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Could this rodent help beat cancer?

Could this rodent help beat cancer?

Naked mole rats are weird.

Resembling pink subterranean buck-toothed sausages, these odd creatures live in underground colonies in East Africa.

Uniquely for mammals, their societies have queens and workers in the same way as ants and termites do.

Even more bizarrely – for a mammal – naked mole rats are virtually cold-blooded, feel no pain on their skin, and can survive in conditions of extreme oxygen deprivation without much fuss.

And it’s this latter trait that led a team of US and Israeli scientists to look for clues to better cancer treatments in mole rats’ biological make-up. Because there appear to be unexpected similarities between the ways that naked mole rats and tumours cope without oxygen.

Take a deep breath

When oxygen levels drop, the cells of our bodies can modify their internal chemistry to protect themselves. But if the oxygen deprivation persists for too long – a situation known as ‘hypoxia’ – cells take drastic action, literally eating their own insides to provide nutrients and prevent DNA damage. This process is called ‘autophagy’. A little of it can go a long way, but too much and cells wither and die.

Scientists are only just starting to understand the molecular switches that govern how our cells eat themselves when oxygen levels drop. This involves turning off certain genes, and turning on others. As with most such systems, this is an extremely complex system that researchers are still getting their heads round.

And it’s a field of research that has particular significance for how we understand cancer.

Cancer and hypoxia

Human tumours grow in a chaotic and haphazard manner, so they’re very often hypoxic – the cells in their interior lack a decent blood supply and consequently they’re severely deprived of oxygen.

But somehow, cancer cells manage to turn off the systems that tell normal cells to eat themselves when the oxygen levels drop too far. This allows them to survive indefinitely in extremely harsh conditions.

This has important implications for how well cancer treatments work – especially radiotherapy. In essence, this is because radiation (and some types of chemotherapy), needs oxygen to be able to damage DNA and thus kill cancer cells. If there’s no oxygen, these treatments aren’t as effective.

Indeed, researchers have found over the years that the more hypoxic a patient’s tumour, the harder it is to treat them with radiotherapy, and the worse their prognosis.

In fact it seems that, in order to survive hypoxia, tumours activate defence mechanisms that make them generally hardier, more resistant to treatment and more aggressive.

Clearly, understanding how normal cells respond to hypoxia, and how tumours subvert this, is extremely important.

Hypoxia research

Several decades of research have identified some of the key molecular players that govern how our cells respond to hypoxia. In the late 90s, a protein called BNIP3 was identified as being able to persuade cells to commit suicide (via a process called apoptosis) – another response to stress -  and in the year 2000 scientists found that this protein was sensitive to oxygen levels.

Further work confirmed that BNIP3 was indeed a central player in hypoxia, controlling both self-eating and cell suicide, in response to low levels of oxygen. But how?

Answers in nature

Researchers are still trying to find out more about the hypoxia response – particularly how it’s controlled, and how cancer cells escape this.

To this end, a team of international scientists decided to look for clues in the natural world – often the source of many advances in the field of cancer (for example, sea squirts, yew trees, broccoli and the Madagascar periwinkle have all been investigated for cancer research… sometimes successfully)

This led to the bright idea of studying how naked mole rats survive the oxygen-deficient conditions deep in their burrows. So the researchers measured the levels of proteins and genes before and after oxygen deprivation, and comparing this to common-or-garden rats who had undergone similar low oxygen conditions.

Publishing their work in the FASEB journal, the researchers found that naked mole rats made far less BNIP3 protein when deprived of oxygen than normal rats did, protecting themselves and allowing them to survive for long periods of time at oxygen levels that kill normal rats.

The researchers think that there might be a fundamental biological switch that governs the hypoxia response – and that this switch might be flipped in cancer cells.

The also discovered some intriguing structural differences in the naked mole rat’s BNIP3 protein itself, although it’s not yet clear whether this is important.

However, this is the first time that ‘turning off’  hypoxia has been seen in nature as a ‘normal’ state of affairs, rather than as a mutation in a tumour.

As the researchers write in the paper,

To date, most autophagy experiments have utilized cultured … cancer cell lines.

Here, we have demonstrated, to the best of our knowledge for the first time, similar responses at the organismal level.

The next step is to work out exactly how naked mole rats keep their BNIP3 levels so low, and then look in cancer cells to find out if there are any similarities.

If there are, then it may be possible to find a way to turn autophagy (and perhaps cell suicide) back on in cancer cells, or re-sensitise cancer cells to radiotherapy.

It may seem perverse to look for answers to such a human condition as cancer in the biology of an obscure desert rodent. But one of the universal truths in biology is that all life on earth shares a common ancestor. We’re all, basically, made of the same stuff.

On the 200th anniversary of Darwin’s birth, it’s somehow fitting that these evolutionary principles are still driving practical research on human disease.

Henry


Reference:

Band, M., Joel, A., Hernandez, A., & Avivi, A. (2009). Hypoxia-induced BNIP3 expression and mitophagy: in vivo comparison of the rat and the hypoxia-tolerant mole rat, Spalax ehrenbergi The FASEB Journal DOI: 10.1096/fj.08-122978

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