in size and live longer, they need stronger cancer suppression capabilities. Large organisms such as elephants and whales have stronger resistance to cancer, while medium-sized organisms have not become extinct due to cancer because, despite the lack of relevant cancer-suppressing genes, they are still able to continue their species due to their stronger fertility. Of course, the anti-tumor mechanisms of different species are also different.

Why do whales live so long?

The bowhead whale (Balaena mysticetus) is a species of whale belonging to the family Balaenidae that lives in Arctic and sub-Arctic waters. The longest-lived bowhead whale known to date can live to 211 years old, while the average lifespan of other whales is only about 60 years old. The reason why the bowhead whale can live so long is closely related to its mechanism of preventing cancer, immune aging, cardiovascular and cerebrovascular diseases, metabolic diseases and neurodegenerative diseases. In particular, in terms of cancer, the bowhead whale has an effective anti-tumor mechanism.

A research team from the University of Buffalo in New York has conducted an in-depth study of the factors that affect the lifespan of bowhead whales. About 4 to 5 million years ago, bowhead whales and right whales diverged into two species, and then bowhead whales evolved a unique gene type. The genome encodes a species-specific reverse transcriptase-cyclin-dependent kinase inhibitor gene (CDKN2CRTG), which can be highly expressed in bowhead whale tissues, slowing down cell division, allowing each cell more time to repair any damage it has suffered, and then producing more cells with similar repair genes to reduce the risk of tumors. This genetic trait is likely one of the many factors that contribute to their longevity.

However, although CDKN2CRTG can protect bowhead whales from cancer and make them live longer, it affects the fertility of male bowhead whales. Due to the presence of this gene, their testicles shrink, affecting sperm production. The testicles of bowhead whales weigh only 200 kilograms. Of course, compared to ordinary men, 200 kilograms of testicles may sound scary, but considering that their close relatives, right whales, have testicles that weigh 1,000 kilograms, they are five times heavier than bowhead whales! Faced with the choice of longevity and smaller testicles millions of years ago, they chose the option of living to more than 200 years old.

Why don't elephants get cancer?

Whales have evolved anti-tumor genes, but have elephants evolved anti-tumor genes too? The San Diego Zoo also supports Peto's paradox. In 2015, they conducted an experimental study on 36 mammals and found that there was really no relationship between the size of animals and the incidence of cancer, from the striped grass mouse weighing only 51 grams to the elephant weighing nearly 5 tons, although there was a 100,000-fold difference in weight between the two.

The secret of elephants' longevity lies in the TP53 gene, also known as P53, which is one of the tumor suppressor genes. It can inhibit excessive cell growth and proliferation, thereby curbing tumor formation. If a cell in an organism is damaged but cannot be repaired, a transcription factor protein expressed by TP53 will control the initiation of the cell cycle, causing the cell to die in apoptosis.

Some people must say that humans and some other mammals also have TP53 genes on their chromosomes, and the transcription factor proteins they express can also inhibit the excessive proliferation of human cells, but why is the cancer incidence rate of only elephants lower? This is related to the fact that elephants have multiple copies of the TP53 gene. It turns out that elephants have 20 copies of the TP53 gene in each cell, while humans only have one copy of TP53 (2 alleles). In this case, each cell of an elephant will express more TP53 protein and will show a higher apoptotic response after DNA damage. Therefore, elephants have a stronger ability to fight cancer, with a cancer mortality rate of about 4.81%, while the cancer mortality rate of humans is 11% to 25%.

What other animals have longer lifespans?

Naked mole rats (Heterocephalus glaber) weigh only 35 grams on average, but can live up to 35 years. Scientists have found in long-term studies that their mortality and risk of cancer do not seem to increase with age, and that special mechanisms such as early contact inhibition are partly responsible for their extended lifespan.

Telomere dynamics at growth factor-related genes in the little brown bat (Myotis lucifugus) are associated with repair mechanisms that prevent ageing-associated DNA damage.

References:

Keane M, Semeiks J, Webb AE, et al. Insights into the evolution of longevity from the bowhead whale genome[J]. Cell reports, 2015, 10(1): 112-122.

Vazquez JM, Kraft M, Lynch V J. A CDKN2C retroduplication in Bowhead whales is associated with the evolution of extremely long lifespans and alerted cell cycle dynamics[J]. bioRxiv, 2022.

Padariya M, Jooste ML, Hupp T, et al. The Elephant evolved p53 isoforms that escape mdm2-mediated repression and cancer[J]. Molecular biology and evolution, 2022, 39(7): msac149.

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[J]. elife, 2016, 5: e11994.

Nunney L. The real war on cancer: the evolutionary dynamics of cancer suppression[J]. Evolutionary applications, 2013, 6(1): 11-19.

Abegglen LM, Caulin AF, Chan A, et al. Potential mechanisms for cancer resistance in elephants and comparative cellular response to DNA damage in humans[J]. Jama, 2015, 314(17): 1850-1860.

Tejada-Martinez D, De Magalhães JP, Opazo J C. Positive selection and gene duplications in tumor suppressor genes reveal clues about how cetaceans resist cancer[J]. Proceedings of the Royal Society B, 2021, 288(1945): 20202592.

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