Why Elephants don’t get Cancer

We know that elephants never forget, but researchers know that they rarely get cancer either. Understanding why elephants are so cancer-resistant may inform future cancer therapeutics for humans.

Peto’s Paradox

We understand cancer as a collection of related diseases resulting from uncontrolled cell division. Intuitively, organisms with more cells should have a greater likelihood of developing cancer. However, in 1977, epidemiologist Richard Peto noticed that mice were more susceptible to cancer than humans, despite having fewer cells. The observation, called Peto’s Paradox, states that across species, cancer incidence does not correlate with the number of cells in an organism1. Scientific evidence seems to substantiate Peto’s Paradox: researchers in a 2015 cancer mortality study analyzed 36 species of frozen mammalian samples obtained from the San Diego Zoo2. The specimen spanned the size of a striped grass mouse (51 g) to the size of an elephant (4800 kg). The researchers found no significant relationship between body mass and cancer incidence.

The molecular basis for Peto’s Paradox is poorly described. Some animals, like naked mole rats, have “anti-crowding” genes that prevent cell division when cells come into contact with one another3. These genes prevent uncontrolled cell division that is characteristic of most cancers. In larger animals, like whales, tumors must become very large to become lethal. In that time, tumors develop “hypertumors,” which destroy their host tumor, much like tumors destroy the human body4. Elephants are also cancer resistant and it is a phenomenon that researchers have struggled to explain.

Cancer resistance may be in the genes

Peto’s Paradox holds true when comparing cancer incidence between humans and elephants. Humans have ~37 trillion cells and a 25% lifetime cancer mortality rate. Elephants have 3.7 quadrillion cells, and only a 5% mortality rate. Age isn’t an underlying cause either, since elephants and humans have similar lifespans (72 years vs. 65 years in elephants).

Elephants’ cells contain multiple copies of a tumor-suppressing gene called TP53. This gene codes for a protein called p53, which helps a cell repair damage to its DNA, or self-destruct if the damage is too severe. This eliminates the likelihood of a cell developing into cancer. Most elephant species have at least 20 pairs of this gene. Asian elephants have at least 30, and African elephants have about 40. Humans only have one. Patients with Li-Fraumeni syndrome have an incomplete copy of the p53 genes and a greatly increased chance of developing cancer in their lifetime.

It appears as if the additional copies of TP53 gene may make elephants particularly resistant to cancer. To explore this theory, researchers at the San Diego Zoo exposed cells from an African elephant and a human with radiation, producing cells with carcinogenic DNA damage. They found that elephant cells died almost twice as often as the human cells. In other experiment, elephant TP53 genes were inserted into mouse cells, causing them to self-destruct as if they were elephant cells when exposed to DNA-damaging drugs5. Finally, researchers compared elephant cell death with cells taken from patients with Li-Fraumeni syndrome and found that elephant cells self-destructed nearly twice the rate as healthy human cells, and nearly five times the rate of cells from patients with the syndrome2.

The research does not prove that the p53 protein is solely responsible for cancer resistance in elephants. Subsequent research showed that the wooly mammoth, a distant relative of the elephant, had 14 copies of the gene, but cancer incidence is unknown. Manatees (the elephant’s closest living relatives) have one copy of the gene, but a similarly low cancer incidence6. Future research will have to determine if there are any other aspects, such as a slower metabolism, that contribute to cancer resistance in elephants. So far, this information has not been incorporated into human cancer therapeutics, but the promising results may inform human cancer treatment in the future.

References

  1. Peto, R., Roe, F. J., Lee, P. N., Levy, L., Clack, J. “Cancer and ageing in mice and men”.  J. Cancer,32(4): 411–426 (1975).
  1. Schiffman, J. “Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans”. JAMA, 314(17): 1850–1860 (2015).
  1. Seluanov, A., Hine, C., Azpurua, J., Feigenson, M., Bozzella, M., Mao, Z., Catania, K.C., Gorbunova V. “Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat”.  Natl. Acad. Sci. U S A106(46): 19352–19357 (2009).
  1. Nagy, J. D., Victor, E. M., Cropper, J. H. “Why don’t all whales have cancer? A novel hypothesis resolving Peto’s paradox”. ICB, 47 (2): 317–328 (2007).
  2. García-Cao I., García-Cao M., Martín-Caballero, J., et al. “Super p53” mice exhibit enhanced DNA damage response, are tumor resistant and age normally”. EMBO J., 21(22): 6225-6235 (2002).
  1. Sulak, M., Fong, L., Mika, K., Chigurupati, S., Yon, L., Mongan, N.P., Emes, R.D, Lynch, V.J. “TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants”. eLife(5): e11994 (2016)
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