Another clue to how the naked mole rat stays cancer free

Could this ‘chipolata with teeth’ hold the key to stopping cancer?

Kilometres of winding tunnels under the tropical grasslands of Ethiopia, Kenya and Somalia could harbour vital clues to preventing cancer and living longer.

The architect of these tunnels – a curious creature called the naked mole rat – might not be the prettiest of animals, but it’s evolved several unique qualities that have piqued the interest of scientists from around the world:

• it’s the only known cold-blooded mammal;
• it doesn’t feel pain through its skin;
• it can survive in conditions of extreme oxygen deprivation;
• and, like ants and bees, it lives in ‘eusocial’ colonies – one of only two mammals known to do so.

But this diminutive rodent has an even more impressive biological trick up its (hairless) sleeve – it has an exceptionally long life span. While many of its rodent contemporaries are lucky to live beyond four years, the naked mole rat can live for more than 30 years.

One of the secrets to its longevity is that it doesn’t get cancer.

Scientists are understandably keen to work out why these creatures are so resistant to cancer. And a fascinating study published today has uncovered a potentially crucial mechanism behind the naked mole rat’s cancer-free life.

Hypersensitive anticancer process

The study, published in the journal Nature, was led by scientists from the University of Rochester in New York. The team has been studying the naked mole rat (and its close cousin the blind mole rat) for several years.

In 2009 they discovered that naked mole rats activate a sort of ‘claustrophobia-induced gene’ called p16 that stops their cells from growing if they become too tightly packed.

This process – called contact inhibition – happens in other animals too (including us), and is a key anticancer mechanism that stops our cells growing out of control.

But in naked mole rats, p16 seems to be hypersensitive to contact inhibition, and this gives them an extra layer of protection against developing cancer.

But why are mole rats’ cells so senstitive? The team set about finding out.

The plot thickens

Their new paper reveals the answer, in the form of a sugar secreted by the mole rat’s cells called hyaluronan.

The researchers’ interest in hyaluronan started accidently, when they noticed something odd whenever they grew naked mole rat cells in the lab. After growing for a few days, their lab equipment started getting clogged up with a thick, gooey substance.

They discovered it was hyaluronan – normally sort of a molecular Polyfilla between the cells of our bodies – and wondered if this gluey substance could somehow be involved in the rats’ hypersensitivity to contact inhibition.

To work this out, they grew naked mole rat cells in the presence of the hyaluronan-munching enzyme called hyaluronidase.

Sure enough, the cells grew into large, dense masses, uninhibited by their neighbours. And when they removed the enzyme the cells stopped growing.

This was compelling evidence that hyaluronan was the signal that switched on the p16 gene to cause contact inhibition.

Heavy weight

But a big question was what made rat’s hyaluronan different to our own? And how did this help prevent cancer?

Hyaluronan molecules are made of long strings of sugar molecules, attached end-to-end, like beads on a string – these can be of varying lengths, depending on the species.

When the researchers purified and analysed mole rat hyaluronan, it turned out to be massive – five times larger than human or mouse hyaluronan.

Could this whopper be why the rats are resistant to cancer? It certainly makes sense – previous research has shown that larger hyaluronans dampen down processes like cell division and inflammation, whereas smaller hyaluronans actually encourage them. Both of these processes are hallmarks of cancer.

Major production, minimal destruction

But the researchers also found that naked mole rats not only produce an unusually large hyaluronan, they produce lots of it – vastly more than us surface-dwellers do.

The team showed why – in naked mole rats, the enzyme that produces hyaluronan is highly overactive, whereas the enzymes that break it down are sluggish and ineffective.

The net effect: lots of hyaluronan.

All fascinating stuff, but circumstantial so far – not enough to hail hyaluronan as an anticancer hero. The next question was whether cutting down levels of hyaluronan could affect the mole rat cells’ susceptibility to cancer.

To answer this, they engineered the rats’ cells to be particularly vulnerable to cancer, by simultaneously switching off a key gene called p53 and switching on one called Ras. Cells with hyaluronan continued to resist cancer.

But when they also took hyaluronan out of the picture (either by over-stimulating the enzyme that breaks it down, or cutting off the enzyme that makes it), the cells became susceptible to forming tumours.

So hyaluronan’s hero status looks justified. This research is persuasive evidence that the molecule plays a key role in helping the naked mole rat stay cancer free.

Elastic fantastic

How did this cancer-resistance mechanism come about? The researchers speculate that it’s a happy accident. They think naked mole rats evolved extremely high levels of whopping great hyaluronan molecules to provide the elastic skin needed for life squeezing in and out of underground tunnels.

It would seem that this has a fantastic side-effect – an in-built tumour resistance mechanism.

Of course, while fascinating research, the usual caveats about such early-stage work apply. Hyaluronon’s role in cancer in humans is a bit of a mystery, and there’s a long way to go before we fully understand it.

And it may even be something tumours can, on occasion, subvert to their own advantage. For example, it seems that the high levels produced by pancreatic tumours protect it from chemotherapy.

Much like in the tunnels of the naked mole rat, there will be many twists and turns to navigate before we know for sure if this peculiar molecule, or the rodent that makes such interesting use of it, could help in the fight against cancer.

Reference

Tian X. et al. (2013). High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat, Nature, DOI: 10.1038/nature12234