Cancer is far from a uniquely human disorder. The uncontrollable replication of cells, triggered by damaged genetic coding, takes place throughout the animal kingdom, with some animals more prone to developing one of several hundreds of types of cancer than others. Elephants, rather curiously, rarely get it, and it’s largely been an enigma as to why.
In fact, a new Cell Reports study led by geneticists at the University of Chicago immediately points out how strange this is. The more cells an organism has – i.e., the larger it is – the greater their risk of developing cancer, and this applies to plenty of species, including our own. Despite this, elephants and their extinct proboscidean relatives, like the mastodons and mammoths, seem to buck this prediction.
Known as “Peto’s paradox”, named after the British epidemiologist that first described the phenomenon in the 1970s, those Chicagoan researchers have just made a major step toward cracking the case. It appears that they have a unique gene that promotes the release of compounds that trigger apoptosis, or cell death, in potentially cancerous cells.
Remarkably, this isn’t any ordinary gene, but a pseudogene, which is an imperfect replica of a gene that’s fully functional. The paper refers to it as a “zombie gene”, one that has long been inactive in the evolutionary story of proboscideans for tens of millions of years but has since been reawakened.
The team note that LIF6 and its p53 partnership “evolved coincident with the evolution of large body sizes,” which infers that the former allowed the latter to take place.
Anti-cancer genes aren’t present in these majestic beasties alone. We have them: p53, for example, is a known anti-cancer gene.
It clearly doesn’t always succeed in its mission: One recent study suggested that malfunctioning p53 genes is responsible for the proliferation of at least half of all known cancers. As the unexpected results of a recent study using CRISPR gene editing also clearly demonstrated, we aren’t fully cognizant of all the machinations of p53, or other cancer genes, just yet.
Elephants, as it happens, have several copies of the single p53 gene we have, all of which stamp out the cancer before it gets a chance to spread. Is it possible their p53 genes are just more effective than ours, or is there something else happening here?
The team wanted to know if there was an anti-cancer gene that elephant’s living relatives – such as the manatee – didn’t have, and after painstaking genetic comparisons, they found one: LIF6.
All mammals have a LIF gene. There are plenty of LIF genes in elephants and their close relatives, but in elephants, one of them, LIF6, is activated when the proteins produced by their p53 genes sound the DNA damage alarm.
After giving the cells of both elephants and their tinier relatives cancer-preceding DNA damage, the team noted that LIF6’s activation and protein production in the former induced not repair, but solely self-destruction in those tainted cells. The powerhouses of those cells, the mitochondria, appear to become punctured, which triggers apoptosis, although the team aren’t quite sure why just yet.
“The elephant cells just died; they were entirely intolerant of DNA damage in a way their relatives' cells were not,” senior author Vincent Lynch, a geneticist and evolutionary biologist at the University of Chicago, said in a statement.
To confirm their findings, the team blocked LIF6 expression in elephant cells and watched as the cancer began to develop. At the same time, they overexpressed LIF6 in the cells of creatures that don’t possess the pseudogene, like Chinese hamsters, and found that they began to fend off the cancer.
Clearly, there are implications here for treating human cancers, but it’s too early to claim we will one day induce the same anti-cancer effect in humans. Elephants are also not our only hope: Plenty of other animals, including whales and naked mole rats, also seem less prone to getting cancer, all without the help of LIF6.