Why do Elephants rarely get Cancer?

I’ve never given a thought to cancer in elephants until researchers at the University of Chicago last week revealed a partial explanation for why elephants are cancer resistant… only about 5% of them die of cancer compared to humans who have 11-25% cancer mortality across different populations.

Because larger animals have more cells and usually live longer than smaller ones, you might expect there to be more opportunity for them to develop cancer. But there’s no connection between body size, lifespan and cancer risk across animal species. This surprising phenomenon is called Peto’s Paradox after the epidemiologist Richard Peto who in 1975 noticed mice and humans have a fairly similar risk of developing cancer despite their vast differences in size and lifespan.

Through evolution, large animal species appear to have developed ways to decrease their cancer risk. Different animals have evolved along various lineages which means a number of mechanisms are probably involved in cancer resistance. Researchers are keen to understand cancer protection processes in order to provide insights into how cancer develops and potential cancer prevention strategies. Studying elephant genetics is providing some significant clues.

The latest research, published in the journal Cell Reports, examined the leukaemia inhibitory factor (LIF) gene in 53 large and small mammals with long lifespans. Researchers found the sea cow, African elephant and hyrax, which all have the same recent (in evolutionary terms) common ancestor, had numerous versions of the LIF gene (11, 10 and 7 copies respectively) while most other mammals had one copy.

Sea cow, African elephant and hyrax
Sea cows (left) and modern elephants (middle) are the closest living relatives of the hyrax (right).

Further investigation of elephant cells showed only one of the LIF duplicates actually did anything. LIF6 makes a protein that tells cells to self-destruct when their DNA is damaged, a process known as apoptosis. It appears that LIF6 has contributed to cancer resistance in the elephant by encouraging faulty cells to die before things get worse and they become cancerous. Studying the evolutionary lineage and extinct relatives of elephants showed that LIF6 did not have a function at first but then came to life – hence it’s referred to as a zombie gene – approximately 25 – 55 million years ago “before the demands of maintaining a larger body existed”. This means that LIF6 has probably helped elephants to develop as large animals but it’s only one part of why they rarely get cancer.

Elephant cell with damaged DNA
Zombie LIF6 tells elephant cells with damaged DNA to self-destruct before they become cancerous

These findings build on previous research on the TP53 gene, known as the “Guardian of the Genome”, which showed elephants have 20 copies of TP53 compared to humans, who have one copy. Importantly, the present study also demonstrated that TP53 interacts with LIF6 to induce apoptosis.

In case anyone’s wondering… within species, size does predict cancer risk to some extent. Larger dog breeds have higher rates of cancer than smaller breeds, and taller people get cancer more frequently than their shorter counterparts. For cancer, sometimes size does matter!

References

A zombie LIF gene in elephants is upregulated by TP53 to induce apoptosis in response to DNA damage, Cell Reports (2018)

Peto’s Paradox: how has evolution solved the problem of cancer prevention? BMC Biology (2017)

Potential mechanisms for cancer resistance in elephants and comparative cellular response to DNA damage in humans, Journal of the American Medical Association (2015)

Peto’s Paradox: Evolution’s prescription for cancer prevention, Trends in Ecology and Evolution (2011)

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