Learning lessons from a rare skin cancer that heals itself

Like the Roman god Janus, the molecule that drives a rare hereditary skin cancer has two 'faces'.

Multiple self-healing squamous epithelioma (MSSE), also known as Ferguson-Smith disease, is a rare inherited cancer that, as its name suggests, can spontaneously heal itself.  Exactly how it does this has baffled scientists for more than 40 years.

But now researchers investigating MSSE have discovered that a ‘two-faced’ molecule lies at the heart of the disease, first kick-starting its development then healing it later on.

As well as solving a long-standing mystery, their findings could be important for many other more common types of cancer too.

MSSE – the cancer that heals itself

MSSE is extremely rare, affecting only a handful of people every year in the UK. It causes flat skin tumours on the hands, arms and face that eventually go away of their own accord, leaving  scars but causing little other lasting damage.

Scientists have known for some time that the condition is caused by an inherited fault in a single gene – most of the patients with the disease can directly trace their ancestry back to one particular family, and the inheritance pattern matches that seen with similar single-gene diseases. But until now, the identity of the genetic culprit has been a mystery.

The scientific sleuths behind the latest discovery are an international team led by Cancer Research UK-funded Dr David Goudie and his colleagues at the University of Dundee, who publish their results in the journal Nature Genetics this week.

Tracking down the culprit

To find the gene responsible for MSSE, the scientists did some classic genetic detective work, trawling through DNA from 60 people with the disease and more than 100 of their relatives who were unaffected by it.

The search revealed that the disease is caused by faults in a gene called TGFBR1 (TGF beta receptor 1).  The gene tells cells to make a ‘receptor’ protein, which sits on the cell surface and receives molecular signals (in the form of a protein called TGF beta) telling a cell what to do – for example, to divide or to stop dividing.

TGFBR1 has been implicated in a number of different types of cancer, and around one in seven people in the general population are thought to carry a version of the gene that may increase their risk of the disease. Cancer drugs that interfere with TGF beta signals are currently being developed.

But unlike many proteins involved in cancer, TGFBR1 is ‘two-faced’. It can either slow the growth of cancer or fuel it, depending on the stage of the tumour.

A two-faced receiver

Thanks to painstaking research by scientists around the world, we now know a fair bit about how TGFBR1 is involved in cancer.

In the early stages of cancer, TGFBR1 sends signals telling a cell to stop dividing, effectively putting the brakes on tumour growth. But after a certain point, TGFBR1 switches to the ‘dark side’, and instead sends signals telling cells to divide faster and accelerating the growth of cancer.

Intriguingly, the reverse seems to happen in MSSE. At first, cells grow rapidly out of control, forming tumours. But then the ‘brakes’ get slammed on, the cancer cells stop growing and the tumours go away.

To find out what was going on in MSSE that makes it behave so differently from more typical cancers, Dr Goudie and his team looked at the specific faults in the TGFBR1 gene from different patients.

They found that these faults either led to the production of a non-functioning version of the receptor protein, or to no receptor being made at all.

A double hit

We all inherit two copies of every gene – one from our mum and one from our dad. In the case of people with MSSE, they’ve inherited one faulty version of the TGFBR1 gene, while the other is fine.  Most of the time this healthy copy is enough to compensate for the faulty one, but trouble starts when the healthy version gets damaged – for example by the natural processes that go on within cells, or ultraviolet radiation from the sun.

The researchers think that cells that end up with a ‘double hit’ – two faulty copies of TGFBR1 –  develop into the skin tumours that characterise MSSE. But they also think that this complete loss of TGFBR1 is responsible for the cancer’s unusual self-healing properties.

This is because TGFBR1 is not the only ‘receiver’ that can intercept signals from TGF beta. As the tumours develop, the scientists suspect that the pattern of TGF beta signals shifts and changes as other receiver proteins come into play.  The complete absence of TGFBR1 in these cancers must somehow be enabling the ‘good’ side of TGF beta signalling to come to the fore, causing the tumours to heal up again.

What does this mean for other types of cancer?

There are hundreds of different types of cancer, from the commonest – such as breast, bowel, lung and prostate cancer – to extremely rare tumours like MSSE.  Although there are important differences between cancers affecting different parts of the body, there are also shared similarities.

Because researchers already know that TGF beta and its receptors are involved in many types of cancer, this new discovery could shed light on a far wider range of tumours. And if scientists can figure out exactly how changes in TGF beta signalling make MSSE cancers vanish, perhaps this knowledge could be harnessed to develop future cancer treatments.

Finally, it’s worth noting that this isn’t the first time that research into a rare hereditary cancer has shed light on more common forms of the disease. It’s often the case that an inherited gene fault turns out to be implicated in ‘sporadic’ cancers – tumours that develop as a result of random DNA damage picked up during a person’s lifetime.

A good example of this is the disease ataxia telangiectasia, caused by inheriting a faulty version of the ATM gene.  Although the disease is extremely rare, researchers now know that the ATM gene is faulty in a number of sporadic cancers, and that people who inherit specific versions of the gene are more likely to develop certain cancers.

So while a story about a rare self-healing cancer may seem like a medical novelty, this new finding could help to reveal more of the molecular secrets that lie at the heart of many more common tumours.

Kat

Reference:

Goudie, D. et al (2011). Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1 Nature Genetics DOI: 10.1038/ng.780