The naked mole rat has a low metabolic rate to keep oxygen demand down, but the key to its cancer resistance appears to lie in its skin.
What would you say to a body that never contracts cancer, shows virtually no signs of aging, outlives its relatives by a factor of 10, and remains virile until the very end? But there is a catch: you would have to look like the naked mole rat, whose appearance immediately invites unkind comparisons.
Researchers have long searched for the secret “X-men” factor that makes the naked mole rat so long-lived. For years they tried and failed to give the animals cancer. Scientists researching cancer treatments can trigger tumours in normal rats with radiation or an injection of carcinogenic chemicals. But mole rats have been zapped with everything researchers can think of and just don’t contract the disease.
Their genome has been scrutinised, revealing several genes related to longevity and cancer resistance. But now researchers have found a clue in a place they didn’t quite expect. The rat’s extremely wrinkled yellow-pink skin may also hold the key to its cancer resistance. It produces a very gluggy form of a substance called hyaluronic acid (HA), a key ingredient of the mortar that holds our cells together.
HA is used in the cosmetic trade as an injectable “filler” to stop wrinkles. The mole rat makes use of it to plump up its skin, making it the rubbery material it needs for the bumps and bruises of a burrowing life. But, as Xiao Tian and colleagues at the University of Rochester in New York report in the July edition of Nature, a fortuitous side effect is that it protects the mole rat from cancer. When they reduced the levels of HA in mole rat cells, they also reduced its cancer resistance.
“Everyone is talking about this finding; it’s pretty convincing,” says Chris Parish, a cancer researcher at the Australian National University in Canberra.
Being the X-man of rodents is just the beginning of the mole rat’s weirdness. A native of East Africa and about the size of a furry house mouse, Heterocephalus glaber lives its entire life in pitch blackness with 70 or so of its hive members. Hive is the operative word. Like insects, their colonies contain a single mating queen, a handful of beaux and a mob of workers. They spend their days burrowing around in tunnels breathing oxygen levels so low any other mammal would pass out.
They are also the only mammal that don’t bother regulating body temperature, probably because their underground climate is pretty stable. They have a low metabolic rate to keep oxygen demands down, and when food supplies run low, they drop their metabolic rate even further. This stop-start lifestyle has been described as “living their life in pulses” and was thought to provide part of the explanation of their extreme life span and cancer resistance. A low metabolic rate, like a flame set to low, produces fewer metabolic by-products such as oxygen free radicals, which are linked to both aging and cancer. But it turns out HA is its biggest secret.
In the University of Rochester study the researchers noticed that when they grew the mole rat’s skin cells in culture dishes, the surrounding fluid grew very gluggy. It turned out the cells were secreting vast amounts of HA, and an extremely large version of it, about five times larger than that produced by mouse or human cells.
That caught the researchers’ attention because others had already reported that larger forms of HA were protective against cancer. In this work, Tian and colleagues showed that the large form of HA stops cells multiplying beyond a certain density. Part of the explanation for mole rats’ tumour resistance may be that the glugginess constrains cells from multiplying. But the bigger HA molecules also bind more strongly to receptors on the cell surface that trigger a particular “off switch” for multiplication. To prove that the HA was responsible for the cancer resistance, they reduced the levels of HA in the skin cells by inhibiting the enzyme that produces it. Sure enough, when these cells were injected into the body of rats they did form a tumour when researchers tried to induce one.
So could the mole rat’s strategy provide a new lead for anti-cancer drugs? Parish certainly thinks so. His promising anti-cancer drug, known as Pi-88, provides a precedent. Now in late phase clinical trials, it raises the levels of heparan sulphate, a molecule that, like HA, fills the spaces between cells. A drug that raises the levels of HA, perhaps by blocking the enzyme that degrades it, might also stop human tumours in their tracks. “It’s certainly a possibility,” says Parish.